General Information on Vitamin E

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[101] Hasanuzzaman M, Nahar K, Anee TI, Fujita M. Glutathione in plants: biosynthesis and physiological role in environmental stress tolerance. Physiol Mol Biol Plants. 2017;23(2):249-268. doi:10.1007/s12298-017-0422-2.

[102] Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease

and health. Int J Biomed Sci.

2008;4(2):89-96.

[93] Stampfer MJ, Hennekens CH, Manson JE et al. Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 1993; 328:

[94] Rimm EB, Stampfer MJ, Ascherio A et al. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 1993; 328: 1450-1456.

[95] Khan, S. R. 1995. Calcium oxalate crystal interaction with renal tubular epithelium, mechanism of crystal adhesion, and its impact on stone development. Urol. Res. 23: 71-79.

[96] Korkmaz, A. and Kolankaya, D. 2009. The protective effects of ascorbic acid against renal ischemia-reperfusion injury in male rats. Ren. Fail. 31: 36-43.

[97] Moreira, M. A., Nascimento, M. A., Bozzo, T. A., Cintra, A., da Silva, S. M., Dalboni, M. A., Mouro, M. G. and Higa, E. M. 2014. Ascorbic acid reduces gentamicin-induced nephrotoxicity in rats through the control of reactive oxygen species. Clin. Nutr. 33: 296-301.

[98] Pena de la Vega, L., Lieske, J. C., Milliner, D., Gonyea, J. and Kelly, D. G. 2004. Urinary oxalate excretion increases in home parenteral nutrition patients on a higher intravenous ascorbic acid dose. J. Parenter. Enteral.

[99] Suanarunsawat, T. and Chaiyabutr, N. 1996. The effect of intravenous infusion of stevioside on the urinary sodium excretion. J. Anim. Physiol. Anim. Nutr. (Berl.) 76: 141-150.

[100] Tosukhowong, P., Boonla, C., Ratchanon, S., Tanthanuch, M., Poonpirome, K., Supataravanich, P., Dissayabutra, T. and Tungsanga, K. 2007. Crystalline composition and etiologic factors of kidney stone in Thailand: update 2007. Asian Biomed.

Nutr 28: 435-438.

1444-1449.

**146**

1: 87-95.

**149**

and degenerative pathologies [3].

**Chapter 8**

**Abstract**

Mediterranean areas

**1. Introduction**

Vitamin E: Natural Antioxidant in

*Samia Ben Mansour-Gueddes and Dhouha Saidana-Naija*

Oxidation has been related to several diseases in humans. Indeed, to protect the body from high free radical damages, organism requires natural resources of antioxidant compounds, such as phenols, tocopherols (α, β, γ, and σ) which have important roles in the cell antioxidant defense system. In Mediterranean areas, olive oils and pepper fruits are considered among the best foods in a diet, which keeps on attracting the interest of scientists due to the health benefits linked with its consumption. The Olive oil and pepper fruits are among the most consumed nutrients in the Mediterranean diet; their richness in naturally powerful antioxidants, such as alpha-tocopherols, polyphenols, carotenoïds, and capsaicinoïds (specific of capsicum species), and monounsaturated fatty acids in olive and seed pepper oils, constitutes good health protection against oxidative damages and inflammation. Also, these phytochemicals shield and prevent the human body from many diseases

such as cardiovascular, coronary, Alzheimer's diseases, and cancers.

**Keywords:** tocopherols, antioxidants, *Olea europaea*, *Capsicum* sp., fruits, oils,

In recent years, oxidation constitutes a major problem in human health. Oxygen is considered a vital element, but its instability has deleterious effects on the human body. At high concentration, free radicals cannot gradually be destroyed, their accumulation in the organism generate oxidative stress. This process can damage all cell structures as lipids, proteins, and DNA and trigger many human diseases, such as cancer, arteriosclerosis, and rheumatoid arthritis. Moreover, it may play a role in neurodegenerative diseases and aging processes [1]. Hence, to protect human organisms against reactive oxygen species (ROS) a request for external nutritional intake rich in antioxidants can assist in coping with this oxidative stress. Many studies accorded that dietary vitamin antioxidants and polyphenols have been explored extensively as an exogenous mechanism of defense against oxidative stress [1, 2]. The antioxidants exert their activity by scavenging the 'free-oxygen radicals' thereby giving rise to a fairly 'stable radical'. The human body produces an insufficient level of antioxidants which are essential for preventing oxidative stress. To protect against oxidant radicals, organism requires natural resources of antioxidant compounds from nutrients of different origins. These bioactive molecules play an important role in helping endogenous antioxidants for the neutralization of free radicals. Nutrient antioxidant deficiency is one of the causes of numerous chronic

the Mediterranean Diet

#### **Chapter 8**

## Vitamin E: Natural Antioxidant in the Mediterranean Diet

*Samia Ben Mansour-Gueddes and Dhouha Saidana-Naija*

#### **Abstract**

Oxidation has been related to several diseases in humans. Indeed, to protect the body from high free radical damages, organism requires natural resources of antioxidant compounds, such as phenols, tocopherols (α, β, γ, and σ) which have important roles in the cell antioxidant defense system. In Mediterranean areas, olive oils and pepper fruits are considered among the best foods in a diet, which keeps on attracting the interest of scientists due to the health benefits linked with its consumption. The Olive oil and pepper fruits are among the most consumed nutrients in the Mediterranean diet; their richness in naturally powerful antioxidants, such as alpha-tocopherols, polyphenols, carotenoïds, and capsaicinoïds (specific of capsicum species), and monounsaturated fatty acids in olive and seed pepper oils, constitutes good health protection against oxidative damages and inflammation. Also, these phytochemicals shield and prevent the human body from many diseases such as cardiovascular, coronary, Alzheimer's diseases, and cancers.

**Keywords:** tocopherols, antioxidants, *Olea europaea*, *Capsicum* sp., fruits, oils, Mediterranean areas

#### **1. Introduction**

In recent years, oxidation constitutes a major problem in human health. Oxygen is considered a vital element, but its instability has deleterious effects on the human body. At high concentration, free radicals cannot gradually be destroyed, their accumulation in the organism generate oxidative stress. This process can damage all cell structures as lipids, proteins, and DNA and trigger many human diseases, such as cancer, arteriosclerosis, and rheumatoid arthritis. Moreover, it may play a role in neurodegenerative diseases and aging processes [1]. Hence, to protect human organisms against reactive oxygen species (ROS) a request for external nutritional intake rich in antioxidants can assist in coping with this oxidative stress. Many studies accorded that dietary vitamin antioxidants and polyphenols have been explored extensively as an exogenous mechanism of defense against oxidative stress [1, 2].

The antioxidants exert their activity by scavenging the 'free-oxygen radicals' thereby giving rise to a fairly 'stable radical'. The human body produces an insufficient level of antioxidants which are essential for preventing oxidative stress. To protect against oxidant radicals, organism requires natural resources of antioxidant compounds from nutrients of different origins. These bioactive molecules play an important role in helping endogenous antioxidants for the neutralization of free radicals. Nutrient antioxidant deficiency is one of the causes of numerous chronic and degenerative pathologies [3].

It has been demonstrated that many vegetables, fruits, medicinal plants, and other foods contain compounds with bioactivity against oxidative stress. This activity has been attributed to vitamin C, vitamin E, α-tocopherol, β-carotene, and polyphenolic compounds [4, 5]. Therefore, research regarding natural antioxidants from foods and plants, particularly from folk medicinal plants, is receiving increasing attention around the world.

In Mediterranean areas, nutrition is specific to each country. The Mediterranean diet takes into account the various religious and cultural traditions, as well as the various national identities, the current needs of Mediterranean populations, respecting regional dietary variations. The Mediterranean model, qualified as a healthy lifestyle [6]. It is considered as a model of sustainable nutrition [7] due to its richness in vegetables, fruits, in a quantity moderate fish, dairy, and meat products, condiments, and spices [8]. In fact, in Mediterranean countries, especially in North Africa, as Tunisia, the diet is based on olive oils, olive derivatives, cereals, Solanaceae species (pepper, tomatoes, potatoes), green vegetables, legumes, fresh and dried fruits. These sources of aliment are rich in macro and micro-nutrient such as fibers, antioxidants (vitamins, polyphenols, carotenoids), oligo-elements. In general, the Mediterranean diet is low in animal fat and fast sugar, but it is rich in fiber, omega 3, and antioxidants. The abundance of fresh fruits and vegetables and the use of olive oil instead of hard fats are key factors for which the Mediterranean diets are renowned. So many researches showed that Mediterranean eating habits appeared to meet all the criteria for a healthy and prudent diet [6, 9, 10].

In addition to macronutrients, humans need vitamins and minerals which are micronutrients required by the body to carry out a range of normal functions. However, these micronutrients are not produced in our bodies and must be derived from the food we eat. Vitamins, such as Vitamin A, B, C, E… are crucial for normal development. These micronutrients protect the organism against many diseases by their antioxidant property. In this context, this work aims to evaluate the richness in antioxidants, especially vitamin E, of the main Mediterranean nutriment olive oils, and pepper and their role in preventing many diseases.

#### **2. Properties of vitamin E**

#### **2.1 Chemical properties**

Vitamin E is composed of eight naturally isoforms, four tocopherols with the same molecular formula C28H48O2 (α-, β-, γ-, and σ-tocopherols), and four tocotrienols with a molecular formula C26H38O2 (α-, β-, γ-, and σ-tocotrienols) (**Figure 1**). These molecules are synthesized by photosynthetic organisms including plants, algae, and cyanobacteria, from homogentisic acid and phytyl-diphosphate or farnesyl-diphosphate reaction in plastid membranes [11]. All homologs are derivatives of 6-chromanol and differ in the number and position of methyl groups on the ring structure. The four tocopherol homologs have a saturated 16-carbon phytyl side chain. Whereas, the tocotrienols homologs have three double bonds on the side chain. The tocopherols and tocotrienols have the same basic chemical structure; the main difference is in the saturation of the aliphatic side chain attached to the chromanol ring [12, 13] (**Figure 1**). The various isoforms are not interchangeable and only α-tocopherol meets the human vitamin E requirements [14].

The reaction of aromatic chromanol ring with phytyl-diphosphate or farnesyldiphosphate, in plastid membranes, synthesize different isomers of tocopherol or tocotrienol.

Vitamin E is a fat-soluble vitamin that exists in different chemical forms. The most active compound is alpha-tocopherol which existed in natural and synthetic forms.

**151**

**Figure 1.**

**Figure 2.**

*Vitamin E: Natural Antioxidant in the Mediterranean Diet*

The natural vitamin E (RRR-α-tocopherol or D-α-tocopherol) consists of a single stereoisomer. While, synthetic vitamin E is a mixture of eight stereoisomers (RRR, RSR, RSS, RRS, SRR, SRS, SSR, SSS) distributed equally (**Figure 2**). Only one of them (1/8th) has a molecular structure identical to that of the natural vitamin. According to many studies, the natural vitamin E is twice as powerful and fixed twice as good as the synthetic version. This means that natural vitamin E reaches the blood and organs at

The stereoisomer S and R are the spatial arrangements of the alpha-tocopherol; The RRR refers to R at the 2,4 and 8 positions, hence RRR-α-tocopherol which correspond to Natural vitamin E. The synthetic Vitamin E agree to eight stereoisomers

Vitamin E is considered a natural phytochemical that is frequently associated with human health [15]. This vitamin is an example of a phenolic antioxidant; it serves as an antioxidant and protects membrane lipids from oxidative degeneration [16]. Therefore, both lipophilicity and membrane localization of vitamin E explain its antioxidant property. In this context, the incorporation of vitamin E into the cell membrane explained their major biologic role to protect polyunsaturated fatty acids (PUFAs) and other components of cell membranes and low-density lipoprotein (LDL) from oxidation by free radicals. Via their localization, within the phospholipid bilayer of cell membranes; It is particularly effective in preventing lipid peroxidation, a series of chemical reactions involving the oxidative deterioration of PUFAs [14].

least twice as good as synthetic ones [13, 14].

*Natural and synthetic Sterio-isoforms of vitamin E [14].*

**2.2 Biological properties of vitamin E in the human body**

S and/or R at positions 2, 4 and 8.

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

*Chemical structure of different isoforms of vitamin E [13].*

*Vitamin E: Natural Antioxidant in the Mediterranean Diet DOI: http://dx.doi.org/10.5772/intechopen.99705*

**Figure 1.** *Chemical structure of different isoforms of vitamin E [13].*

#### **Figure 2.**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

appeared to meet all the criteria for a healthy and prudent diet [6, 9, 10].

and pepper and their role in preventing many diseases.

**2. Properties of vitamin E**

**2.1 Chemical properties**

In addition to macronutrients, humans need vitamins and minerals which are micronutrients required by the body to carry out a range of normal functions. However, these micronutrients are not produced in our bodies and must be derived from the food we eat. Vitamins, such as Vitamin A, B, C, E… are crucial for normal development. These micronutrients protect the organism against many diseases by their antioxidant property. In this context, this work aims to evaluate the richness in antioxidants, especially vitamin E, of the main Mediterranean nutriment olive oils,

Vitamin E is composed of eight naturally isoforms, four tocopherols with the same molecular formula C28H48O2 (α-, β-, γ-, and σ-tocopherols), and four tocotrienols with a molecular formula C26H38O2 (α-, β-, γ-, and σ-tocotrienols) (**Figure 1**). These molecules are synthesized by photosynthetic organisms including plants, algae, and cyanobacteria, from homogentisic acid and phytyl-diphosphate or farnesyl-diphosphate reaction in plastid membranes [11]. All homologs are derivatives of 6-chromanol and differ in the number and position of methyl groups on the ring structure. The four tocopherol homologs have a saturated 16-carbon phytyl side chain. Whereas, the tocotrienols homologs have three double bonds on the side chain. The tocopherols and tocotrienols have the same basic chemical structure; the main difference is in the saturation of the aliphatic side chain attached to the chromanol ring [12, 13] (**Figure 1**). The various isoforms are not interchangeable and only α-tocopherol meets the human vitamin E requirements [14].

The reaction of aromatic chromanol ring with phytyl-diphosphate or farnesyldiphosphate, in plastid membranes, synthesize different isomers of tocopherol or

Vitamin E is a fat-soluble vitamin that exists in different chemical forms. The most active compound is alpha-tocopherol which existed in natural and synthetic forms.

ing attention around the world.

It has been demonstrated that many vegetables, fruits, medicinal plants, and other foods contain compounds with bioactivity against oxidative stress. This activity has been attributed to vitamin C, vitamin E, α-tocopherol, β-carotene, and polyphenolic compounds [4, 5]. Therefore, research regarding natural antioxidants from foods and plants, particularly from folk medicinal plants, is receiving increas-

In Mediterranean areas, nutrition is specific to each country. The Mediterranean diet takes into account the various religious and cultural traditions, as well as the various national identities, the current needs of Mediterranean populations, respecting regional dietary variations. The Mediterranean model, qualified as a healthy lifestyle [6]. It is considered as a model of sustainable nutrition [7] due to its richness in vegetables, fruits, in a quantity moderate fish, dairy, and meat products, condiments, and spices [8]. In fact, in Mediterranean countries, especially in North Africa, as Tunisia, the diet is based on olive oils, olive derivatives, cereals, Solanaceae species (pepper, tomatoes, potatoes), green vegetables, legumes, fresh and dried fruits. These sources of aliment are rich in macro and micro-nutrient such as fibers, antioxidants (vitamins, polyphenols, carotenoids), oligo-elements. In general, the Mediterranean diet is low in animal fat and fast sugar, but it is rich in fiber, omega 3, and antioxidants. The abundance of fresh fruits and vegetables and the use of olive oil instead of hard fats are key factors for which the Mediterranean diets are renowned. So many researches showed that Mediterranean eating habits

**150**

tocotrienol.

*Natural and synthetic Sterio-isoforms of vitamin E [14].*

The natural vitamin E (RRR-α-tocopherol or D-α-tocopherol) consists of a single stereoisomer. While, synthetic vitamin E is a mixture of eight stereoisomers (RRR, RSR, RSS, RRS, SRR, SRS, SSR, SSS) distributed equally (**Figure 2**). Only one of them (1/8th) has a molecular structure identical to that of the natural vitamin. According to many studies, the natural vitamin E is twice as powerful and fixed twice as good as the synthetic version. This means that natural vitamin E reaches the blood and organs at least twice as good as synthetic ones [13, 14].

The stereoisomer S and R are the spatial arrangements of the alpha-tocopherol; The RRR refers to R at the 2,4 and 8 positions, hence RRR-α-tocopherol which correspond to Natural vitamin E. The synthetic Vitamin E agree to eight stereoisomers S and/or R at positions 2, 4 and 8.

#### **2.2 Biological properties of vitamin E in the human body**

Vitamin E is considered a natural phytochemical that is frequently associated with human health [15]. This vitamin is an example of a phenolic antioxidant; it serves as an antioxidant and protects membrane lipids from oxidative degeneration [16]. Therefore, both lipophilicity and membrane localization of vitamin E explain its antioxidant property. In this context, the incorporation of vitamin E into the cell membrane explained their major biologic role to protect polyunsaturated fatty acids (PUFAs) and other components of cell membranes and low-density lipoprotein (LDL) from oxidation by free radicals. Via their localization, within the phospholipid bilayer of cell membranes; It is particularly effective in preventing lipid peroxidation, a series of chemical reactions involving the oxidative deterioration of PUFAs [14].

Vitamin E under the term α-tocopherol is a powerful biological antioxidant. It is the major lipid-soluble component in the cell antioxidant defense system and is exclusively obtained from the diet. Among the eight isomers, The RRRα-tocopherol is the most isoform of vitamin E that is essential for humans and is preferentially retained within the organism [14, 17, 18]. This is explained in part by the specific selection of RRR-α-tocopherol by the α-tocopherol transfer protein and in part by its low rate of degradation and elimination compared with the other vitamers, especially tocotrienols, which are rapidly metabolized and excreted similarly as other xenobiotics [14]. Also, [19] mentioned that γ-Tocopherol is slightly less efficient than α-tocopherol as a scavenger of oxygen radicals, but it is an efficient scavenger of reactive nitrogen species due to the unsubstituted 5-position on the chromanol ring. This isomer of Tocopherol is present in significant amounts in the human diet especially in several widely consumed vegetable oils [14].

This form is considered the most important fat-soluble antioxidant in humans metabolizing peroxyl radicals [19]. Such molecules readily donate the hydrogen from the hydroxyl (-OH) group on the ring structure to free radicals, which then become unreactive. On donating the hydrogen, the phenolic compound itself becomes a relatively unreactive free radical because the unpaired electron on the oxygen atom is usually delocalized into the aromatic ring structure thereby increasing its stability [14].

The potent lipid-soluble antioxidant property of α-tocopherol is to maintain the integrity of long-chain polyunsaturated fatty acids in the membranes of cells and thus maintain their bioactivity [20]. The α-tocopherol protects the peroxidation of unsaturated fatty acids of the cell membrane. When peroxyl radicals (ROO• ) are formed, these react 1000-times faster with vitamin E (Vit E-OH) than with polyunsaturated fatty acids (PUFA: ROOH) [21]. The hydroxyl (OH) group in the chromanol head of α-tocopherol can donate hydrogen to scavenge lipid peroxyl radicals (ROO• ) generated from the peroxidation of the lipids to form the corresponding lipid hydroperoxide and the tocopheryl radical (Vit E-O• ). The tocopheryl radical (Vit E-O• ) reacts with vitamin C, thereby oxidizing the latter and returning

#### **Figure 3.**

*The antioxidant property of Vitamin E and its regeneration by other antioxidants "Vitamin E recycling". Vitamin E-OH: alpha-tocopherol; Vitamin E-O.: tocopheryl radical; NADP: nicotinamide adenine diphosphate; NADPH: reduced NADP. The peroxidation of unsaturated lipids leads to forming lipid peroxyl radicals (ROO·).* α*-tocopherol easily diffuses into cell membranes, due to its lipophilic nature, and scavenges rapidly, with a hydroxyl group, the lipid peroxyl radicals and protects polyunsaturated fatty acids from lipid peroxidation. The redox reaction between tocopherol and harmful lipid peroxide radicals leads to forming neutral lipid hydroperoxide and an unreactive vitamin E radical (Vitamin E-O.). The presence of other antioxidants, such as vitamin C, is required to regenerate the antioxidant capacity of* α*-tocopherol.*

**153**

**4. Vitamin E in olive trees**

**4.1 Importance of vitamin E in olive oil**

*Vitamin E: Natural Antioxidant in the Mediterranean Diet*

vitamin E to its reduced state. The presence of other antioxidants such as vitamin C is required to regenerate the antioxidant capacity of α-tocopherol (**Figure 3**).

The Mediterranean diet (MedDi) is characterized by a high content of bioactive phytochemicals especially the antioxidants such as polyphenols, carotenoids, vitamins C and E which are key components of many plant foods. These bioactive compounds in (MedDi) have a particular interest in the prevention of many diseases such as cancer, cardiovascular diseases, etc. [22]. Also, the major dietary sources of vitamin E are fruits, vegetables, nuts, and oils. Vitamin E is known to inhibit lipid peroxidation eventually protecting DNA from damage involved in the

Antioxidants from our diet play an important role in helping endogenous antioxidants for neutralizing free radical species. Thus, free radicals are involved in some diseases including tumor inflammation, hemorrhagic shock, atherosclerosis, diabetes, infertility, gastrointestinal ulcerogenesis, asthma, rheumatoid arthritis,

By its natural antioxidant property, vitamin E plays a key role in maintaining health and preventing many chronic and degenerative diseases [26]. In fact, vitamin E could help avoid or delay coronary heart disease, it could also prevent atherosclerosis by inhibits or reduces the oxidation of low-density lipoprotein (LDL) cholesterol which is associated with the development of atherosclerosis [27]. Also, the supplement of this nutrient plays a cardioprotective role and decreases cardiovascular events [28, 29], and avoids the formation of blood clots that could lead to a heart attack or venous thromboembolism [30]. Nutrient antioxidant deficiency is

Among the different forms of vitamin E, alpha-tocopherol constitutes the most biologically active form and is preferentially absorbed and retained in the body. It has anti-inflammatory, antiplatelet, and vasodilator properties with which vitamin E enhances the immune system presents the capacity to promote health, prevents and treats many diseases [29, 31]. Also, due to its natural properties to be fat-soluble and to incorporate into biological membranes, alpha-tocopherol prevents protein oxidation and inhibits lipid peroxidation, thereby maintaining cell membrane integrity and protecting the cell against damage [32]. Alpha-tocopherol also

modulates the expression of various genes, plays a key role in neurological function, inhibits platelet aggregation, and enhances vasodilatation. Many researches showed that the supplementation of vitamin E (200–400 mg/day) may be suitable to moderate some aspects of degenerative diseases such as Parkinson's disease, reduce tissue injury arising from ischaemia and reperfusion during surgery, delay cataract

Olive fruits and olive oils are considered excellent Mediterranean nutriments. Their consumption in the Mediterranean diet (MedDi) constitutes the cause of

cardiovascular disorders, neurodegenerative diseases, etc. [24, 25].

one of the causes of numerous chronic and degenerative pathologies [1].

development, and improve mobility in arthritis sufferers [33].

The interaction of vitamins E and C has led to the idea of "vitamin E recycling", where the antioxidant function of oxidized vitamin E is continuously restored by

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

**3. Role of vitamin E against diseases**

other antioxidants (**Figure 3**).

pathogenesis of cancer [23].

#### *Vitamin E: Natural Antioxidant in the Mediterranean Diet DOI: http://dx.doi.org/10.5772/intechopen.99705*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

human diet especially in several widely consumed vegetable oils [14].

This form is considered the most important fat-soluble antioxidant in humans metabolizing peroxyl radicals [19]. Such molecules readily donate the hydrogen from the hydroxyl (-OH) group on the ring structure to free radicals, which then become unreactive. On donating the hydrogen, the phenolic compound itself becomes a relatively unreactive free radical because the unpaired electron on the oxygen atom is usually delocalized into the aromatic ring structure thereby increasing its stability [14]. The potent lipid-soluble antioxidant property of α-tocopherol is to maintain the integrity of long-chain polyunsaturated fatty acids in the membranes of cells and thus maintain their bioactivity [20]. The α-tocopherol protects the peroxidation of unsaturated fatty acids of the cell membrane. When peroxyl radicals (ROO•

are formed, these react 1000-times faster with vitamin E (Vit E-OH) than with polyunsaturated fatty acids (PUFA: ROOH) [21]. The hydroxyl (OH) group in the chromanol head of α-tocopherol can donate hydrogen to scavenge lipid peroxyl

*The antioxidant property of Vitamin E and its regeneration by other antioxidants "Vitamin E recycling". Vitamin E-OH: alpha-tocopherol; Vitamin E-O.: tocopheryl radical; NADP: nicotinamide adenine diphosphate; NADPH: reduced NADP. The peroxidation of unsaturated lipids leads to forming lipid peroxyl radicals (ROO·).* α*-tocopherol easily diffuses into cell membranes, due to its lipophilic nature, and scavenges rapidly, with a hydroxyl group, the lipid peroxyl radicals and protects polyunsaturated fatty acids from lipid peroxidation. The redox reaction between tocopherol and harmful lipid peroxide radicals leads to forming neutral lipid hydroperoxide and an unreactive vitamin E radical (Vitamin E-O.). The presence of other antioxidants, such as vitamin C, is required to regenerate the antioxidant capacity of* α*-tocopherol.*

sponding lipid hydroperoxide and the tocopheryl radical (Vit E-O•

) generated from the peroxidation of the lipids to form the corre-

) reacts with vitamin C, thereby oxidizing the latter and returning

)

). The tocopheryl

Vitamin E under the term α-tocopherol is a powerful biological antioxidant. It is the major lipid-soluble component in the cell antioxidant defense system and is exclusively obtained from the diet. Among the eight isomers, The RRRα-tocopherol is the most isoform of vitamin E that is essential for humans and is preferentially retained within the organism [14, 17, 18]. This is explained in part by the specific selection of RRR-α-tocopherol by the α-tocopherol transfer protein and in part by its low rate of degradation and elimination compared with the other vitamers, especially tocotrienols, which are rapidly metabolized and excreted similarly as other xenobiotics [14]. Also, [19] mentioned that γ-Tocopherol is slightly less efficient than α-tocopherol as a scavenger of oxygen radicals, but it is an efficient scavenger of reactive nitrogen species due to the unsubstituted 5-position on the chromanol ring. This isomer of Tocopherol is present in significant amounts in the

**152**

**Figure 3.**

radicals (ROO•

radical (Vit E-O•

vitamin E to its reduced state. The presence of other antioxidants such as vitamin C is required to regenerate the antioxidant capacity of α-tocopherol (**Figure 3**).

The interaction of vitamins E and C has led to the idea of "vitamin E recycling", where the antioxidant function of oxidized vitamin E is continuously restored by other antioxidants (**Figure 3**).

#### **3. Role of vitamin E against diseases**

The Mediterranean diet (MedDi) is characterized by a high content of bioactive phytochemicals especially the antioxidants such as polyphenols, carotenoids, vitamins C and E which are key components of many plant foods. These bioactive compounds in (MedDi) have a particular interest in the prevention of many diseases such as cancer, cardiovascular diseases, etc. [22]. Also, the major dietary sources of vitamin E are fruits, vegetables, nuts, and oils. Vitamin E is known to inhibit lipid peroxidation eventually protecting DNA from damage involved in the pathogenesis of cancer [23].

Antioxidants from our diet play an important role in helping endogenous antioxidants for neutralizing free radical species. Thus, free radicals are involved in some diseases including tumor inflammation, hemorrhagic shock, atherosclerosis, diabetes, infertility, gastrointestinal ulcerogenesis, asthma, rheumatoid arthritis, cardiovascular disorders, neurodegenerative diseases, etc. [24, 25].

By its natural antioxidant property, vitamin E plays a key role in maintaining health and preventing many chronic and degenerative diseases [26]. In fact, vitamin E could help avoid or delay coronary heart disease, it could also prevent atherosclerosis by inhibits or reduces the oxidation of low-density lipoprotein (LDL) cholesterol which is associated with the development of atherosclerosis [27]. Also, the supplement of this nutrient plays a cardioprotective role and decreases cardiovascular events [28, 29], and avoids the formation of blood clots that could lead to a heart attack or venous thromboembolism [30]. Nutrient antioxidant deficiency is one of the causes of numerous chronic and degenerative pathologies [1].

Among the different forms of vitamin E, alpha-tocopherol constitutes the most biologically active form and is preferentially absorbed and retained in the body. It has anti-inflammatory, antiplatelet, and vasodilator properties with which vitamin E enhances the immune system presents the capacity to promote health, prevents and treats many diseases [29, 31]. Also, due to its natural properties to be fat-soluble and to incorporate into biological membranes, alpha-tocopherol prevents protein oxidation and inhibits lipid peroxidation, thereby maintaining cell membrane integrity and protecting the cell against damage [32]. Alpha-tocopherol also modulates the expression of various genes, plays a key role in neurological function, inhibits platelet aggregation, and enhances vasodilatation. Many researches showed that the supplementation of vitamin E (200–400 mg/day) may be suitable to moderate some aspects of degenerative diseases such as Parkinson's disease, reduce tissue injury arising from ischaemia and reperfusion during surgery, delay cataract development, and improve mobility in arthritis sufferers [33].

#### **4. Vitamin E in olive trees**

#### **4.1 Importance of vitamin E in olive oil**

Olive fruits and olive oils are considered excellent Mediterranean nutriments. Their consumption in the Mediterranean diet (MedDi) constitutes the cause of

many health-promoting effects. The olive oils are characterized by their richness in oleic acid, vitamin E, polyphenols, and some other minor components some of which are known to be anti-inflammatory, make it the model functional food [34]. Olive oils, virgin, and extra virgin are a symbol of the Mediterranean Diet. Alpha-tocopherol was the most abundant tool and detected in all the studied olive oil samples [35]. Many research proved that the levels of tocopherols in olive oils are high variety and geographic areas-dependent.

The alpha-tocopherol is more active than others β > γ > δ against free radicals. It protects free fatty acids from peroxidation. The tocopherol radicals are resonance stabilized within the chromanol ring and do not propagate the chain reactions or are rapidly recycled back to the corresponding tocopherol, allowing each tocopherol to participate in many peroxidation chain-breaking events. One tocopherol molecule can protect about 103–108 polyunsaturated fatty acids at low peroxide values [36]. According to [37], α-tocopherol represented almost 95% of total tocopherols and their contribution is greater than the rest of tocopherols; their content in virgin olive oils varies from 97 to 785 mg/kg. In fact, α-tocopherol concentration ranges from 170 to 485 mg/kg in Spanish varieties [37]; 160 to 428 mg/kg in the


#### **Table 1.**

*Total tocopherols and* α*-tocopherol composition in olive oils of different varieties from Mediterranean countries.*

**155**

brain function.

*Vitamin E: Natural Antioxidant in the Mediterranean Diet*

Argentinean oils [38]; 98–370 mg/kg in the Greek oils [37], 97–403 mg/kg in oils from Turkey [39], 120–478 mg/kg in oils from Tunisia [40], and 138–298 mg/kg in

Olive oil is the main source of fats in Mediterranean diets. This type of diet has often been associated with improving the resistance to certain diseases, including cardiovascular disease and illness degenerative. Many scientific studies have focused on the nutritional aspect of olive oil to understand the mechanisms of this phenomenon. The first explanation is its specific fatty acid composition. The proportion of saturated fatty acids is very low (14%); while the majority of monounsaturated fatty acids (MUFA) is oleic acid. Essential polyunsaturated fatty acids (PUFA) are also present in interesting proportions in the oil. MUFA supplement allows to increase the resistance of LDL to oxidation [50], thus reducing one of the

The Extra Virgin Olive Oil (EVOO) is one of the most important health-protective foods in the Mediterranean diet [51]. The high-quality EVOO is considered as a true pharm-food. This oil contains a relevant concentration of efficient chemopreventive molecules, including Tyrosol, hydroxytyrosol, tocopherols (vitamin E), β-carotene, and phenolic compounds [51, 52]. [53] showed the ability of VOO phenolic compounds to shield lipoproteins from oxidation and to reduce systolic blood pressure in hypertensive individuals. These antioxidants compounds are thought to be beneficial to protect against neurodegenerative diseases and cardiovascular diseases [54]. Also, [27] suggested that the antioxidants compounds in EVOO can prevent and treat cancers, diabetes, neurodegenerative diseases, inflammation, and aging. They have an antimicrobial property and also play an important role in strengthening the immune system and protecting certain tissues and organs from damage. The presence of phenolic compounds and tocopherols in Extra Virgin Olive Oil (EVOO) protects the unsaturated fatty acids from peroxidation, thus contributes to the stability of cellular brain structures [51, 55] and it has beneficial effects on learning and memory [55]. The phenolic compound and tocopherols have often been linked to reducing the risk of cognitive decline and are essential for proper

Pepper is a very important vegetable worldwide and has economic and agrofood importance in many countries. In the Mediterranean, pepper is cultivated in the warm regions particularly in Tunisia where its cultivation has spread due to its strong uses in Tunisian cuisine. Pepper fruits were appreciated and consumed mostly as fresh food or dried as a spice. The nutritional contribution due to the presence of beneficial healthy-related compounds, Pepper is among the most fascinating and consumed spice foods, largely appreciated for its flavor, high nutritional

Pepper is a usual part of a traditional Mediterranean diet. Hot peppers are intensively used as food additives for their pungency, aroma, and color [57]. Their consumption is nutritionally valuable and also contains ingredients that promote health. The presence of phytochemicals and antioxidants in fruits increases its importance in controlling diseases to protect the human body from the harmful

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

**4.2 Effect of olive oils in many diseases**

factors that can cause coronary heart disease [9].

**5. Impact of pepper composition in human health**

**5.1 Importance of pepper in Mediterranean diet**

and health contribution to human diets [56].

the Portuguese oils [41] (**Table 1**).

Argentinean oils [38]; 98–370 mg/kg in the Greek oils [37], 97–403 mg/kg in oils from Turkey [39], 120–478 mg/kg in oils from Tunisia [40], and 138–298 mg/kg in the Portuguese oils [41] (**Table 1**).

#### **4.2 Effect of olive oils in many diseases**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

high variety and geographic areas-dependent.

**Countries Varieties Total Tocopherol** 

Morisca Picual Manzanilla-cacerena Corniche Verdial de Badajoz Carrasquena

Kolovi

Domat Gemlik

Frantoio

Chemlali Chemlali Sfax Chemlali Zarzis Oueslati Sayali Zalmati Zarrazi Meski Neb Jmal El Hor Jdallou

Arima Chemlal Zenata Chemlal (SBA) Sigoise Sebra

Spain Arbequina

Greece Koroneiki

Turkey Ayvalik

Italy Leccino

Tunisia Chetoui

Algeria Chemlal Bordj

many health-promoting effects. The olive oils are characterized by their richness in oleic acid, vitamin E, polyphenols, and some other minor components some of which are known to be anti-inflammatory, make it the model functional food [34]. Olive oils, virgin, and extra virgin are a symbol of the Mediterranean Diet. Alpha-tocopherol was the most abundant tool and detected in all the studied olive oil samples [35]. Many research proved that the levels of tocopherols in olive oils are

The alpha-tocopherol is more active than others β > γ > δ against free radicals. It protects free fatty acids from peroxidation. The tocopherol radicals are resonance stabilized within the chromanol ring and do not propagate the chain reactions or are rapidly recycled back to the corresponding tocopherol, allowing each tocopherol to participate in many peroxidation chain-breaking events. One tocopherol molecule can protect about 103–108 polyunsaturated fatty acids at low peroxide values [36]. According to [37], α-tocopherol represented almost 95% of total tocopherols and their contribution is greater than the rest of tocopherols; their content in virgin olive oils varies from 97 to 785 mg/kg. In fact, α-tocopherol concentration ranges from 170 to 485 mg/kg in Spanish varieties [37]; 160 to 428 mg/kg in the

**(mg/kg)**

121 ± 22 123 ± 28

183.27 ± 15.5 160.78 ± 18.7 114.87 ± 9.73

455.25 ± 4.4 270.7 ± 1.7

405.65 ± 4.17 199 467 400 204 282 351 208 - - - -

Maroc Picholine marocaine 311 ± 11.4 272.0 ± 8.0 [48]

*Total tocopherols and* α*-tocopherol composition in olive oils of different varieties from Mediterranean countries.*

202.35 188.55 240.1 215.6

α**- tocopherol (mg/kg)**

117 ± 21 110 ± 15

180.43 ± 15.17 106.8 ± 18.27 112.59 ± 9.49

> 405.6 ± 4.6 230.0 ± 1.6

385.35 ± 2.48 184 425 374 185 264 336 193 74.6 ± 4.6 232.29 ± 2.00 335.27 ± 1.16 364.23 ± 3.30

> 193.55 179.72 228.11 202.9

**References**

[37]

[42]

[35]

[43]

[44] [44] [45] [45] [45] [45] [45] [46] [47] [47] [47] [47]

[49]

**154**

**Table 1.**

Olive oil is the main source of fats in Mediterranean diets. This type of diet has often been associated with improving the resistance to certain diseases, including cardiovascular disease and illness degenerative. Many scientific studies have focused on the nutritional aspect of olive oil to understand the mechanisms of this phenomenon. The first explanation is its specific fatty acid composition. The proportion of saturated fatty acids is very low (14%); while the majority of monounsaturated fatty acids (MUFA) is oleic acid. Essential polyunsaturated fatty acids (PUFA) are also present in interesting proportions in the oil. MUFA supplement allows to increase the resistance of LDL to oxidation [50], thus reducing one of the factors that can cause coronary heart disease [9].

The Extra Virgin Olive Oil (EVOO) is one of the most important health-protective foods in the Mediterranean diet [51]. The high-quality EVOO is considered as a true pharm-food. This oil contains a relevant concentration of efficient chemopreventive molecules, including Tyrosol, hydroxytyrosol, tocopherols (vitamin E), β-carotene, and phenolic compounds [51, 52]. [53] showed the ability of VOO phenolic compounds to shield lipoproteins from oxidation and to reduce systolic blood pressure in hypertensive individuals. These antioxidants compounds are thought to be beneficial to protect against neurodegenerative diseases and cardiovascular diseases [54]. Also, [27] suggested that the antioxidants compounds in EVOO can prevent and treat cancers, diabetes, neurodegenerative diseases, inflammation, and aging. They have an antimicrobial property and also play an important role in strengthening the immune system and protecting certain tissues and organs from damage. The presence of phenolic compounds and tocopherols in Extra Virgin Olive Oil (EVOO) protects the unsaturated fatty acids from peroxidation, thus contributes to the stability of cellular brain structures [51, 55] and it has beneficial effects on learning and memory [55]. The phenolic compound and tocopherols have often been linked to reducing the risk of cognitive decline and are essential for proper brain function.

### **5. Impact of pepper composition in human health**

#### **5.1 Importance of pepper in Mediterranean diet**

Pepper is a very important vegetable worldwide and has economic and agrofood importance in many countries. In the Mediterranean, pepper is cultivated in the warm regions particularly in Tunisia where its cultivation has spread due to its strong uses in Tunisian cuisine. Pepper fruits were appreciated and consumed mostly as fresh food or dried as a spice. The nutritional contribution due to the presence of beneficial healthy-related compounds, Pepper is among the most fascinating and consumed spice foods, largely appreciated for its flavor, high nutritional and health contribution to human diets [56].

Pepper is a usual part of a traditional Mediterranean diet. Hot peppers are intensively used as food additives for their pungency, aroma, and color [57]. Their consumption is nutritionally valuable and also contains ingredients that promote health. The presence of phytochemicals and antioxidants in fruits increases its importance in controlling diseases to protect the human body from the harmful

effects of free radicals [58]. Therefore, integrating a pepper-rich diet in our daily meals can prevent cardiovascular diseases, could help in fighting blood cholesterol levels, and can have, by capsaicin, an antidiabetic activity [58, 59].

#### **5.2 Antioxidants in pepper fruits**

Pepper fruits are recognized for their richness in phytochemicals and antioxidants with high nutritional value. The fruits are considered an excellent source of macro and micro-nutrients such as provitamin A, vitamins C and E, carotenoïds, capsaicinoïds, minerals, polyphenols, phytosterol, metabolites with famous antioxidant properties that positively affect human health [60–62]. These phytochemicals are influenced by a variety of peppers and environmental factors. The analysis of 23 accessions of peppers, collected from multiple Peruvian locations, showed that the tocopherols varied strongly from 0.23 to 29.1 mg/100 g, the total polyphenols between 0.97 and 2.77 g gallic acid equivalents (GAE)/100 g and the concentrations of capsaicinoïds range from 1.0 mg/100 g to 1515.5 mg/100 g (GAE)/100 g [63]. So, the consumption of pepper fruits and integrating a pepper-rich diet into our daily meals can be helpful in the continuing quest to combating micronutrient deficiency [64].

Peppers are considered one of the best sources of natural vitamin E and C. Many studies showed that the level of α-tocopherol in dry red pepper powder is similar to those in spinach and asparagus and four-fold higher than that in dry tomatoes [64]. The recommended daily intake of vitamin E was 15 mg/day of α-tocopherol for both women and men. Pepper fruits can supply above 100% α-tocopherol per 100 g serving depending on the cultivar [61]. Also, the red pepper seed oils showed a high antioxidant capacity due to their richness in bioactive phytochemical compounds such as polyphenols, carotenoids, tocopherols,

#### **Figure 4.**

*Graphical abstract of the main antioxidants commonly present in olive oils and pepper fruits, characteristic of the Mediterranean diet, such as phenolic compounds, carotenoids, tocopherols and oleic acid. The capsaicin is specific to capsicum species, which have anti-inflammatory properties.*

**157**

*Vitamin E: Natural Antioxidant in the Mediterranean Diet*

phytosterols, and unsaturated fatty acids especially the linoleic acids which are higher than those of oleaginous seed oils [62]. It has been reported that polyphenols and tocopherol were the predominant antioxidant compounds in red pepper seed oils; Which γ-tocopherol was the main tocopherol at 278.65 mg/100 g seed oil, followed by alpha-tocopherol and delta-tocopherol [62]. The ratio between α- and γ-tocopherol depends on the number of seeds in the chili powder. As a matter of fact, the amount of α-tocopherol in the pericarp is higher, however, γ-tocopherol is

Hot pepper fruits are rich in capsaicinoïds, unique compounds of Capsicum species, which are responsible for the pungency. Capsaicin is widely influenced by the variety and maturity stages and by environmental factors [65]. These alcaloïds have antioxidant, anti-inflammatory, analgesic properties and are characterized by great medical and pharmacological values [58, 66]. These molecules also have a therapeutic effect as a neuropharmacological tool. Their effect in the treatment of painful conditions has been evaluated, such as rheumatic diseases [66]. Many recent studies have shown the effective treatment of capsaicinoïds for several sensory nerve fiber disorders, including arthritis and human immunodeficiency virus [67]. In this context, the proposed diet rich in pepper fruits can be considered an excellent strategy to improve the nutritional value of the population due to its high antioxidants and

The pepper fruits and olive oil constitute an excellent nutrient, for their richness

in antioxidants (**Figure 4**). Since these Mediterranean foods have an important effect on human health, it is encouraged, around the world, to consume them.

The Mediterranean diet is rich in nutrients that have antioxidant properties. Particularly olive oil and pepper fruits constitute the most abundant and consumed vegetable nutriments in MedDi areas. Their richness in polyphenols, tocopherols, carotenoids, chlorophylls, unsaturated fatty acids, olive oils constitute a health treasure. These minor components are known to prevent and protect the human organism against many diseases such as cardiovascular, coronary diseases; also, some of these antioxidants have anti-inflammatory action, make it the model functional food. Pepper fruits are mostly consumed by the Mediterranean population as traditional spices and food products. Fruits are characterized by a means of antioxidants such as vitamin A alpha and gamma tocopherols, vitamin C, capsaicinoïds, polyphenols. The consumption of both nutriments rich in natural powerful antioxidants, such as tocopherols and polyphenols, constitutes a good strategy for reducing oxidative damage and to improve the health state of the human body,

This work was supported by the Laboratory of Amelioration of the Olive Tree Productivity and Product Quality. The author is grateful to all the members of the

The authors declare no conflict of interest for this chapter.

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

more dominating in the seeds [63].

phenolic compound content.

and preventing it from diseases.

**Acknowledgements**

olive Tree institute.

**Conflict of interest**

**6. Conclusion**

*Vitamin E: Natural Antioxidant in the Mediterranean Diet DOI: http://dx.doi.org/10.5772/intechopen.99705*

phytosterols, and unsaturated fatty acids especially the linoleic acids which are higher than those of oleaginous seed oils [62]. It has been reported that polyphenols and tocopherol were the predominant antioxidant compounds in red pepper seed oils; Which γ-tocopherol was the main tocopherol at 278.65 mg/100 g seed oil, followed by alpha-tocopherol and delta-tocopherol [62]. The ratio between α- and γ-tocopherol depends on the number of seeds in the chili powder. As a matter of fact, the amount of α-tocopherol in the pericarp is higher, however, γ-tocopherol is more dominating in the seeds [63].

Hot pepper fruits are rich in capsaicinoïds, unique compounds of Capsicum species, which are responsible for the pungency. Capsaicin is widely influenced by the variety and maturity stages and by environmental factors [65]. These alcaloïds have antioxidant, anti-inflammatory, analgesic properties and are characterized by great medical and pharmacological values [58, 66]. These molecules also have a therapeutic effect as a neuropharmacological tool. Their effect in the treatment of painful conditions has been evaluated, such as rheumatic diseases [66]. Many recent studies have shown the effective treatment of capsaicinoïds for several sensory nerve fiber disorders, including arthritis and human immunodeficiency virus [67]. In this context, the proposed diet rich in pepper fruits can be considered an excellent strategy to improve the nutritional value of the population due to its high antioxidants and phenolic compound content.

The pepper fruits and olive oil constitute an excellent nutrient, for their richness in antioxidants (**Figure 4**). Since these Mediterranean foods have an important effect on human health, it is encouraged, around the world, to consume them.

#### **6. Conclusion**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

levels, and can have, by capsaicin, an antidiabetic activity [58, 59].

**5.2 Antioxidants in pepper fruits**

deficiency [64].

effects of free radicals [58]. Therefore, integrating a pepper-rich diet in our daily meals can prevent cardiovascular diseases, could help in fighting blood cholesterol

Pepper fruits are recognized for their richness in phytochemicals and antioxidants with high nutritional value. The fruits are considered an excellent source of macro and micro-nutrients such as provitamin A, vitamins C and E, carotenoïds, capsaicinoïds, minerals, polyphenols, phytosterol, metabolites with famous antioxidant properties that positively affect human health [60–62]. These phytochemicals are influenced by a variety of peppers and environmental factors. The analysis of 23 accessions of peppers, collected from multiple Peruvian locations, showed that the tocopherols varied strongly from 0.23 to 29.1 mg/100 g, the total polyphenols between 0.97 and 2.77 g gallic acid equivalents (GAE)/100 g and the concentrations of capsaicinoïds range from 1.0 mg/100 g to 1515.5 mg/100 g (GAE)/100 g [63]. So, the consumption of pepper fruits and integrating a pepper-rich diet into our daily meals can be helpful in the continuing quest to combating micronutrient

Peppers are considered one of the best sources of natural vitamin E and C. Many studies showed that the level of α-tocopherol in dry red pepper powder is similar to those in spinach and asparagus and four-fold higher than that in dry tomatoes [64]. The recommended daily intake of vitamin E was 15 mg/day of α-tocopherol for both women and men. Pepper fruits can supply above 100% α-tocopherol per 100 g serving depending on the cultivar [61]. Also, the red pepper seed oils showed a high antioxidant capacity due to their richness in bioactive phytochemical compounds such as polyphenols, carotenoids, tocopherols,

*Graphical abstract of the main antioxidants commonly present in olive oils and pepper fruits, characteristic of the Mediterranean diet, such as phenolic compounds, carotenoids, tocopherols and oleic acid. The capsaicin is* 

*specific to capsicum species, which have anti-inflammatory properties.*

**156**

**Figure 4.**

The Mediterranean diet is rich in nutrients that have antioxidant properties. Particularly olive oil and pepper fruits constitute the most abundant and consumed vegetable nutriments in MedDi areas. Their richness in polyphenols, tocopherols, carotenoids, chlorophylls, unsaturated fatty acids, olive oils constitute a health treasure. These minor components are known to prevent and protect the human organism against many diseases such as cardiovascular, coronary diseases; also, some of these antioxidants have anti-inflammatory action, make it the model functional food. Pepper fruits are mostly consumed by the Mediterranean population as traditional spices and food products. Fruits are characterized by a means of antioxidants such as vitamin A alpha and gamma tocopherols, vitamin C, capsaicinoïds, polyphenols. The consumption of both nutriments rich in natural powerful antioxidants, such as tocopherols and polyphenols, constitutes a good strategy for reducing oxidative damage and to improve the health state of the human body, and preventing it from diseases.

#### **Acknowledgements**

This work was supported by the Laboratory of Amelioration of the Olive Tree Productivity and Product Quality. The author is grateful to all the members of the olive Tree institute.

#### **Conflict of interest**

The authors declare no conflict of interest for this chapter.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

#### **Author details**

Samia Ben Mansour-Gueddes\* and Dhouha Saidana-Naija Olive Tree Institute, Sousse, Tunisia

\*Address all correspondence to: bm\_samiatn@yahoo.fr

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**159**

*Vitamin E: Natural Antioxidant in the Mediterranean Diet*

[9] Gerber M and Hoffman R. The Mediterranean Diet: Health, sciences and society. British Journal of Nutrition.

2015; 113, S4-S10. DOI:10.1017/

Mediterranean food products: research and development. In: MediTERRA-CIHEAM, Presses de Sciences Po editors, 2012 p. 265-282. DOI:10.3917/

[11] Fritsche S, Wang X and Jung C. Recent Advances in our Understanding of Tocopherol Biosynthesis in Plants: An Overview of Key Genes, Functions, and Breeding of Vitamin E Improved Crops, Antioxidants. 2017; 6(99):1-18. DOI:

[10] Boskou D. Chapter 13:

S0007114514003912

scpo.chea.2012.02

10.3390/antiox6040099

[12] Rizvi S, Raza ST, Ahmed F, Ahmad A, Abbas S, and Mahdi F. The Role of Vitamin E in Human Health and Some Diseases. Sultan Qaboos Univ Med J. 2014; 14(2): e157–e165.

Safety, Pharmacokinetic, and

Pancreatic Ductal Neoplasia. E BioMedicine. 2015; 2(12):1987-1995. DOI: 10.1016/j.ebiom.2015.11.025.

174-186. DOI: 10.1017/ S0954422407202938

[13] Springett GM, Husain K, Neuger A, Centeno B, Chen DT, Hutchinson TZ, Lush RM, Sebti S, Malafa MP. A Phase I

Pharmacodynamic Presurgical Trial of Vitamin E δ-tocotrienol in Patients with

[14] Brigelius-Flohe R. Bioactivity of vitamin E. Nutr. Res. Rev. 2006, 19:

[15] Epriliati I and Ginjom I. Chapter 9: Bioavailability of Phytochemicals. In: Venketeshwer R Editor, Phytochemicals - A Global Perspective of Their Role in Nutrition and Health. InTechOpen; 2012 401-428. DOI:10.5772/26702

[16] Dhalaria R, Verma R, Kumar D, Puri S, Tapwal A, Kumar V, Nipovimova

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

Antioxidants in Disease and Health. Int

[1] Pham-Huy LA, He H and Pham-Huy C. Free Radicals,

J Biomed Sci. 2008; 4(2): 89-96.

[2] Billingsley H and Carbone S. The antioxidant potential of the Mediterranean diet in patients at high cardiovascular risk: an in-depth review

of the Predimed. Nutrition and Diabetes. 2018; 8:13. DOI 10.1038/

[3] Lobo VA, Patil A, Phata K, and Chandra N. Free radicals, antioxidants and functional foods: Impact on

DOI:10.4103/0973-7847.70902

[4] Krishnaiah D, Sarbatly R and Nithyanandam R. A review of the antioxidant potential of medicinal plant

species. Food and Bioproducts Processing. 2011; 89: 217-233.

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**Author details**

Olive Tree Institute, Sousse, Tunisia

provided the original work is properly cited.

Samia Ben Mansour-Gueddes\* and Dhouha Saidana-Naija

\*Address all correspondence to: bm\_samiatn@yahoo.fr

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[4] Krishnaiah D, Sarbatly R and Nithyanandam R. A review of the antioxidant potential of medicinal plant species. Food and Bioproducts Processing. 2011; 89: 217-233.

[5] Moure A, Jose M, Daniel C, Franco J, Domı́nguez, M, Sineiro J, Domı́nguez H, Núñez JM, Parajó JC. Natural antioxidants from residual sources. Food Chemistry. 2001; 72 (2):145-171. DOI: 10.1016/ S0308-8146(00)00223-5

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[10] Boskou D. Chapter 13: Mediterranean food products: research and development. In: MediTERRA-CIHEAM, Presses de Sciences Po editors, 2012 p. 265-282. DOI:10.3917/ scpo.chea.2012.02

[11] Fritsche S, Wang X and Jung C. Recent Advances in our Understanding of Tocopherol Biosynthesis in Plants: An Overview of Key Genes, Functions, and Breeding of Vitamin E Improved Crops, Antioxidants. 2017; 6(99):1-18. DOI: 10.3390/antiox6040099

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American Oil Chemist's Society. 2007; 84(12): 1125-1136. DOI:10.1007/

[39] Arslan D, Karabekir Y, Schreiner M. Variations of phenolic compounds, fatty

characteristics of Sarıulak olive oil as induced by growing area. Food Res Int. 2013; 54 (2):1897-1906. DOI:10.1016/j.

[40] Baccouri O, Guerfel M, Baccouri B, Cerretani L, Bendini A, Lercker G, Zarrouk M, Daoud B, Miled D. Chemical composition and oxidative stability of Tunisian Monovarietal virgin olive oils with regard to fruit ripening. Food Chemistry. 2008; 109(4):743-754. DOI:10.1016/j. foodchem.2008.01.034

[41] Matos LC, Cunha SC, Amaral JS, Pereira JA, Andrade PB, Seabra RM,

characterization of three varietal olive oils (Cvs. Cobrançosa, Madural and Verdeal Transmontana) extracted from olives with different maturation indices. Food Chem. 2007;102(1):406-414. DOI:10.1016/j.foodchem.2005.12.031

[42] Mikrou T, Pantelidou E, Parasyri N, Papaioannou A, Kapsokefalou M, Gardeli C and Mallouchos A. Varietal and Geographical Discrimination of Greek Monovarietal Extra Virgin Olive Oils Based on Squalene, Tocopherol, and Fatty Acid Composition. Molecules, 2020; 25 (3818): 1-14. DOI:10.3390/

[43] Najafi V, Barzegar M, Sahari M. Physicochemical Properties and Oxidative Stability of Some Virgin and Processed Olive Oils. Journal of Agricultural Science and Technology.

[44] Ben Temime S, Baccouri B, Taamalli W, Abaza L, Daoud D, Zarrouk M. Location effects on

oxidative stability of chétoui virgin olive

Oliveira BP. Chemometric

molecules25173818

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s11746-007-1140-7.

foodres.2013.06.016.

acids and some qualitative

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[35] Dagdelen A, Tumen G, Ozcan MM and Dundar E. Determination of tocopherol contents of some olive varieties harvested at different ripening periods. Natural Product Research. 2012; 26 (15), 1454-1457. DOI:10.1080/1

[36] Špika MJ, Kraljić K and Škevin D. Tocopherols: Chemical Structure, Bioactivity, and Variability in Croatian Virgin Olive Oils. In: Dimitrios Boskou and Maria Lisa Clodoveo editors, IntechOpen, DOI: 10.5772/64658.

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[34] Perona JS and Botham KM. Olive Oil as a Functional Food: Nutritional and Health Benefits. In: Aparicio, Harwood J. Handbook of Olive Oil, Springer, 2nd editions. 2013; pp. 677-714|.

[35] Dagdelen A, Tumen G, Ozcan MM and Dundar E. Determination of tocopherol contents of some olive varieties harvested at different ripening periods. Natural Product Research. 2012; 26 (15), 1454-1457. DOI:10.1080/1 4786419.2011.605364.

[36] Špika MJ, Kraljić K and Škevin D. Tocopherols: Chemical Structure, Bioactivity, and Variability in Croatian Virgin Olive Oils. In: Dimitrios Boskou and Maria Lisa Clodoveo editors, IntechOpen, DOI: 10.5772/64658.

[37] Franco MN, Galeano-Díaz T, Sánchez J, De Miguel C and Martín-Vertedor D. Total Phenolic Compounds and Tocopherols Profiles of Seven Olive Oil Varieties Grown in the South-West of Spain. Journal of Oleo Sciences. 2014; 63, (2) 000-000. DOI: 10.5650/jos.ess13098

[38] Ceci LN and Carelli AA. Characterization of Monovarietal Argentinian Olive Oils from New Productive Zones. Journal of the

American Oil Chemist's Society. 2007; 84(12): 1125-1136. DOI:10.1007/ s11746-007-1140-7.

[39] Arslan D, Karabekir Y, Schreiner M. Variations of phenolic compounds, fatty acids and some qualitative characteristics of Sarıulak olive oil as induced by growing area. Food Res Int. 2013; 54 (2):1897-1906. DOI:10.1016/j. foodres.2013.06.016.

[40] Baccouri O, Guerfel M, Baccouri B, Cerretani L, Bendini A, Lercker G, Zarrouk M, Daoud B, Miled D. Chemical composition and oxidative stability of Tunisian Monovarietal virgin olive oils with regard to fruit ripening. Food Chemistry. 2008; 109(4):743-754. DOI:10.1016/j. foodchem.2008.01.034

[41] Matos LC, Cunha SC, Amaral JS, Pereira JA, Andrade PB, Seabra RM, Oliveira BP. Chemometric characterization of three varietal olive oils (Cvs. Cobrançosa, Madural and Verdeal Transmontana) extracted from olives with different maturation indices. Food Chem. 2007;102(1):406-414. DOI:10.1016/j.foodchem.2005.12.031

[42] Mikrou T, Pantelidou E, Parasyri N, Papaioannou A, Kapsokefalou M, Gardeli C and Mallouchos A. Varietal and Geographical Discrimination of Greek Monovarietal Extra Virgin Olive Oils Based on Squalene, Tocopherol, and Fatty Acid Composition. Molecules, 2020; 25 (3818): 1-14. DOI:10.3390/ molecules25173818

[43] Najafi V, Barzegar M, Sahari M. Physicochemical Properties and Oxidative Stability of Some Virgin and Processed Olive Oils. Journal of Agricultural Science and Technology. 2015; 17(4): 847-858

[44] Ben Temime S, Baccouri B, Taamalli W, Abaza L, Daoud D, Zarrouk M. Location effects on oxidative stability of chétoui virgin olive oil. Journal of Food Biochemistry. 2006; 30 (6): 659-670. DOI: 10.1111/j.1745-4514.2006.00086.x

[45] Laroussi-Mezghani S, Le Dréau Y, Molinet J, Hammami M, Grati-Kamoun N, Artaud J. Biodiversity of Tunisian virgin olive oils: varietal origin classification according to their minor compounds. Eur. Food Res. Technol. 2016; 242:1087-1099.

[46] Sakouhi F, Harrabi S, Absalon C, Sbei K, Boukhchina S, Kallel H. α-Tocopherol and fatty acids contents of some Tunisian table olives (*Olea europaea* L.): Changes in their composition during ripening and processing. Food Chemistry. 2008;108: 833-839.

[47] Krichene D, Taamalli W, Daoud D, Salvador MD, Fregapane G, Zarrouk M. Phenolic compounds, tocopherols and other minor components in virgin olive oils of some Tunisian varieties. Journal of Food Biochemistry. 2007; 31 (2): 179-194. DOI:10.111 1/j.1745-4514.2007.00107.

[48] Haddam M, Chimi H and Amine A. Formulation d'une huile d'olive de bonne qualité. Oilseeds and fats, Crops and Lipids. 2014; 21(5): 2-10.

[49] Bendi Djelloul MC, Amrani SM, Rovellini P, Chenoune R. Phenolic compounds and fatty acids content of some West Algerian olive oils. Communicata Scientiae. 2020, 1: 1-11. DOI : 10.14295/cs.v11i0.3247

[50] Bonanome A, Pagnan A, Biffanti S. Effect of Dietary Monounsaturated and Polyunsaturated Fatty Acids on the Susceptibility of Plasma Low-Density Lipoproteins to Oxidative Modification. Arterioscler Thromb. 1992; 12: 529-533. DOI :10.1161/01.ATV.12.4.529

[51] Lanza B and Ninfali P. Antioxidants in Extra Virgin Olive Oil and Table Olives: Connections between

Agriculture and Processing for Health Choices. Antioxidants. 2020; 9 (41): 1-17. DOI:10.3390/antiox9010041

[52] Rocha J, Borges N and Pinho O. Table olives and health. Journal of Nutritional Science. 2020; 9(e57): 1-16. doi:10.1017/jns.2020.50

[53] Castellano JM and Perona JS. Effects of virgin olive oil phenolic compounds on health: solid evidence or just another fiasco? Grasas y Aceites. 2021; 72(2): e404. DOI: 10.3989/gya.0217201

[54] Aridi YS, Walker JL, Wright ORL. The association between the Mediterranean dietary pattern and cognitive health: A systematic review. Nutrients. 2017; 9 (674): 1-23. DOI. org/10.3390/nu9070674.

[55] Nilsson M. Effects of the Mediterranean diet on brain function: Underlying mechanisms [Bachelor Degree Project]. University of Skovde; 2019.

[56] Tripodi P, Schiavi M, Lo Scalzo R. Multi-Scale Evaluation on Two Locations and Digital Fruit Imaging Highlight Morpho-Agronomic Performances and Antioxidant Properties in Chili Pepper Hybrids. Agronomy. 2021; 11(805):1-12. DOI:10.3390/agronomy11040805

[57] Saha S, Walia S, Kundu A, Kaur C, Singh J and Sisodia R. Capsaicinoids, Tocopherol, and Sterols Content in Chili (Capsicum sp.) by Gas Chromatographic-Mass Spectrometric Determination. International Journal of Food Properties. 2015; 18(7): 1535-1545. DOI: 10.1080/10942912.2013.833222

[58] Motukuri K and Jaswanthi N. Chapter 1-9: Hot Pepper (*Capsicum annuum* L.): An Alternative Food to Reduce Micronutrient Deficiencies in Human. In book Capsicum. 2020. DOI:10.5772/intechopen.92198

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[67] Cvetkovi CT, Ranilovi CJ, Gajari D,

Tomic-Obrdalj H, Šubari CD, Moslavac T, Cikoš AM and Joki CS. Podravka and Slavonka Varieties of Pepper Seeds (*Capsicum annuum* L.) as a New Source of Highly Nutritional Edible Oil. Foods. 2020; 9 (1262): 1-21.

DOI:10.3390/foods9091262

2010; 4(1): 93-97.

intechopen.78243.

*DOI: http://dx.doi.org/10.5772/intechopen.99705*

[59] Bonaccio M, Di Castelnuovo A, Costanzo S, Ruggiero E, De Curtis A, Persichillo M, Tabolacci C, Facchiano F, Cerletti C, Donati MB, De Gaetano G, Iacoviello L. Chili Pepper Consumption and Mortality in Italian Adults, J Am Coll Cardiol. 2019, 74 (25): 3139-3149. DOI: 10.1016/j.jacc.2019.09.068.

[60] Materska M and Perucka I. Antioxidant activity of the main phenolic compounds isolated from hot pepper fruit (*Capsicum annuum* L.). Journal of Agriculture and Food Chemistry. 2005; 53(5): 1750-1756.

DOI:10.1021/jf035331k

363-370.

[61] Wahyuni Y, Ballester AR, Sudarmonowati E, Bino RJ and Bovy AG. Secondary Metabolites of Capsicum Species and Their Importance

in the Human Diet. J. of Natural Products. 2013; 76 (4):783-793. DOI:10.1021/np300898z

[62] Chouaibi M, Rezigc L, Hamdic S, Ferrari G. Chemical characteristics and compositions of red pepper seed oils extracted by different methods,

Industrial Crops & Products. 2019; 128:

[63] Meckelmann SW, Riegel DW, van Zonneveld M, RíosL, Peña K, Mueller-Seitz E and Petz M. Capsaicinoids, flavonoids, tocopherols, antioxidant capacity and color attributes in 23 native Peruvian chili peppers (Capsicum spp.) grown in three different locations. European Food Research and

Technology. 2014; 240 (2): 273-283.DOI:

[64] Olatunji TL and Afolayan AJ. The suitability of Chili pepper (*Capsicum annuum* L.) for alleviating human micronutrient dietary deficiencies. Food

10.1007/s00217-014-2325-6

Sci Nutr. 2018; 6: 2239-2251.

[65] Ben Mansour-Gueddes S,

Tarchoun N, Teixeira Da Silva JA and Saguem S. Agronomic and Chemical

Doi:10.1002/fsn3.790

*Vitamin E: Natural Antioxidant in the Mediterranean Diet DOI: http://dx.doi.org/10.5772/intechopen.99705*

[59] Bonaccio M, Di Castelnuovo A, Costanzo S, Ruggiero E, De Curtis A, Persichillo M, Tabolacci C, Facchiano F, Cerletti C, Donati MB, De Gaetano G, Iacoviello L. Chili Pepper Consumption and Mortality in Italian Adults, J Am Coll Cardiol. 2019, 74 (25): 3139-3149. DOI: 10.1016/j.jacc.2019.09.068.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

Agriculture and Processing for Health Choices. Antioxidants. 2020; 9 (41): 1-17. DOI:10.3390/antiox9010041

[52] Rocha J, Borges N and Pinho O. Table olives and health. Journal of Nutritional Science. 2020; 9(e57): 1-16.

[53] Castellano JM and Perona JS. Effects of virgin olive oil phenolic compounds on health: solid evidence or just another fiasco? Grasas y Aceites. 2021; 72(2): e404. DOI: 10.3989/gya.0217201

[54] Aridi YS, Walker JL, Wright ORL.

Mediterranean diet on brain function: Underlying mechanisms [Bachelor Degree Project]. University of

[56] Tripodi P, Schiavi M, Lo Scalzo R. Multi-Scale Evaluation on Two Locations and Digital Fruit Imaging Highlight Morpho-Agronomic Performances and Antioxidant Properties in Chili Pepper Hybrids. Agronomy. 2021; 11(805):1-12. DOI:10.3390/agronomy11040805

[57] Saha S, Walia S, Kundu A, Kaur C, Singh J and Sisodia R. Capsaicinoids, Tocopherol, and Sterols Content in Chili (Capsicum sp.) by Gas

Chromatographic-Mass Spectrometric

Journal of Food Properties. 2015; 18(7):

Determination. International

10.1080/10942912.2013.833222

[58] Motukuri K and Jaswanthi N. Chapter 1-9: Hot Pepper (*Capsicum annuum* L.): An Alternative Food to Reduce Micronutrient Deficiencies in Human. In book Capsicum. 2020. DOI:10.5772/intechopen.92198

1535-1545. DOI:

The association between the Mediterranean dietary pattern and cognitive health: A systematic review. Nutrients. 2017; 9 (674): 1-23. DOI.

org/10.3390/nu9070674.

Skovde; 2019.

[55] Nilsson M. Effects of the

doi:10.1017/jns.2020.50

oil. Journal of Food Biochemistry. 2006;

[45] Laroussi-Mezghani S, Le Dréau Y,

Grati-Kamoun N, Artaud J. Biodiversity of Tunisian virgin olive oils: varietal origin classification according to their minor compounds. Eur. Food Res. Technol. 2016; 242:1087-1099.

[46] Sakouhi F, Harrabi S, Absalon C, Sbei K, Boukhchina S, Kallel H.

some Tunisian table olives (*Olea europaea* L.): Changes in their composition during ripening and processing. Food Chemistry. 2008;108:

833-839.

179-194. DOI:10.111 1/j.1745-4514.2007.00107.

Lipids. 2014; 21(5): 2-10.

α-Tocopherol and fatty acids contents of

[47] Krichene D, Taamalli W, Daoud D, Salvador MD, Fregapane G, Zarrouk M. Phenolic compounds, tocopherols and other minor components in virgin olive oils of some Tunisian varieties. Journal of Food Biochemistry. 2007; 31 (2):

[48] Haddam M, Chimi H and Amine A. Formulation d'une huile d'olive de bonne qualité. Oilseeds and fats, Crops and

[49] Bendi Djelloul MC, Amrani SM, Rovellini P, Chenoune R. Phenolic compounds and fatty acids content of

Communicata Scientiae. 2020, 1: 1-11.

[50] Bonanome A, Pagnan A, Biffanti S. Effect of Dietary Monounsaturated and Polyunsaturated Fatty Acids on the Susceptibility of Plasma Low-Density Lipoproteins to Oxidative Modification. Arterioscler Thromb. 1992; 12: 529-533.

[51] Lanza B and Ninfali P. Antioxidants in Extra Virgin Olive Oil and Table Olives: Connections between

some West Algerian olive oils.

DOI : 10.14295/cs.v11i0.3247

DOI :10.1161/01.ATV.12.4.529

10.1111/j.1745-4514.2006.00086.x

30 (6): 659-670. DOI:

Molinet J, Hammami M,

**162**

[60] Materska M and Perucka I. Antioxidant activity of the main phenolic compounds isolated from hot pepper fruit (*Capsicum annuum* L.). Journal of Agriculture and Food Chemistry. 2005; 53(5): 1750-1756. DOI:10.1021/jf035331k

[61] Wahyuni Y, Ballester AR, Sudarmonowati E, Bino RJ and Bovy AG. Secondary Metabolites of Capsicum Species and Their Importance in the Human Diet. J. of Natural Products. 2013; 76 (4):783-793. DOI:10.1021/np300898z

[62] Chouaibi M, Rezigc L, Hamdic S, Ferrari G. Chemical characteristics and compositions of red pepper seed oils extracted by different methods, Industrial Crops & Products. 2019; 128: 363-370.

[63] Meckelmann SW, Riegel DW, van Zonneveld M, RíosL, Peña K, Mueller-Seitz E and Petz M. Capsaicinoids, flavonoids, tocopherols, antioxidant capacity and color attributes in 23 native Peruvian chili peppers (Capsicum spp.) grown in three different locations. European Food Research and Technology. 2014; 240 (2): 273-283.DOI: 10.1007/s00217-014-2325-6

[64] Olatunji TL and Afolayan AJ. The suitability of Chili pepper (*Capsicum annuum* L.) for alleviating human micronutrient dietary deficiencies. Food Sci Nutr. 2018; 6: 2239-2251. Doi:10.1002/fsn3.790

[65] Ben Mansour-Gueddes S, Tarchoun N, Teixeira Da Silva JA and Saguem S. Agronomic and Chemical

Evaluation of Seven Hot Pepper (*Capsicum annuum* L.) Populations Grown in an Open Field. Fruit, Vegetable and Cereal Science and Biotechnology, Global Science Books. 2010; 4(1): 93-97.

[66] Antonious GF. Chapter 2: Capsaicinoids and Vitamins in Hot Pepper and Their Role in Disease Therapy. In: Handbook of Capsaicin and its Human Therapeutic Development. Kentucky State University, Frankfort, KY, USA, 2018; 13-40. DOI.org/10.5772/ intechopen.78243.

[67] Cvetkovi CT, Ranilovi CJ, Gajari D, Tomic-Obrdalj H, Šubari CD, Moslavac T, Cikoš AM and Joki CS. Podravka and Slavonka Varieties of Pepper Seeds (*Capsicum annuum* L.) as a New Source of Highly Nutritional Edible Oil. Foods. 2020; 9 (1262): 1-21. DOI:10.3390/foods9091262

**165**

**Chapter 9**

**Abstract**

Vitamin E: Recommended Intake

Data of vitamin E intake and status are controversial. Vitamin E is an essential micronutrient for humans and achieving an optimal status is assumed to produce beneficial health outcomes. Dietary intake recommendations for vitamin E vary considerably by different countries and organizations. It appears to be still a challenge to define these despite the wealth of data published. Vitamin E requirements have been proposed to depend on other nutritional factors, such as the intake of polyunsaturated fatty acids (PUFA). Although several foods contain naturally occurring sources of vitamin E, it is frequently the case that the intake recommendations are not achieved. Several other dietary factors affect the need for vitamin E. In this regard, significant challenges to be considered include the efficiency of other tocopherol variants and their properties that could affect the revision of the nutritional recommendations for vitamin E. Particularly, an ever-increasing evidence indicates that other vitamin E homologs may potentially present with a higher biological activity. Low dietary consumption of vitamin E, coupled with compelling evidence that increased intake of vitamin E above current recommendations for the

**Keywords:** vitamin E recommendations, tocopherols, tocotrienols, nutrition,

Vitamin E was first described in 1922 by Evans and Bishop as a dietary factor essential to prevent fetal reabsorption in rats [1], vitamin E was soon after identified as an antioxidant of polyunsaturated lipids [2]. Evans and Bishop (1922) reported the discovery of a molecule that was lacking in rats on a diet based on lard, and which resulted in an impaired fertility [3]. This deficiency was reversed by the administration of lipid extract prepared from cereals, which was defined as the "antisterility factor" [4]. Finally, vitamin E was officially recognized as the 5th vitamin in 1925. Subsequently, the name "tocopherol" originating from the Greek words "toc" (child) and "phero" (to bring forth) was conceived to characterize the roles of vitamin E as an essential dietary compound for a normal fetal development

Vitamin E is a fat-soluble compound. The name represents a collective title for 4 tocopherols (α-, β-, γ-, and δ-tocopherol) and 4 tocotrienols (α-, β-, γ-, and δ-tocotrienols) that are present in food and exhibit antioxidant properties, however which cannot be interconverted, and only α-tocopherol meets the requirements for

*Marianna Schwarzova, Katarina Fatrcova-Sramkova,* 

*Eva Tvrda and Miroslava Kacaniova*

general population may benefit older individuals.

requirement, dietary intake, food source

the daily intake of vitamin E in humans [5].

**1. Introduction**

and childhood.

#### **Chapter 9**

## Vitamin E: Recommended Intake

*Marianna Schwarzova, Katarina Fatrcova-Sramkova, Eva Tvrda and Miroslava Kacaniova*

#### **Abstract**

Data of vitamin E intake and status are controversial. Vitamin E is an essential micronutrient for humans and achieving an optimal status is assumed to produce beneficial health outcomes. Dietary intake recommendations for vitamin E vary considerably by different countries and organizations. It appears to be still a challenge to define these despite the wealth of data published. Vitamin E requirements have been proposed to depend on other nutritional factors, such as the intake of polyunsaturated fatty acids (PUFA). Although several foods contain naturally occurring sources of vitamin E, it is frequently the case that the intake recommendations are not achieved. Several other dietary factors affect the need for vitamin E. In this regard, significant challenges to be considered include the efficiency of other tocopherol variants and their properties that could affect the revision of the nutritional recommendations for vitamin E. Particularly, an ever-increasing evidence indicates that other vitamin E homologs may potentially present with a higher biological activity. Low dietary consumption of vitamin E, coupled with compelling evidence that increased intake of vitamin E above current recommendations for the general population may benefit older individuals.

**Keywords:** vitamin E recommendations, tocopherols, tocotrienols, nutrition, requirement, dietary intake, food source

#### **1. Introduction**

Vitamin E was first described in 1922 by Evans and Bishop as a dietary factor essential to prevent fetal reabsorption in rats [1], vitamin E was soon after identified as an antioxidant of polyunsaturated lipids [2]. Evans and Bishop (1922) reported the discovery of a molecule that was lacking in rats on a diet based on lard, and which resulted in an impaired fertility [3]. This deficiency was reversed by the administration of lipid extract prepared from cereals, which was defined as the "antisterility factor" [4]. Finally, vitamin E was officially recognized as the 5th vitamin in 1925. Subsequently, the name "tocopherol" originating from the Greek words "toc" (child) and "phero" (to bring forth) was conceived to characterize the roles of vitamin E as an essential dietary compound for a normal fetal development and childhood.

Vitamin E is a fat-soluble compound. The name represents a collective title for 4 tocopherols (α-, β-, γ-, and δ-tocopherol) and 4 tocotrienols (α-, β-, γ-, and δ-tocotrienols) that are present in food and exhibit antioxidant properties, however which cannot be interconverted, and only α-tocopherol meets the requirements for the daily intake of vitamin E in humans [5].

As an antioxidant vitamin E protects cell membranes from oxidation and destruction [4]. Oxidative processes are normal cellular events, but uncontrolled oxidation, particularly of membrane lipids and lipoproteins, has been implicated in a variety of degenerative conditions, including cancer, rheumatoid arthritis, drugassociated toxicity, coronary heart disease, diabetes, and acute clinical conditions, such as ischemia–reperfusion injury [6–9]. According to the widespread consensus, vitamin E is a powerful antioxidant molecule, which may be found in lipid compartments such as cell membranes because of its hydrophobic chemistry. Its primary function lies in the prevention of lipid peroxidation [10], leading to the preservation of the membrane stability. Vitamin E is also essential in the stabilization of erythrocytes and in the nerve conductivity of the central as well as peripheral nervous system [11, 12]. The molecule prevents hemolytic anemia and neurological dysfunction associated with its deficiency, such as ataxia, neuro-, myo- or retinopathy. The vitamin is also highly efficient in the prevention or stabilization of a variety of health complications because of its antioxidant, anti-inflammatory, antiaggregant and immune-enhancing properties [13]. However, the beneficial effects of vitamin E in human health may also be due to the ability of its phosphorylated metabolite to modulate signal transduction and gene expression in numerous conditions, including inflammation and immune system disorders [14]. This chapter aims to provide a brief overview of the current strategies that are employed to define the intake recommendation for vitamin E. Furthermore, we wish to evaluate the available evidence on the fundamental biological roles of vitamin E in the human body to in order to establish intake requirements for vitamin E to exhibit its antioxidant properties by protecting the polyunsaturated fatty acids (PUFAs) from being oxidized in human tissues. The question which will be addressed in this chapter is how the current vitamin E status (as measured by vitamin E intakes and serum levels) of populations in various countries differs. Special attention is also given to the vitamin E food sources.

#### **2. Vitamin E intake recommendations**

Vitamin E is defined as an essential micronutrient for humans, and its beneficial health outcomes are dependent upon reaching its optimal nutritional status. A variety of dietary intake recommendations for vitamin E have been established around the world, all of which point out to its ability to act as a chain-breaking antioxidant and thus to protect the stability of the cell membrane [1].

#### **2.1 Determination vitamin E intake recommendations**

In Europe, the **European Food Safety Authority (EFSA)** recently concluded that the recommended daily allowance (RDA), average requirements (ARs) and population reference intakes (PRIs) for vitamin E (in the form of α-tocopherol) cannot be established for adults, children and infants equally. As such, EFSA determined adequate intakes (AIs), which are based on intakes that had been observed in a supposedly healthy population that presents with no apparent α-tocopherol insufficiency in the EU [15].

The EFSA Panel on Dietetic Products, Nutrition and Allergies proposed RDA to replaced by a newly defined adequate intake (AI), depending on age, as follows: men, 13 mg/d; women, 11 mg/d (**Table 1**); and infants/children, 5–13 mg/d [15].

The US **Institute of Medicine (IOM)** define vitamin E recommendations for generally healthy population as intake level of 12 mg/d and above (**Table 1**).

**167**

*Vitamin E: Recommended Intake*

*gestation test.*

*(a)Adequate Intake.*

*(e)'vitamin E requirement'. (f)mg α-TE/g PUFA. (g)'Safe' intakes.*

*2004)*

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

as women older than 14 years of age [16].

*Nutrition Council; DH UK Department of Health.*

*(c)PRI – Population Reference Intake.*

*(b)Applicable to RRR-, RSR-, RRS- and RSS-isomers of α-tocopherol only.*

*Vitamin E dietary reference values (DRVs) for adults - overview [15].*

adults aged 75 years and over [17].

distinguish between age and/or sex.

degree of haemolysis.

This value has been characterized as the Estimated Average Requirement (EAR) and is defined as the amount needed to meet the requirements of 50% healthy people, and it became the foundation to determine RDA, which is predicted to meet the dietary demands of 97.5% healthy individuals. In the case of the USA, the RDA for vitamin E is established to be 15 mg/d α-tocopherol for men as well

*EFSA European Food Safety Authority; IOM US Institute of Medicine of the National Academy of Science; D-A-CH Deutschland (Germany)-Austria-Confoederatio Helvetica (Switzerland); WHO/FAO World Health Organization/ Food and Agriculture Organization of the United Nations; AFSSA Agence Française de Sécurité Sanitaire des Aliments; NCM Nordic Council of Ministers; SCF Scientific Committee on Food, NL Netherlands Food and* 

*(d)Data were insufficient to set PRIs; the indicated figures represent the 'best estimates of requirements' (WHO/FAO,* 

**EFSA** (2015)(a) ≥18 13 11 **IOM** (2000)(b)(c) ≥19–50 15 15 **D-A-CH** (2013)(a) ≥19 13-15 12 **WHO/FAO** (2004)(d) ≥19 10 7.5 **AFSSA** (2001) 20–74 12 12 **NCM** (2014)(a)(b) ≥18 10 8 **SCF** (1993)(e)(f) ≥18 0.4 0.4 **NL** (1992)(c)(f) ≥18 0.67 0.67 **DH** (1999)(g) >18 >4 >3 *DRVs in α-tocopherol equivalents is defined by the biological activity of 1 mg natural α-tocopherol in the resorption-*

**Age (years) Men (mg/d) Women (mg/d)**

The current intake recommendations for vitamin E vary between 3 and 15 mg/d

The IOM [16, 18] recommends Vitamin E dietary reference doses based on a previous extensive research. The IOM recommendations are based on a premise that there is no scientific basis to assume variations in the demand for vitamin E between men and women, or that aging could impair its absorption or secretion. As such, the IOM recommendations do not discriminate between sex or age in adults. On the other hand, DACH reference values [18, 19] for Germany, Austria and Switzerland published in the same year and based on a similar methodology, does

In the meantime, IOM and DACH applied two different methodological approaches to estimate the recommendations for dietary vitamin E intake. On one hand, IOM is based on the prevention of deficiency symptoms, particularly the sensitivity of erythrocytes to hemolysis. Available human data reveal that subjects with plasma concentrations of at least 12 μmol/L α-tocopherol present with a low

in different countries and depending on the age and gender of the person. The current adult Dietary Reference Values (DRVs) for vitamin E in UK is determined >3 mg/d, in German-speaking countries 15 mg/d for adult. The French Food Safety Agency (AFSSA) derived a separate reference value of 20–50 mg/d for


*DRVs in α-tocopherol equivalents is defined by the biological activity of 1 mg natural α-tocopherol in the resorptiongestation test.*

*EFSA European Food Safety Authority; IOM US Institute of Medicine of the National Academy of Science; D-A-CH Deutschland (Germany)-Austria-Confoederatio Helvetica (Switzerland); WHO/FAO World Health Organization/ Food and Agriculture Organization of the United Nations; AFSSA Agence Française de Sécurité Sanitaire des Aliments; NCM Nordic Council of Ministers; SCF Scientific Committee on Food, NL Netherlands Food and Nutrition Council; DH UK Department of Health.*

*(a)Adequate Intake.*

*(b)Applicable to RRR-, RSR-, RRS- and RSS-isomers of α-tocopherol only.*

*(c)PRI – Population Reference Intake.*

*(d)Data were insufficient to set PRIs; the indicated figures represent the 'best estimates of requirements' (WHO/FAO, 2004)*

*(e)'vitamin E requirement'.*

*(f)mg α-TE/g PUFA.*

*(g)'Safe' intakes.*

#### **Table 1.**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

As an antioxidant vitamin E protects cell membranes from oxidation and destruction [4]. Oxidative processes are normal cellular events, but uncontrolled oxidation, particularly of membrane lipids and lipoproteins, has been implicated in a variety of degenerative conditions, including cancer, rheumatoid arthritis, drugassociated toxicity, coronary heart disease, diabetes, and acute clinical conditions, such as ischemia–reperfusion injury [6–9]. According to the widespread consensus, vitamin E is a powerful antioxidant molecule, which may be found in lipid compartments such as cell membranes because of its hydrophobic chemistry. Its primary function lies in the prevention of lipid peroxidation [10], leading to the preservation of the membrane stability. Vitamin E is also essential in the stabilization of erythrocytes and in the nerve conductivity of the central as well as peripheral nervous system [11, 12]. The molecule prevents hemolytic anemia and neurological dysfunction associated with its deficiency, such as ataxia, neuro-, myo- or retinopathy. The vitamin is also highly efficient in the prevention or stabilization of a variety of health complications because of its antioxidant, anti-inflammatory, antiaggregant and immune-enhancing properties [13]. However, the beneficial effects of vitamin E in human health may also be due to the ability of its phosphorylated metabolite to modulate signal transduction and gene expression in numerous conditions, including inflammation and immune system disorders [14]. This chapter aims to provide a brief overview of the current strategies that are employed to define the intake recommendation for vitamin E. Furthermore, we wish to evaluate the available evidence on the fundamental biological roles of vitamin E in the human body to in order to establish intake requirements for vitamin E to exhibit its antioxidant properties by protecting the polyunsaturated fatty acids (PUFAs) from being oxidized in human tissues. The question which will be addressed in this chapter is how the current vitamin E status (as measured by vitamin E intakes and serum levels) of populations in various countries differs. Special attention is also given to

Vitamin E is defined as an essential micronutrient for humans, and its beneficial health outcomes are dependent upon reaching its optimal nutritional status. A variety of dietary intake recommendations for vitamin E have been established around the world, all of which point out to its ability to act as a chain-breaking antioxidant

In Europe, the **European Food Safety Authority (EFSA)** recently concluded that the recommended daily allowance (RDA), average requirements (ARs) and population reference intakes (PRIs) for vitamin E (in the form of α-tocopherol) cannot be established for adults, children and infants equally. As such, EFSA determined adequate intakes (AIs), which are based on intakes that had been observed in a supposedly healthy population that presents with no apparent α-tocopherol

The EFSA Panel on Dietetic Products, Nutrition and Allergies proposed RDA to replaced by a newly defined adequate intake (AI), depending on age, as follows: men, 13 mg/d; women, 11 mg/d (**Table 1**); and infants/children,

The US **Institute of Medicine (IOM)** define vitamin E recommendations for generally healthy population as intake level of 12 mg/d and above (**Table 1**).

**166**

the vitamin E food sources.

insufficiency in the EU [15].

5–13 mg/d [15].

**2. Vitamin E intake recommendations**

and thus to protect the stability of the cell membrane [1].

**2.1 Determination vitamin E intake recommendations**

*Vitamin E dietary reference values (DRVs) for adults - overview [15].*

This value has been characterized as the Estimated Average Requirement (EAR) and is defined as the amount needed to meet the requirements of 50% healthy people, and it became the foundation to determine RDA, which is predicted to meet the dietary demands of 97.5% healthy individuals. In the case of the USA, the RDA for vitamin E is established to be 15 mg/d α-tocopherol for men as well as women older than 14 years of age [16].

The current intake recommendations for vitamin E vary between 3 and 15 mg/d in different countries and depending on the age and gender of the person.

The current adult Dietary Reference Values (DRVs) for vitamin E in UK is determined >3 mg/d, in German-speaking countries 15 mg/d for adult. The French Food Safety Agency (AFSSA) derived a separate reference value of 20–50 mg/d for adults aged 75 years and over [17].

The IOM [16, 18] recommends Vitamin E dietary reference doses based on a previous extensive research. The IOM recommendations are based on a premise that there is no scientific basis to assume variations in the demand for vitamin E between men and women, or that aging could impair its absorption or secretion. As such, the IOM recommendations do not discriminate between sex or age in adults.

On the other hand, DACH reference values [18, 19] for Germany, Austria and Switzerland published in the same year and based on a similar methodology, does distinguish between age and/or sex.

In the meantime, IOM and DACH applied two different methodological approaches to estimate the recommendations for dietary vitamin E intake. On one hand, IOM is based on the prevention of deficiency symptoms, particularly the sensitivity of erythrocytes to hemolysis. Available human data reveal that subjects with plasma concentrations of at least 12 μmol/L α-tocopherol present with a low degree of haemolysis.

On the other hand, the DACH recommendations, supported by EFSA, regard dietary intake of PUFA to estimate the demands for vitamin E. The basic vitamin E demand of 4 mg/d and a ratio of 0.4 mg α-tocopherol/g of dietary linoleic acid were used to compute vitamin E requirements [18]. Dietary vitamin E demands were estimated at levels of 12 and 15 mg/d based on a general dietary PUFA consumption, which differs between women and men due to the differences in energy intake.

It is nevertheless intriguing to observe, that despite two different methods, both approaches will result in reference values ranging between 10 and 30 mg/d.

It is recommended that a baseline α-tocopherol requirement should be estimated to which extra vitamin E compensating for the dietary PUFA intake can be added to finally obtain an appropriate balance of dietary fatty acids with vitamin E. Nevertheless, the optimum demand for vitamin E is also directly correlated to the amount and degree of dietary PUFA unsaturation. In order to assess the precise vitamin E prerequisites in infants, children, adolescent, adult men and women, an extended observation is imperative to deplete the body's vitamin E storage in order to describe anypotential long-term adverse or harmful consequences that are often complicated to be diagnosed at an early stage. Currently however it is not possible to carry out any long-term follow-up or depletion studies due to ethical reasons [18, 20].

#### **2.2 Vitamin E – other nutritional factors**

It has been suggested that vitamin E requirements depend on a variety of other nutritional factors, primarily on the ingestion of polyunsaturated fatty acids (PUFAs). Based on this factor, an increased demand for vitamin E should be regarded for RDA calculation, which has been estimated to oscillate between 15 and 25 mg/d or more [18, 19].

Various reports revealed that the nutritional demand for vitamin E requirement is associated with the dietary intake of PUFAs, which is why in order to calculate the actual vitamin E requirement, a basal vitamin E demand as well as an additional requirement for dietary PUFAs may be taken into consideration. Preclinical as well as human data point out to the fact that a minimal basal need for 4–5 mg/d of RRR-α-tocopherol is necessary even if the diet is lacking PUFAs [20]. Nevertheless, no consensus exists on the precise vitamin E/PUFA ratio in order to establish the vitamin requirement since a strictly pre-determined vitamin E/PUFA proportion may not be relevant to all diets or health conditions. On the other hand, the demand for vitamin E increases proportionally to the PUFA consumption and to the level of the PUFA unsaturation in the diet. As such, currently available human data hypothesize that the additional dietary need for vitamin E fluctuates between 0.4 and 0.6 mg RRR-α-tocopherol/g of PUFA, particularly in the case of a diet containing an average amount of PUFAs with linoleic acid being the predominant dietary PUFA [18]. What is more, animal experiments reveal that in case of fatty acids presenting with a higher degree of unsaturation, the demand for vitamin E increases almost in a linear fashion correspondingly to the extent of PUFA unsaturation in the relative proportions of 0.3, 2, 3, 4, 5, and 6 for, or alternatively, mono-, di-, tri-, tetra-, penta-, and hexaenoic fatty acids. Summarizing evidence from human as well as animal studies, it may be suggested that in the case of a standard ingestion of PUFAs, the estimated dietary need for vitamin E oscillates between 12 and 20 mg/d [20].

Generaly, the recommended intake of vitamin E should correlate with the amount of polyunsaturated fatty acids (PUFA) in food: 1 g of diene fatty acid or rather diene equivalent requires an intake of 0.5 mg RRR-α-TOH.

An optimal daily intake of vitamin E may be broken down into two categories: a required daily intake that provides enough vitamin E for the molecule to exhibit its basic biological effects, as well as a second one, which is determined by a higher

**169**

10–11% men.

*Vitamin E: Recommended Intake*

**2.3 Vitamin E – dietary intake**

tions [1].

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

ingestion range that promotes its additional beneficial properties that may assist in the disease prevention. The most favorable intake of vitamin E in healthy subjects, defined as the actual dose that is associated with its major positive attributes in the absence of possible adverse effects, remains to be determined in appropriately designed and executed trials, which represents a considerable hurdle to be overcome in the definition process of appropriate nutritional vitamin E recommenda-

As the data come from different countries, it is important to take into account the differences in dietary behaviors in a comprehensive assessment of vitamin E intake. Nevertheless, a substantial number of countries are still not represented. Furthermore, the studies applied various scientific strategies to assess the intake of dietary vitamin E. If just one single 24-hour dietary anamnesis was performed per person, this might not necessarily reflect on an everyday nutrient ingestion, based on a day-to-day fluctuation. Other reports were based on 3-day food records, providing a better notion of the dietary routine [21]. Other research strategies may

Diet, nutritional status, lifestyle and environmental factors are among the most complicated issues to be investigated with respect to chronic diseases [22]. Large multicentre nutritional studies are accompanied by additional challenges to assess, correlate, and understand dietary exposure in a comparable way across countries, as

Generally speaking, the intake of vitamin E is low and very similar across regions all around the world. According to a recent systematic review, dietary ingestion of α-tocopherol and other vitamin E derivates is well below the RDA for the majority of the population, or even lower than the EAR of 12 mg/d, which is applicable equally for developing as well as industrialized countries [23]. The biggest investigation focused on the vitamin E intake is the pan-European EPIC study involving 36 000 participants recruited across 10 European countries and followed-up for as long as 15 years. Details on the dietary patterns, lifestyle characteristics, anthropometric measurements, and medical history were collected in the EPIC study at recruitment (1992–1999). While the overall mean consumption of vitamin E was 11.9 mg/d, an intriguing regional difference was observed: the intake was higher in the southern countries in comparison to the northern ones [24]. This revelation may be explained by the differences in the food preferences, particularly

include food frequency questionnaires or a dietary history.

well as to conclude evidence and recommendations.

in the case of vegetable oils, which are more popular in the south.

significantly when extrapolated to the total nutrient intake.

The NHANES study showed a mean intake of α-tocopherol of 7.2, 6.8, 6.1, 6.0 mg/d in men aged 19–50 years, >50 years, women aged 19–50 years, and > 50 years, respectively [25]. Vitamin E RDA (15 mg/d) was recorded only in 4% women and 5% men, while EAR (12 mg/d) was observed in 7–8% women and

The prevalence of inadequate vitamin E intake was reported to be 92.5% in the total Brasil adolescent population, 91.6% in boys, and 93.5% in girls (p = 0.358). Brasil adolescents aged 10 to 13 years showed a less inadequate ingestion (p < 0.001) when compared to those aged 14 to 19 years: 87.7% and 95.1%, respectively [26] (**Table 2**). Jordão et al. [26] identified a high prevalence of vitamin E inadequacy, verified by a low intake of the nutrient, and the observation that ultra-processed foods, such as cookies, packaged snacks, and margarine, provided for almost 33% of the vitamin E content ingested by adolescents in Campinas. Furthermore, healthy foods considered as critical dietary sources of vitamin E did not contribute

#### *Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

**2.2 Vitamin E – other nutritional factors**

25 mg/d or more [18, 19].

On the other hand, the DACH recommendations, supported by EFSA, regard dietary intake of PUFA to estimate the demands for vitamin E. The basic vitamin E demand of 4 mg/d and a ratio of 0.4 mg α-tocopherol/g of dietary linoleic acid were used to compute vitamin E requirements [18]. Dietary vitamin E demands were estimated at levels of 12 and 15 mg/d based on a general dietary PUFA consumption, which differs between women and men due to the differences in energy intake. It is nevertheless intriguing to observe, that despite two different methods, both

approaches will result in reference values ranging between 10 and 30 mg/d. It is recommended that a baseline α-tocopherol requirement should be estimated to which extra vitamin E compensating for the dietary PUFA intake can be added to finally obtain an appropriate balance of dietary fatty acids with vitamin E. Nevertheless, the optimum demand for vitamin E is also directly correlated to the amount and degree of dietary PUFA unsaturation. In order to assess the precise vitamin E prerequisites in infants, children, adolescent, adult men and women, an extended observation is imperative to deplete the body's vitamin E storage in order to describe anypotential long-term adverse or harmful consequences that are often complicated to be diagnosed at an early stage. Currently however it is not possible to carry out any long-term follow-up or depletion studies due to ethical reasons [18, 20].

It has been suggested that vitamin E requirements depend on a variety of other nutritional factors, primarily on the ingestion of polyunsaturated fatty acids (PUFAs). Based on this factor, an increased demand for vitamin E should be regarded for RDA calculation, which has been estimated to oscillate between 15 and

dietary need for vitamin E oscillates between 12 and 20 mg/d [20].

rather diene equivalent requires an intake of 0.5 mg RRR-α-TOH.

Generaly, the recommended intake of vitamin E should correlate with the amount of polyunsaturated fatty acids (PUFA) in food: 1 g of diene fatty acid or

An optimal daily intake of vitamin E may be broken down into two categories: a required daily intake that provides enough vitamin E for the molecule to exhibit its basic biological effects, as well as a second one, which is determined by a higher

Various reports revealed that the nutritional demand for vitamin E requirement is associated with the dietary intake of PUFAs, which is why in order to calculate the actual vitamin E requirement, a basal vitamin E demand as well as an additional requirement for dietary PUFAs may be taken into consideration. Preclinical as well as human data point out to the fact that a minimal basal need for 4–5 mg/d of RRR-α-tocopherol is necessary even if the diet is lacking PUFAs [20]. Nevertheless, no consensus exists on the precise vitamin E/PUFA ratio in order to establish the vitamin requirement since a strictly pre-determined vitamin E/PUFA proportion may not be relevant to all diets or health conditions. On the other hand, the demand for vitamin E increases proportionally to the PUFA consumption and to the level of the PUFA unsaturation in the diet. As such, currently available human data hypothesize that the additional dietary need for vitamin E fluctuates between 0.4 and 0.6 mg RRR-α-tocopherol/g of PUFA, particularly in the case of a diet containing an average amount of PUFAs with linoleic acid being the predominant dietary PUFA [18]. What is more, animal experiments reveal that in case of fatty acids presenting with a higher degree of unsaturation, the demand for vitamin E increases almost in a linear fashion correspondingly to the extent of PUFA unsaturation in the relative proportions of 0.3, 2, 3, 4, 5, and 6 for, or alternatively, mono-, di-, tri-, tetra-, penta-, and hexaenoic fatty acids. Summarizing evidence from human as well as animal studies, it may be suggested that in the case of a standard ingestion of PUFAs, the estimated

**168**

ingestion range that promotes its additional beneficial properties that may assist in the disease prevention. The most favorable intake of vitamin E in healthy subjects, defined as the actual dose that is associated with its major positive attributes in the absence of possible adverse effects, remains to be determined in appropriately designed and executed trials, which represents a considerable hurdle to be overcome in the definition process of appropriate nutritional vitamin E recommendations [1].

As the data come from different countries, it is important to take into account the differences in dietary behaviors in a comprehensive assessment of vitamin E intake. Nevertheless, a substantial number of countries are still not represented. Furthermore, the studies applied various scientific strategies to assess the intake of dietary vitamin E. If just one single 24-hour dietary anamnesis was performed per person, this might not necessarily reflect on an everyday nutrient ingestion, based on a day-to-day fluctuation. Other reports were based on 3-day food records, providing a better notion of the dietary routine [21]. Other research strategies may include food frequency questionnaires or a dietary history.

#### **2.3 Vitamin E – dietary intake**

Diet, nutritional status, lifestyle and environmental factors are among the most complicated issues to be investigated with respect to chronic diseases [22]. Large multicentre nutritional studies are accompanied by additional challenges to assess, correlate, and understand dietary exposure in a comparable way across countries, as well as to conclude evidence and recommendations.

Generally speaking, the intake of vitamin E is low and very similar across regions all around the world. According to a recent systematic review, dietary ingestion of α-tocopherol and other vitamin E derivates is well below the RDA for the majority of the population, or even lower than the EAR of 12 mg/d, which is applicable equally for developing as well as industrialized countries [23]. The biggest investigation focused on the vitamin E intake is the pan-European EPIC study involving 36 000 participants recruited across 10 European countries and followed-up for as long as 15 years. Details on the dietary patterns, lifestyle characteristics, anthropometric measurements, and medical history were collected in the EPIC study at recruitment (1992–1999). While the overall mean consumption of vitamin E was 11.9 mg/d, an intriguing regional difference was observed: the intake was higher in the southern countries in comparison to the northern ones [24]. This revelation may be explained by the differences in the food preferences, particularly in the case of vegetable oils, which are more popular in the south.

The NHANES study showed a mean intake of α-tocopherol of 7.2, 6.8, 6.1, 6.0 mg/d in men aged 19–50 years, >50 years, women aged 19–50 years, and > 50 years, respectively [25]. Vitamin E RDA (15 mg/d) was recorded only in 4% women and 5% men, while EAR (12 mg/d) was observed in 7–8% women and 10–11% men.

The prevalence of inadequate vitamin E intake was reported to be 92.5% in the total Brasil adolescent population, 91.6% in boys, and 93.5% in girls (p = 0.358). Brasil adolescents aged 10 to 13 years showed a less inadequate ingestion (p < 0.001) when compared to those aged 14 to 19 years: 87.7% and 95.1%, respectively [26] (**Table 2**). Jordão et al. [26] identified a high prevalence of vitamin E inadequacy, verified by a low intake of the nutrient, and the observation that ultra-processed foods, such as cookies, packaged snacks, and margarine, provided for almost 33% of the vitamin E content ingested by adolescents in Campinas. Furthermore, healthy foods considered as critical dietary sources of vitamin E did not contribute significantly when extrapolated to the total nutrient intake.


**171**

**Table 2.**

KiGGS study.

In Germany infants and children up to age twelve commonly do not reach the recommended levels of vitamin E intake [31], as shown in a number of studies including the VELS investigation and the EsKiMo study, a follow-up of the

*Selection of surveys/studies regarding intake vitamin E and serum (α-tocopherol) concentrations.*

*Vitamin E: Recommended Intake*

**State/city/years/**

Brazil/South America/ city Campinas ISACamp (2014–2015) ISACamp-Nutri (2015–2016) Jordão et al. [26]

South Africa/ Sharpeville periphery of city Johannesburg Oldewage-Theron et al. [29]

Korea/Soul (2009–2010) Kim & Cho [30]

**[Ref.]**

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

Brazilian adolescents aged 10–19 years (n = 891; 463 M/428F) M: 10-13y n = 169 14-19y n = 294 F: 10-13y n = 143 14-19y n = 285

(n = 235; 39 M/196F) mean age 73.4 ± 7.0y (60-93y) BMI

M: 25.7 ± 4.6 kg/

(64.1% normal

 (20.9% normal BMI; 31.1% overweight and 47.4% obese)

20-59y old health

m2

m2

BMI) F: 29.9 ± 6.4 kg/

adults (n = 106; 33 M/73F)

**Subjects (n: M/F) Intake of vitamin** 

**E (estimation methods)**

food consumption assessment questionnaire that contained the 24-hour recall mean (95%CI) M: 10-13y 2.8 mg/d (2.5–3.1) 14-19y 3.4 mg/d (3.0–3.7) F: 10-13y 3.5 mg/d (2.8–4.2) 14-19y 3.6 mg/d (2.8–4.4)

two 24-h recall (DRI

(3 consecutive 24-h food recalls) dietary α-TE/day: 17.68 ± 14.34 and total α-TE/day: 19.55 ± 15.78 mg (dietary + supplemental vitE) α-tocopherol equivalent (α-TE) daily α-TOH 3.07 ± 2.27 mg daily γ-TOH 5.98 ± 3.74 mg • 12.3% consumed vitamin E less than the AIs for vitamin E

by HPLC

M: n = 39

mean ± SD (95%CI) deficient <1.2 mg/L) marginal 1.2–1.6 mg/L

2.01 ± 1.11 mg/L (1.65–2-37) deficient 8 (20.5%) marginal 9 (23.1%) F: n = 196

2.07 ± 1.12 mg/L (1.92–2.23) deficient 41 (20.9%) marginal 29 (14.8%) total: n = 235

2.07 ± 1.11 mg/L (1.92–2.21) deficient 49 (20.9%) marginal 38 (16.2%)

plasma α-TOH M: 15.45 ± 10.16 μmol/L F: 15.00 ± 4.54 μmol/L • 23% < 12 μmol/L indicating a biochemical deficiency of vitE

• 89.6% < 20 μmol/L

12 mg/d) M: (n = 26) 5.4 ± 5.2 mg/d 88%DRI F: (n = 113) 4.0 ± 0.5 mg/d 96%

DRI total: (n = 139) 4.3 ± 5.8 mg/d 95%

DRI

**Plasma/serum concentration**


#### *Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

older European adults aged 55-70y and 70-85y (n = 387; 195 M/192F) Clermont-Ferrand (France) n = 95 Grenoble (France)

n = 106 Coleraine (Northem Ireland)

n = 95 Roma (Italy) n = 96

healthy Irish adult population aged 18 years and above; mean 40.3 ± 15.9 years BMI 25.9 ± 3.9 kg/

m2 (n = 601; 305 M/296F)

US population aged >18 years M: 19-50y n = 1141 >50y n = 997 F: 19-50y n = 1196 >50y n = 1017

**Subjects (n: M/F) Intake of vitamin** 

n = 36000 11.9 mg α-TE/day

**E (estimation methods)**

4-day recall-record

(record over four consecutive survey

days) (dietary + supplemental vitE) α-tocopherol equivalent (α-TE) vitamin E intake quartiles: Q1: 6.0 ± 1.1 mg/d Q2: 9.0 ± 0.7 mg/d Q3: 11.9 ± 1.0 mg/d Q1: 20.5 ± 8.5 mg/d

(dietary + supplemental vitE) α-tocopherol equivalent (α-TE) M: 19-50y 7.2 ± 0.1 mg/d M: >50y 6.8 ± 0.2 mg/d F: 19-50y 6.1 ± 0.1 mg/d F: >50y 6.0 ± 0.2 mg/d

method (2 week and 2 weekend days) mean ± SD; (dietary adequacy as % of RDA); [% of subjects at dietary risk] middle-aged (55-70y): C-Ferrand (France) M: 11.3 ± 6.3 mg/d; (141 ± 79%); [8%] F: 9.5 ± 4.6 mg/d; (118 ± 57%); [15%] older aged (70-85y) Grenoble (France) M: 7.1 ± 3.0 mg/d; (89 ± 37%); [26%] F: 7.1 ± 4.8 mg/d; (91 ± 59%); [33%] Roma (Italy) M: 13.7 ± 3.3 mg/d; (172 ± 41%); [0%] F: 12.3 ± 2.6 mg/d; (154 ± 32%); [0%]

**Plasma/serum concentration**

α-TOH (HPLC) mean ± SD

plasma α-TOH (HPLC)

Q1: 24.0b

Q2: 25.8a

Q3: 25.4a

Q1: 25.7a

vitamin E intake quartiles:

± 5.9 μmol/L

± 7.4 μmol/L

± 6.3 μmol/L

± 7.1 μmol/L

middle-aged (55-70y): C-Ferrand (France) M: 28.2 ± 5.2 μmol/L F: 28.8 ± 5.4 μmol/L Coleraine (N. Ireland) M: 28.4 ± 6.0 μmol/L F: 29.0 ± 4.9 μmol/L older aged (70-85y) Grenoble (France) M: 29.7 ± 5.4 μmol/L F: 32.5 ± 5.5 μmol/L Roma (Italy) M: 29.3 ± 5.8 μmol/L F: 29.4 ± 6.2 μmol/L

**State/city/years/**

**[Ref.]**

Europe pan-European EPIC study recruitment participants in (1992–1999) Jenab et al. [24]

West Europe ZENITH study (2002–2005) Polito et al. [27]

Ireland/Europe (2008–2010) The National Adult Nutrition Survey (NANS) Zhao et al. [28]

US/North America (NHANES) (2001–2002) Gao et al. [25]

**170**

**Table 2.**

*Selection of surveys/studies regarding intake vitamin E and serum (α-tocopherol) concentrations.*

In Germany infants and children up to age twelve commonly do not reach the recommended levels of vitamin E intake [31], as shown in a number of studies including the VELS investigation and the EsKiMo study, a follow-up of the KiGGS study.

Although the recommended amount of vitamin E is higher for men than for women, Dutch women consume less vitamin E more often compared to Dutch men [32].

Numerous research groups analyzing compliance to the vitamin E intake recommendations in Americans have found that a significant number of individuals consume insufficient amount [33, 34]. Data by Traber [35] suggest that more than 90% of United States Americans consume insufficient amounts of vitamin E from natural sources. Bjelakovic et al. [36] claims that when combined with the dietary ingestion, the total intake of vitamin E of antioxidant supplement users in the United States exceeds 700% of the estimated average requirement.

A systematic review (2000–2012) by Péter et al. [37] focused on vitamin E intake levels and serum concentrations in order to obtain a global overview of α-tocopherol status. The authors state that only 17 studies (12.9%) included both intake data as well as vitamin E status measured in blood. Most of the studies (132) were conducted in Europe (47.7%), followed by North America (24.2%), and the Western Pacific region (14.8%). Worldwide, 82% of the population had a vitamin E intake below 15 mg/d, 91% in North and South America, 80% in Europe and 79% in the Asian-Pacific region.

Nutrient intake in children and adolescents in Slovakia was studied in 1991–1994 and 1995–1999. Apart from these surveys, no nationally representative data were found for Slovakia, which would be carried out since 2000, which is why a comprehensive information on vitamin E intake and status in all age groups of the population are missing. The Slovak surveys were not indeed nationally representative but were nationwide and designed to "recruit a diverse sample of entities of different ages and socio-economic backgrounds" [38].

The situation is similar in other countries, particularly in the case of Central and Eastern Europe, Africa, Asia (India), and South America [37].

Evidence in the literature that vitamin E intake does not correlate with plasma levels of α-tocopherol is inconclusive [28, 35]. Previous studies have shown that total α-tocopherol intake was positively associated with the plasma α-tocopherol levels [28], while the main indicator of plasma α-tocopherol concentration was the intake of vitamin E supplements [28]. However, other studies have shown that plasma concentrations of α-tocopherol correlated weakly with dietary vitamin E ingestion [16]. The reasons for the lack of a conclusive correlation may lie in the variations of the activity of the α-tocopherol transfer protein [35], genes involved in lipid metabolism [28, 39] and micronutrients with a synergistic effect, such as vitamin C [28, 40]. Niki et al. [41] revealed that lipid peroxidation and oxidative damage may lead to decline in the levels of plasma and tissue α-tocopherol, which may be another plausible argument for different relationships observed between the vitamin E intake and plasma α-tocopherol levels.

Many scientists believe that it is difficult for an individual to consume more than 15 mg/d α-tocopherol form food (RRR-α-tocopherol) alone, without increasing fat intake above recommended levels [42].

#### **3. Vitamin E status**

Unlike vitamins A and D, vitamin E does not have a specific carrier protein in the plasma. Instead, it is rapidly transferred from chylomicra to plasma lipoproteins, to which it binds nonspecifically. The metabolism of circulating chylomicra can result in tocopherols being transferred directly to tissues by partitioning into their plasma membranes, or indirectly by transfer to and between circulating lipoproteins [43]. 90% of the tocopherol is transported by the lymph, the rest by the

**173**

**Table 3.**

*Concentration of α-tocopherol in human tisseues [43].*

*Vitamin E: Recommended Intake*

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

tissues where it has a universal protective effect (**Table 3**).

dividual variation in response to ingested vitamin E [43].

portal circulation. It is stored 65% in LDL-c, 8% in VLDL and about 24% in HDLc. There is a close correlation between tocopherol concentration and total plasma lipid content [44]. These transport processes can be disrupted under dyslipidemic conditions. Patients with hypercholesterolemia and/or hypertriglyceridemia show reduced plasma uptake of newly absorbed vitamin E [43]. Vitamin E is present in all

All tocopherols and tocotrienols belonging to the vitamin E family are absorbed from the intestine to a comparable extent and are subsequently transported via chylomicrons and HDL-c to the liver. Within liver, α-tocopherol is sorted out and is distributed to the bloodstream via VLDL and HDL-c [45]. Consequently, among all vitamin E varieties α-tocopherol is present at the highest proportion in the body, followed by γ-tocopherol. Inversely, tocotrienols are usually not found in tissues [46]. That postprandial levels of tocopherols exceed those of tocotrienols reflects the more rapid metabolic degradation of the latter [43]. In the meantime, only minimal concentrations of β- and δ-tocopherols are found in the blood plasma. An advantageous distribution of α-tocopherol in comparison to other vitamin E forms comes from a faster metabolic rate of the other tocopherols as well as from the α-tocopherol transfer protein (α-TTP). Because of this affinity, α-tocopherol is largely excreted through the urine, while most of the absorbed β-, γ- and δ-tocopherol will be secreted into the bile and subsequently excreted in the feces [13]. Nevertheless, as each class of lipoproteins derives its tocopherols ultimately from chylomicra, α-tocopherol transport by the latter is the major source of interin-

Until today and nearly a century after the discovery of vitamin E [1], the molecular mechanisms controlling cellular sorting and preferential retention of one of the

As with other serum nutrients, vitamin E concentrations are affected primarily by age and a variety of lifestyle factors (obesity, smoking, alcohol consumption, etc.) [47]. Differences in the serum and tissue levels of vitamin E have been studied on different occasions. According to Campbell et al. [48] vitamin E decreased in

**μg/g Tissue μg/g Lipid**

eight vitamin E congeners, α-tocopherol, are still incompletely understood.

**Tissue α-tocopherol**

Adipose 150 0.2 Adrenal 132 0.7 Hypophysis 40 1.2 Testis 40 1.0 Platelets 30 1.3 Heart 20 0.7 Muscle 19 0.4 Liver 13 0.3 Ovary 11 0.6 Plasma 9.5 1.4 Uterus 9 0.7 Kidney 7 0.3 Erythrocytes 2.3 0.5

#### *Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

United States exceeds 700% of the estimated average requirement.

men [32].

the Asian-Pacific region.

ages and socio-economic backgrounds" [38].

vitamin E intake and plasma α-tocopherol levels.

intake above recommended levels [42].

**3. Vitamin E status**

Eastern Europe, Africa, Asia (India), and South America [37].

Although the recommended amount of vitamin E is higher for men than for women, Dutch women consume less vitamin E more often compared to Dutch

Numerous research groups analyzing compliance to the vitamin E intake recommendations in Americans have found that a significant number of individuals consume insufficient amount [33, 34]. Data by Traber [35] suggest that more than 90% of United States Americans consume insufficient amounts of vitamin E from natural sources. Bjelakovic et al. [36] claims that when combined with the dietary ingestion, the total intake of vitamin E of antioxidant supplement users in the

A systematic review (2000–2012) by Péter et al. [37] focused on vitamin E intake levels and serum concentrations in order to obtain a global overview of α-tocopherol status. The authors state that only 17 studies (12.9%) included both intake data as well as vitamin E status measured in blood. Most of the studies (132) were conducted in Europe (47.7%), followed by North America (24.2%), and the Western Pacific region (14.8%). Worldwide, 82% of the population had a vitamin E intake below 15 mg/d, 91% in North and South America, 80% in Europe and 79% in

Nutrient intake in children and adolescents in Slovakia was studied in 1991–1994 and 1995–1999. Apart from these surveys, no nationally representative data were found for Slovakia, which would be carried out since 2000, which is why a comprehensive information on vitamin E intake and status in all age groups of the population are missing. The Slovak surveys were not indeed nationally representative but were nationwide and designed to "recruit a diverse sample of entities of different

The situation is similar in other countries, particularly in the case of Central and

Many scientists believe that it is difficult for an individual to consume more than 15 mg/d α-tocopherol form food (RRR-α-tocopherol) alone, without increasing fat

Unlike vitamins A and D, vitamin E does not have a specific carrier protein in the plasma. Instead, it is rapidly transferred from chylomicra to plasma lipoproteins, to which it binds nonspecifically. The metabolism of circulating chylomicra can result in tocopherols being transferred directly to tissues by partitioning into their plasma membranes, or indirectly by transfer to and between circulating lipoproteins [43]. 90% of the tocopherol is transported by the lymph, the rest by the

Evidence in the literature that vitamin E intake does not correlate with plasma levels of α-tocopherol is inconclusive [28, 35]. Previous studies have shown that total α-tocopherol intake was positively associated with the plasma α-tocopherol levels [28], while the main indicator of plasma α-tocopherol concentration was the intake of vitamin E supplements [28]. However, other studies have shown that plasma concentrations of α-tocopherol correlated weakly with dietary vitamin E ingestion [16]. The reasons for the lack of a conclusive correlation may lie in the variations of the activity of the α-tocopherol transfer protein [35], genes involved in lipid metabolism [28, 39] and micronutrients with a synergistic effect, such as vitamin C [28, 40]. Niki et al. [41] revealed that lipid peroxidation and oxidative damage may lead to decline in the levels of plasma and tissue α-tocopherol, which may be another plausible argument for different relationships observed between the

**172**

portal circulation. It is stored 65% in LDL-c, 8% in VLDL and about 24% in HDLc. There is a close correlation between tocopherol concentration and total plasma lipid content [44]. These transport processes can be disrupted under dyslipidemic conditions. Patients with hypercholesterolemia and/or hypertriglyceridemia show reduced plasma uptake of newly absorbed vitamin E [43]. Vitamin E is present in all tissues where it has a universal protective effect (**Table 3**).

All tocopherols and tocotrienols belonging to the vitamin E family are absorbed from the intestine to a comparable extent and are subsequently transported via chylomicrons and HDL-c to the liver. Within liver, α-tocopherol is sorted out and is distributed to the bloodstream via VLDL and HDL-c [45]. Consequently, among all vitamin E varieties α-tocopherol is present at the highest proportion in the body, followed by γ-tocopherol. Inversely, tocotrienols are usually not found in tissues [46]. That postprandial levels of tocopherols exceed those of tocotrienols reflects the more rapid metabolic degradation of the latter [43]. In the meantime, only minimal concentrations of β- and δ-tocopherols are found in the blood plasma. An advantageous distribution of α-tocopherol in comparison to other vitamin E forms comes from a faster metabolic rate of the other tocopherols as well as from the α-tocopherol transfer protein (α-TTP). Because of this affinity, α-tocopherol is largely excreted through the urine, while most of the absorbed β-, γ- and δ-tocopherol will be secreted into the bile and subsequently excreted in the feces [13]. Nevertheless, as each class of lipoproteins derives its tocopherols ultimately from chylomicra, α-tocopherol transport by the latter is the major source of interindividual variation in response to ingested vitamin E [43].

Until today and nearly a century after the discovery of vitamin E [1], the molecular mechanisms controlling cellular sorting and preferential retention of one of the eight vitamin E congeners, α-tocopherol, are still incompletely understood.

As with other serum nutrients, vitamin E concentrations are affected primarily by age and a variety of lifestyle factors (obesity, smoking, alcohol consumption, etc.) [47].

Differences in the serum and tissue levels of vitamin E have been studied on different occasions. According to Campbell et al. [48] vitamin E decreased in


#### **Table 3.**

*Concentration of α-tocopherol in human tisseues [43].*

participants aged over 80 years, which may be associated with a generally reduced food intake in elderly people. Inversely, hepatic levels of vitamin E have been reported to be unaffected by age [49]. According to other reports, increased serum concentrations of vitamin E were found in people older than 60 years [47, 50, 51], which may be explained by an age-dependent rise in the levels of serum cholesterol and lipoproteins [50]. Arguabely, this phenomenon may exhibit protective effects against extensive lipid peroxidation occuring as a side effect of aging [49, 52]. In the meantime, Succari et al. [51] hypothesize that lifestyle and age-associated changes independent of serum cholesterol/lipoprotein levels could be responsible for an increased vitamin E level observed in elderly French women [53].

With respect to smoking as an important factor contributing to the fluctuations of vitamin E, Al-Azemi et al. [54] and Shah et al. [55] reported that smokers presented with lower serum concetrations of α-tocopherol in comparison to nonsmokers (**Table 4**).

The presence of 5-nitro-gamma-tocopherol in the blood plasma of smokers indicates that vitamin E can be nitrated by reactive nitrogen species heavely overproduced during smoking, coupled with inflammatory processes frequently observed in smokers. This process will then enhance the turnover of tocopherols and lead to a reduction of carboxyethyl-chromanyl metabolites in smokers [56].

Alcoholism could also contribute to decreased serum levels of α-tocopherol, partially due to malnutrition [57]. *In vivo* studies have also revealed that chronic consumption of alcohol is associated with lower hepatic levels of α-tocopherol, which may be caused by decreased amounts of α-tocopherol in the hepatic mitochondria [57–59].

#### **3.1 Assessment of vitamin E status**

Vitamin E status is often assessed by determining the concentration of α-tocopherol in blood plasma or serum [60].

Human studies published in the 1950s and 1960s aimed to address vitamin E levels that could prevent peroxide-induced hemolysis as well as a reduction in the cell survival in subjects on a vitamin E-deprived diet over a period of six years [1]. It was found that ingestion of 12 mg α-tocopherol/day was sufficient to reach a threshold level of 12 μmol/L serum α-tocopherol exhibiting protective effects on the organism. This conclusion was then extrapolated to the definition of the Estimated Average Requirement (EAR) which became the theoretical ground for RDA calculated. Even though this approach has been heavely criticized, currently there is no alternative for the RDA calculation that has been agreed upon. Accordingly, the American Institute of Medicine (IOM) defined the levels of serum α-tocopherol as deficient, if these are to be found below 12 μmol/L [16].


**175**

18.5 μmol/L [4].

*Vitamin E: Recommended Intake*

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

commonly analyzed after 12–24 h of fasting.

is recommended according to D-A-CH association [61].

mL, or 11.5 μmol/L is considered deficient [4].

cardiovascular diseases below this limit [24].

**3.2 Vitamin E status in the population**

ized for ensuring optimal diagnosis and comparability [59].

reliable marker for an adequate vitamin status in humans.

Thus, more accurate vitamin E levels may be assessed as follows:

To evaluate tocopherol levels in the human body, the serum concentration is

Tocopherol exchanges rapidly between the lipoproteins mediated by the phospholipid transfer protein [43], and between lipoproteins and erythrocyte (about one-quarter of total erythrocyte vitamin E turns over every hour); thus, the level of vitamin E and the concentration of erythrocytes are strongly correlated (as red blood cells carry 15–25% of total vitamin E found in the blood) [43]. As vitamin E is a membrane-protective molecule, tocopherol levels found in the plasma are inversely correlated to the sensitivity toward oxidative hemolysis. This association makes the plasma levels of alpha-tocopherol a suitable indicator of vitamin E status. In the healthy population concentrations above 0.5 mg/dL (12 μmol/L) are associated with hemolysis prevention and are accepted as indicators of nutritional adequacy [43]. For adults, an amount of 0.5–2 mg tocopherols/100 mL plasma (12–46 μmol/L)

As noted by Traber [35], circulating α-TOH concetrations are not necessarily a

Serum concentrations of vitamin E are significantly affected by the levels of lipids, which is why they do not reflect its tissue levels in a consistent manner [62].

effective serum vitamin E level tocopherol / =α− (cholesterol triglycerides + )

Based on the equation, a ratio above 0.8 mg α-tocopherol/g total lipids is considered to be normal. In the case of individuals with normal levels of serum lipids, the concentration of serum α-tocopherol levels serve as an adequate estimate of vitamin E sufficiency. Any cocentration of alpha-tocopherol lower than 0.5 mg/dL or 5 μg/

Supplementation of α-TOH, for example increased amount of α-CEHC in urine. Hence, α-CEHC in urine can be used as a marker for α-TOH status in healthy humans [63] or at a minimum as a marker for an adequate level of α-TOH [64]. Péter et al. [37] determined ranges of α-tocopherol concentrations based on a systematic review of the global state of alpha-tocopherol as the concentration in functional deficiency range (≤12 μmol/L), concentration between functional deficiency and desirable threshold (13–29 μmol/L), and finally concentration in desirable range (≥30 μmol/L). Alpha-tocopherol levels less than 20 μmol/L, is yet a more conservative cut-off marker, because of the apparent increased risk for

More attention should be given to further explore of measuring vitamin E serum levels as they may be a much more useful marker to assess vitamin E status rather than relying on dietary intake reports. Determining the right analytical parameters for evaluating vitamin E status is critically important; however it is also crucial that new analytical parameters and procedures be validated, optimized and standard-

Plasma α-tocopherol concentrations in humans range from 11 to 37 μmol/L, whereas γ-tocopherol concentrations are roughly 2–5 μmol/L, and tocotrienol concentrations are less than 1 μmol/L in non-supplemented humans [65]. In an US national survey, the 5th percentile for vitamin E serum levels was 0.62 mg/dL or 14.3 μmol/L, and the 25th percentile was 0.79 mg/dL or

#### **Table 4.**

*Plasma α- and γ-tocopherol in smokers and non-smokers [56].*

#### *Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

increased vitamin E level observed in elderly French women [53].

reduction of carboxyethyl-chromanyl metabolites in smokers [56].

smokers (**Table 4**).

chondria [57–59].

12 μmol/L [16].

**3.1 Assessment of vitamin E status**

α-tocopherol in blood plasma or serum [60].

**Metabolite Non-smokers**

*Plasma α- and γ-tocopherol in smokers and non-smokers [56].*

participants aged over 80 years, which may be associated with a generally reduced food intake in elderly people. Inversely, hepatic levels of vitamin E have been reported to be unaffected by age [49]. According to other reports, increased serum concentrations of vitamin E were found in people older than 60 years [47, 50, 51], which may be explained by an age-dependent rise in the levels of serum cholesterol and lipoproteins [50]. Arguabely, this phenomenon may exhibit protective effects against extensive lipid peroxidation occuring as a side effect of aging [49, 52]. In the meantime, Succari et al. [51] hypothesize that lifestyle and age-associated changes independent of serum cholesterol/lipoprotein levels could be responsible for an

With respect to smoking as an important factor contributing to the fluctuations of vitamin E, Al-Azemi et al. [54] and Shah et al. [55] reported that smokers presented with lower serum concetrations of α-tocopherol in comparison to non-

The presence of 5-nitro-gamma-tocopherol in the blood plasma of smokers indicates that vitamin E can be nitrated by reactive nitrogen species heavely overproduced during smoking, coupled with inflammatory processes frequently observed in smokers. This process will then enhance the turnover of tocopherols and lead to a

Alcoholism could also contribute to decreased serum levels of α-tocopherol, partially due to malnutrition [57]. *In vivo* studies have also revealed that chronic consumption of alcohol is associated with lower hepatic levels of α-tocopherol, which may be caused by decreased amounts of α-tocopherol in the hepatic mito-

Vitamin E status is often assessed by determining the concentration of

Human studies published in the 1950s and 1960s aimed to address vitamin E levels that could prevent peroxide-induced hemolysis as well as a reduction in the cell survival in subjects on a vitamin E-deprived diet over a period of six years [1]. It was found that ingestion of 12 mg α-tocopherol/day was sufficient to reach a threshold level of 12 μmol/L serum α-tocopherol exhibiting protective effects on the organism. This conclusion was then extrapolated to the definition of the Estimated Average Requirement (EAR) which became the theoretical ground for RDA calculated. Even though this approach has been heavely criticized, currently there is no alternative for the RDA calculation that has been agreed upon. Accordingly, the American Institute of Medicine (IOM) defined the levels of serum α-tocopherol as deficient, if these are to be found below

α-tocopherol (μmol/L) 16.0 ± 4.0 15.9 ± 5.0 γ-tocopherol (μmol/L) 1.76 ± 0.98 1.70 ± 0.69 5-nitro-γ-tocopherol (nmol/L) 4.03 ± 3.10\* 8.02 ± 8.33

**(n = 19)**

**Smokers (n = 15)**

**174**

*Note: \**

**Table 4.**

*P < 0.05.*

To evaluate tocopherol levels in the human body, the serum concentration is commonly analyzed after 12–24 h of fasting.

Tocopherol exchanges rapidly between the lipoproteins mediated by the phospholipid transfer protein [43], and between lipoproteins and erythrocyte (about one-quarter of total erythrocyte vitamin E turns over every hour); thus, the level of vitamin E and the concentration of erythrocytes are strongly correlated (as red blood cells carry 15–25% of total vitamin E found in the blood) [43]. As vitamin E is a membrane-protective molecule, tocopherol levels found in the plasma are inversely correlated to the sensitivity toward oxidative hemolysis. This association makes the plasma levels of alpha-tocopherol a suitable indicator of vitamin E status. In the healthy population concentrations above 0.5 mg/dL (12 μmol/L) are associated with hemolysis prevention and are accepted as indicators of nutritional adequacy [43].

For adults, an amount of 0.5–2 mg tocopherols/100 mL plasma (12–46 μmol/L) is recommended according to D-A-CH association [61].

As noted by Traber [35], circulating α-TOH concetrations are not necessarily a reliable marker for an adequate vitamin status in humans.

Serum concentrations of vitamin E are significantly affected by the levels of lipids, which is why they do not reflect its tissue levels in a consistent manner [62]. Thus, more accurate vitamin E levels may be assessed as follows:

effective serum vitamin E level tocopherol / =α− (cholesterol triglycerides + )

Based on the equation, a ratio above 0.8 mg α-tocopherol/g total lipids is considered to be normal. In the case of individuals with normal levels of serum lipids, the concentration of serum α-tocopherol levels serve as an adequate estimate of vitamin E sufficiency. Any cocentration of alpha-tocopherol lower than 0.5 mg/dL or 5 μg/ mL, or 11.5 μmol/L is considered deficient [4].

Supplementation of α-TOH, for example increased amount of α-CEHC in urine. Hence, α-CEHC in urine can be used as a marker for α-TOH status in healthy humans [63] or at a minimum as a marker for an adequate level of α-TOH [64].

Péter et al. [37] determined ranges of α-tocopherol concentrations based on a systematic review of the global state of alpha-tocopherol as the concentration in functional deficiency range (≤12 μmol/L), concentration between functional deficiency and desirable threshold (13–29 μmol/L), and finally concentration in desirable range (≥30 μmol/L). Alpha-tocopherol levels less than 20 μmol/L, is yet a more conservative cut-off marker, because of the apparent increased risk for cardiovascular diseases below this limit [24].

More attention should be given to further explore of measuring vitamin E serum levels as they may be a much more useful marker to assess vitamin E status rather than relying on dietary intake reports. Determining the right analytical parameters for evaluating vitamin E status is critically important; however it is also crucial that new analytical parameters and procedures be validated, optimized and standardized for ensuring optimal diagnosis and comparability [59].

#### **3.2 Vitamin E status in the population**

Plasma α-tocopherol concentrations in humans range from 11 to 37 μmol/L, whereas γ-tocopherol concentrations are roughly 2–5 μmol/L, and tocotrienol concentrations are less than 1 μmol/L in non-supplemented humans [65].

In an US national survey, the 5th percentile for vitamin E serum levels was 0.62 mg/dL or 14.3 μmol/L, and the 25th percentile was 0.79 mg/dL or 18.5 μmol/L [4].

Results on vitamin status presented in a review from Valtuena et al. [66] and Böhm et al. [60] were published between 2001 and 2011. Besides data from the United States and India, several studies were conducted in Europe (Austria, France, Germany, Greece, Slovakia - only children and adolescents, and Sweden). Intake surveys as well as the assessment of vitamin E concentrations in the blood plasma/ serum of children and teenagers were performed in a number of countries. While the intake oscillated between 2.1 and 12.2 mg/dL, the plasma or serum levels of vitamin E ranged between 16.9 and 29.2 μmol/L.

In the case of rural Nepal, about 33% of pregnant females were affected by a severe vitamin E deficiency (less than 10 μmol α-tocopherol/L serum) [67]. Vitamin E status was found to be even worse in Bangladesh, where almost 65% of women in early pregnancy presented with a more severe vitamin E deficiency (< 9.3 μmol α-tocopherol/L serum). On the other hand, a recent study has reported that more than 65% of South Korean adults presented with suboptimal blood vitamin E levels (12–30 μmol α-tocopherol/L serum; lower than the threshold set at 30 μmol/L, as per recommendations by the German Federal Ministry of Health Consensus Statement [68]), while 25% of the participants were vitamin E deficient (less than 12 μmol α-tocopherol/L serum) [46]. Zhao et al. [28] have demonstrated a positive relationship between vitamin E intake and plasma α-tocopherol concentration and plasma n-3 PUFA profile (**Table 2**).

Malik et al. [69] collated for the purpose of review limited available data from 31 studies on vitamin E status in healthy people from Asia, the most populated continent.

Despite a substantial quantity of reports focused on the evaluation of the vitamin E status, data on the extent of vitamin E deficiency from Asian countries, such as India, are lacking. In this sense, information on validated biomarkers for vitamin E status are missing, and no consensus exists on cut off values to define a possible vitamin E deficiency. As such, a possible interpretation of the collected data is complicated.

With respect to a threshold concentration of 20 μmol/L as recommended by various nutritionists [35], data collected from previous studies reveal that 27% Americans, 80% Middle Eastern/Africans, 62% Asians, and 19% Europeans presented with serum levels below this value. Average blood serum concentrations of 20 μmol/L α-tocopherol can be acheived in normal adults on a balanced diet, which includes nuts, seeds and whole grains. Inversely, only 21% of the total data revised in global review [17] indicated a desirable serum concentration of α-tocopherol equal to or above 30 μmol/L. Furthermore, 66% of all subentries ranged between 12 and 30 μmol/L.

Several prospective observational studies (**Table 5**) suggested that a serum α-tocopherol concentration of 30 μmol/L or above has beneficial effects on human health, with alleged applications including prevention of cardiovascular disease and different types of cancer, higher baseline serum concentrations of α-tocopherol were associated with lower total and cause-specific mortality; the lowest total mortality was observed at 30 μmol/L serum α-tocopherol concentrations.

On the other hand, results from the large SELECT trial reveal that vitamin E supplements (400 IU/day [180 mg/d] as *dl*-alpha-tocopheryl acetate) may harm adult men in the general population by increasing their risk for prostate cancer [76]. Follow-up studies are assessing whether the cancer risk was associated with baseline blood amounts of vitamin E and selenium prior to the consumption of supplements as well as whether changes in one or more genes might increase a man's risk to develop prostate cancer while consuming supplemental vitamin E.

#### **3.3 Deficiency of vitamin E (hypovitaminosis)**

There exists a subtle difference in definitions describing levels of vitamin intake [59]. Whereas vitamin deficiency is caused by diseases, metabolic disorders [31], or

**177**

*Vitamin E: Recommended Intake*

Mangialasche et al. [70]

Meydani et al. [72] Meydani et al. [73]

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

Wright et al. [71] To examine whether

Pallast et al. [74] The effect of 50- and

100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons

To examined the relation of all plasma vitamin E forms and markers of vitamin E damage to mild cognitive impairment (MCI) and Alzheimer's disease (AD)

baseline serum α-tocopherol concentrations are associated with total and cause-specific mortality

The effect of vitamin E supplementation and in vivo immune response in healthy elderly subjects

**Source Aim of the study Treatment Results and conclusion of** 

plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γtocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people

A prospective cohort study Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC)

29 092 Finnish male smokers aged 50–69 y who participated in

Fasting serum α-TOH was measured at baseline by using

Elderly (n = 88); age ≥ 65

60, 200, 800 mg/d for

Elderly (n = 161); age

baseline plasma α-TOH 29.4 ± 6.9 μmol/L

50, 100 mg/d for 6 months

65–80

Study

the study

HPLC

235 days

**the study**

• Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.

• Higher circulating concentrations of α-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers

• ⇑DTH and antibody titer to hepatitis B and tetanus

• with 200 and 800 mg • Subjects in the upper tertile of serum α-TOH concentration (>48.4 μmol/L [2.08 mg/dL]) after supplementation • dose of 200 IU vitamin E was shown to be most effective in improving T cell–mediated functions, compared with 60- or 800-IU/d doses

• ⇑Number of

positive DTH response with 100 mg • ⇑Diameter of induration of DTH response in a • ⇔ IL-2 production • significant trend toward increased postintervention plasma α-TOH • 50 mg supll: ⇑ by 10.1 ± 5.0 μmol/L • 100 mg supll: ⇑ by 15.8 ± 7.4 μmol/L


#### *Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

vitamin E ranged between 16.9 and 29.2 μmol/L.

plasma n-3 PUFA profile (**Table 2**).

Results on vitamin status presented in a review from Valtuena et al. [66] and Böhm et al. [60] were published between 2001 and 2011. Besides data from the United States and India, several studies were conducted in Europe (Austria, France, Germany, Greece, Slovakia - only children and adolescents, and Sweden). Intake surveys as well as the assessment of vitamin E concentrations in the blood plasma/ serum of children and teenagers were performed in a number of countries. While the intake oscillated between 2.1 and 12.2 mg/dL, the plasma or serum levels of

In the case of rural Nepal, about 33% of pregnant females were affected by a severe vitamin E deficiency (less than 10 μmol α-tocopherol/L serum) [67]. Vitamin E status was found to be even worse in Bangladesh, where almost 65% of women in early pregnancy presented with a more severe vitamin E deficiency (< 9.3 μmol α-tocopherol/L serum). On the other hand, a recent study has reported that more than 65% of South Korean adults presented with suboptimal blood vitamin E levels (12–30 μmol α-tocopherol/L serum; lower than the threshold set at 30 μmol/L, as per recommendations by the German Federal Ministry of Health Consensus Statement [68]), while 25% of the participants were vitamin E deficient (less than 12 μmol α-tocopherol/L serum) [46]. Zhao et al. [28] have demonstrated a positive relationship between vitamin E intake and plasma α-tocopherol concentration and

Malik et al. [69] collated for the purpose of review limited available data from 31 studies on vitamin E status in healthy people from Asia, the most populated continent. Despite a substantial quantity of reports focused on the evaluation of the vitamin E status, data on the extent of vitamin E deficiency from Asian countries, such as India, are lacking. In this sense, information on validated biomarkers for vitamin E status are missing, and no consensus exists on cut off values to define a possible vitamin E deficiency. As such, a possible interpretation of the collected data is complicated. With respect to a threshold concentration of 20 μmol/L as recommended by various nutritionists [35], data collected from previous studies reveal that 27% Americans, 80% Middle Eastern/Africans, 62% Asians, and 19% Europeans presented with serum levels below this value. Average blood serum concentrations of 20 μmol/L α-tocopherol can be acheived in normal adults on a balanced diet, which includes nuts, seeds and whole grains. Inversely, only 21% of the total data revised in global review [17] indicated a desirable serum concentration of α-tocopherol equal to or above 30 μmol/L.

Furthermore, 66% of all subentries ranged between 12 and 30 μmol/L.

develop prostate cancer while consuming supplemental vitamin E.

**3.3 Deficiency of vitamin E (hypovitaminosis)**

Several prospective observational studies (**Table 5**) suggested that a serum α-tocopherol concentration of 30 μmol/L or above has beneficial effects on human health, with alleged applications including prevention of cardiovascular disease and different types of cancer, higher baseline serum concentrations of α-tocopherol were associated with lower total and cause-specific mortality; the lowest total mortality was observed at 30 μmol/L serum α-tocopherol concentrations.

On the other hand, results from the large SELECT trial reveal that vitamin E supplements (400 IU/day [180 mg/d] as *dl*-alpha-tocopheryl acetate) may harm adult men in the general population by increasing their risk for prostate cancer [76]. Follow-up studies are assessing whether the cancer risk was associated with baseline blood amounts of vitamin E and selenium prior to the consumption of supplements as well as whether changes in one or more genes might increase a man's risk to

There exists a subtle difference in definitions describing levels of vitamin intake [59]. Whereas vitamin deficiency is caused by diseases, metabolic disorders [31], or

**176**


#### **Table 5.**

*Selection of prospective observational studies regarding serum α-tocopherol concentrations.*

impaired absorption of the vitamin. Vitamin undersupply is characterized as an intake issue and they can result from insufficient dietary intake, which does not achieve reference values [31]. Because of an abundance of tocopherols in the human diet, its deficiency is rare except in individuals with pancreatic insufficiency or other conditions causing substantial fat malabsorption, or protein-energy malnutrition and may be caused by rare genetic defects affecting vitamin E metabolism or transport [4].

Vitamin E can be mobilized from adipose tissue for a relatively long time [77], so that the symptoms of slightly vitamin E deficiency may manifest following many years, even decades [59].

Nevertheless, a severe vitamin E deficiency may reveal itself almost immediately in acute symptoms such as neuro- and myopathy, as vitamin E is essential for an optimal development and condition of the central nervous system [78]. Insufficient vitamin E saturation can occur in intestinal resection, in severe liver disease (e.g., biliary cirrhosis) and in cystic fibrosis (less frequently). In the absence of vitamin E, the accumulation of radicals with lipoperoxidation in humans leads to various defects in membrane function, muscle metabolism and the nervous system [1]. These reactions should be considered if vitamin E is not absorbed or cannot be used.

Next to dietary habits, hereditary disorders are known to cause primary and secondary vitamin E deficiencies or inadequate vitamin E bioavailability [59].

Although several foods contain naturally occurring sources of vitamin E, it is frequently the case that the intake recommendations are not achieved. Several other dietary factors affect the need for vitamin E. Two are most important in this regard: selenium and PUFAs.

Selenium spares the need for vitamin E. In contrast, the dietary intake of PUFAs directly affects the need for vitamin E. Previous studies have established values neccessary for the incremental impact of dietary PUFAs on the nutritional demand for vitamin E in the range of 0.18–0.60 mg α-tocopherol/g PUFA. Even though the upper limit of the established range is often noted as a guideline to estimate the needs for vitamin E, it must be said that there is no consensus with respect to the quantitation of this certainly critical relationship [43].

**179**

**4. Conclusions**

*Vitamin E: Recommended Intake*

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

**3.4 Excess intake of vitamin E (hypervitaminosis)**

appear to be able to tolerate rather high levels [43].

been revealed to have any persistent adverse effects [43].

Vitamin E has been viewed as one of the least toxic of the vitamins. No syndrome of acute vitamin E toxicity has been described. Both animals and humans

When obtained from food sources alone, vitamin E has no documented evidence of toxicity. However, evidence of pro-oxidant damage has been found to be associated with supplements, but usulally only at very high doses (for example at >1000 mg/d) [13, 79]. In the case of humans, daily doses as high as 400 IU are recognized to be nontoxic, while high oral dosages reaching up to 3200 IU, have not

These opinions were questioned a few years ago by a meta-analysis comprising 19 trials, and hypothesizing that supplemental vitamin E (≥400 IU/day) could contribute to an all-cause mortality [43]. Nevertheless, a recently published meta-analysis which comprised even a larger set (57) of trial data, suggested that vitamin E supplements do not have an impact on the all-cause mortality even at doses up to 5500 IU/ day [80]. In premature infants, high-dose vitamin E treatment was associated with increased risk for sepsis. Chronic intake of supplements in excess of 400 IU daily has been associated with increased risk of hemorrhage and all-cause mortality [4].

Factors, they could influence the interpretation of data from studies focused on intake of vitamin E, are several: e.g., the NHANES study [25] reported the most data on serum concentrations, differentiated by gender, age group, and race; the EPIC study [81] focused on intake levels, differentiated by country, gender, and age categories, whereas race was not differentiated. No distinction has been made between representative and nonrepresentative studies. No consideration could be given to the quality of the dietary assessment data or to the standardization of blood assays in different studies, and supplement use was not always sufficiently reported [17]. Higher vitamin E doses than the RDA seem to significantly increase the general mortality. In a meta-analysis by Bjelakovic et al. [36] vitamin E at a dose above the RDA (> 15 mg) significantly increased the mortality of the subjects (RR 1.03, 95% CI 1.00 to 1.05, I2 = 0%). The effects of vitamin E on the mortality seemed neutral when administered in doses within the RDAs, however the available data are sparse. In observational studies, high α-tocopherol intake was reported to be associated with a lower risk of cardiovascular disease, type 2 diabetes, hypertension, cancer, loss of cognitive function, and Alzheimer's disease [82]. Nevertheless, randomized, placebo-controlled intervention trials did not support these observations [25]. Recent studies speculate about possible adverse effects of high dose vitamin E supplements [25]. To avoid risks associated with high-dose nutritional supplements, emphasis on an

optimal food intake of vitamin E within the range of the DRI is crucial.

Dietary intake recommendations for vitamin E are set in many countrie, however there is an ongoing need to review, establish, and harmonize dietary vitamin E requirements and daily allowance across populations. It has become clear that despite a major scientific progress, new understanding on a molecular level, as well as a broad variety of animal and human studies generating valuable data, the challenge to agree upon general and uniform dietary intake recommendations for vitamin E remains persistent. The key element in defining the recommended dietary recommendations for essential vitamin E is, of course, the biomarker chosen, and all agencies and science authorithis are trying to agree on a suitable biomarker. In future, more dietary intake data as well as status data are needed for specific

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

To determine the tocopherol concentrations in serum after two diets with identical nutrient content but with different fat quality

**Source Aim of the study Treatment Results and conclusion of** 

males)

20 moderately hyperlipidemic, healthy subjects (6 females and 14

double-blind crossover study

two isoenergetic diets in a randomized order during two 3-week periods, wash-out period of 3–4 weeks

**the study**

• ⇑lipid-corrected serum concentrations of α- and γ-TOH during the diet rich in rapeseed oil (by 7 and 23%, respectively, P < 0.001) compared with on the baseline diet, while these concentrations ⇓ (by 5 and 37%, respectively, P < 0.01) during the diet rich in saturated fat • ⇓ ratio between α- and γ-TOH significantly during the rapeseed oil diet (−23%, P < 0.01) and ⇑ (+46%, P < 0.001) during the

butter diet

impaired absorption of the vitamin. Vitamin undersupply is characterized as an intake issue and they can result from insufficient dietary intake, which does not achieve reference values [31]. Because of an abundance of tocopherols in the human diet, its deficiency is rare except in individuals with pancreatic insufficiency or other conditions causing substantial fat malabsorption, or protein-energy malnutrition and may be caused by rare genetic defects affecting vitamin E metabolism or transport [4]. Vitamin E can be mobilized from adipose tissue for a relatively long time [77], so that the symptoms of slightly vitamin E deficiency may manifest following many

*Selection of prospective observational studies regarding serum α-tocopherol concentrations.*

Nevertheless, a severe vitamin E deficiency may reveal itself almost immediately in acute symptoms such as neuro- and myopathy, as vitamin E is essential for an optimal development and condition of the central nervous system [78]. Insufficient vitamin E saturation can occur in intestinal resection, in severe liver disease (e.g., biliary cirrhosis) and in cystic fibrosis (less frequently). In the absence of vitamin E, the accumulation of radicals with lipoperoxidation in humans leads to various defects in membrane function, muscle metabolism and the nervous system [1]. These reactions should be considered if vitamin E is not absorbed or cannot be used. Next to dietary habits, hereditary disorders are known to cause primary and secondary vitamin E deficiencies or inadequate vitamin E bioavailability [59]. Although several foods contain naturally occurring sources of vitamin E, it is frequently the case that the intake recommendations are not achieved. Several other dietary factors affect the need for vitamin E. Two are most important in this regard:

Selenium spares the need for vitamin E. In contrast, the dietary intake of PUFAs

directly affects the need for vitamin E. Previous studies have established values neccessary for the incremental impact of dietary PUFAs on the nutritional demand for vitamin E in the range of 0.18–0.60 mg α-tocopherol/g PUFA. Even though the upper limit of the established range is often noted as a guideline to estimate the needs for vitamin E, it must be said that there is no consensus with respect to the

quantitation of this certainly critical relationship [43].

**178**

years, even decades [59].

Ohrvall et al. [75]

**Table 5.**

selenium and PUFAs.

#### **3.4 Excess intake of vitamin E (hypervitaminosis)**

Vitamin E has been viewed as one of the least toxic of the vitamins. No syndrome of acute vitamin E toxicity has been described. Both animals and humans appear to be able to tolerate rather high levels [43].

When obtained from food sources alone, vitamin E has no documented evidence of toxicity. However, evidence of pro-oxidant damage has been found to be associated with supplements, but usulally only at very high doses (for example at >1000 mg/d) [13, 79]. In the case of humans, daily doses as high as 400 IU are recognized to be nontoxic, while high oral dosages reaching up to 3200 IU, have not been revealed to have any persistent adverse effects [43].

These opinions were questioned a few years ago by a meta-analysis comprising 19 trials, and hypothesizing that supplemental vitamin E (≥400 IU/day) could contribute to an all-cause mortality [43]. Nevertheless, a recently published meta-analysis which comprised even a larger set (57) of trial data, suggested that vitamin E supplements do not have an impact on the all-cause mortality even at doses up to 5500 IU/ day [80]. In premature infants, high-dose vitamin E treatment was associated with increased risk for sepsis. Chronic intake of supplements in excess of 400 IU daily has been associated with increased risk of hemorrhage and all-cause mortality [4].

Factors, they could influence the interpretation of data from studies focused on intake of vitamin E, are several: e.g., the NHANES study [25] reported the most data on serum concentrations, differentiated by gender, age group, and race; the EPIC study [81] focused on intake levels, differentiated by country, gender, and age categories, whereas race was not differentiated. No distinction has been made between representative and nonrepresentative studies. No consideration could be given to the quality of the dietary assessment data or to the standardization of blood assays in different studies, and supplement use was not always sufficiently reported [17].

Higher vitamin E doses than the RDA seem to significantly increase the general mortality. In a meta-analysis by Bjelakovic et al. [36] vitamin E at a dose above the RDA (> 15 mg) significantly increased the mortality of the subjects (RR 1.03, 95% CI 1.00 to 1.05, I2 = 0%). The effects of vitamin E on the mortality seemed neutral when administered in doses within the RDAs, however the available data are sparse.

In observational studies, high α-tocopherol intake was reported to be associated with a lower risk of cardiovascular disease, type 2 diabetes, hypertension, cancer, loss of cognitive function, and Alzheimer's disease [82]. Nevertheless, randomized, placebo-controlled intervention trials did not support these observations [25]. Recent studies speculate about possible adverse effects of high dose vitamin E supplements [25]. To avoid risks associated with high-dose nutritional supplements, emphasis on an optimal food intake of vitamin E within the range of the DRI is crucial.

#### **4. Conclusions**

Dietary intake recommendations for vitamin E are set in many countrie, however there is an ongoing need to review, establish, and harmonize dietary vitamin E requirements and daily allowance across populations. It has become clear that despite a major scientific progress, new understanding on a molecular level, as well as a broad variety of animal and human studies generating valuable data, the challenge to agree upon general and uniform dietary intake recommendations for vitamin E remains persistent. The key element in defining the recommended dietary recommendations for essential vitamin E is, of course, the biomarker chosen, and all agencies and science authorithis are trying to agree on a suitable biomarker. In future, more dietary intake data as well as status data are needed for specific

subgroups to adjust recommendations for vitamin E intake. However, well-founded recommendations are a reflection of current nutritional science and certainly not a definitive opinion. We are aware that research in the field of nutrition will bring new knowledge and conclusions, and that the nutritional recommendations for vitamin E within the European area will also have their dynamism and development. At present, only expertly based and transparently compiled recommendations can succeed and be applied in practical life. We believe that this emerging knowledge is worth of consideration to improve nutritional recommendations and the criteria to design the next generation of prevention trials on age-related and chronic diseases. More research is needed to understand the molecular action of metabolites and/or their targets in order to further develop therapeutic strategies and improve nutritional recommendations on vitamin E.

### **Acknowledgements**

This work has been supported by the grants of the VEGA no. 1/0180/20.

### **Conflict of interest**

The autors declare no conflict of interest.

### **Author details**

Marianna Schwarzova1 , Katarina Fatrcova-Sramkova1 , Eva Tvrda2 and Miroslava Kacaniova3 \*

1 Faculty of Agrobiology and Food Sources, Department of Human Nutrition, Slovak University of Agriculture in Nitra, Nitra, Slovak Republic

2 Faculty of Biotechnology and Food Sciences, Department of Animal Physiology, Slovak University of Agriculture in Nitra, Nitra, Slovak Republic

3 Faculty Horticulture and Landscape Engineering, Department of Fruit Science, Viticulture and Enology, Slovak University of Agriculture in Nitra, Nitra, Slovak Republic

\*Address all correspondence to: miroslava.kacaniova@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**181**

*Vitamin E: Recommended Intake*

**References**

[1] Galli F, Azzi A, Birringer M,

[2] Wolf G. The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill. J.

lipid-soluble vitamins – further adjustment needed? Lancet. 2000;**355**(9220):2013-2014. DOI: 10.1016/S0140-6736(00)02345-X

[4] Morsy TA, Alanazi AD. A minioverview of vitamin E. Journal of the Egyptian Society of Parasitology.

[5] Traber MG. Vitamin E regulatory mechanisms. Annual Review of Nutrition. 2007;**27**(1):347-362. DOI: 10.1146/annurev.nutr.27.061406.093819

[6] Halliwell B. Oxidants and human diseases: some new concepts 1. The FASEB Journal. 1987;**1**(5):358-364. DOI:

10.1096/fasebj.1.5.2824268

[7] Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview. Methods in Enzymology. 1990;**186**:1-85. DOI: 10.1016/ 0076-6879(90)86093-B

[8] Cheeseman KH, Slater TF. An introduction to free radical

[9] Morrissey PA, Quinn PB, Sheehy PJA. Newer aspects of micronutrients in chronic disease: vitamin E. Proceedings of the Nutrition

biochemistry. British medical bulletin. 1993;**49**(3):481-493. DOI: 10.1093/ oxfordjournals.bmb.a072625

[3] Traber MG, Jialal I. Measurement of

Nutr. 2005;**135**:363-366.

2020;**50**(2):247-257.

*DOI: http://dx.doi.org/10.5772/intechopen.97381*

Cook-Mills JM, Eggersdorfer M, Frank J, Cruciani G, Lorkowski S, Özer, K. Vitamin E: Emerging aspects and new directions. Free Radical Biology and Medicine. 2017;**102**:16-36. DOI: 10.1016/j.freeradbiomed.2016.09.017

Society. 1994;**53**(3):571-582. DOI:

[10] Zhang X, Feng M, Liu F, Qin L, Qu R, Li D, et al. Subacute oral toxicity of BDE-15, CDE-15, and HODE-15 in ICR male mice: assessing effects on hepatic oxidative stress and metals status and ascertaining the protective role of vitamin E. Environ Sci Pollut Res Int. 2014;**21**(3):1924-1935. DOI: 10.1007/

[11] Sokol RJ, Kayden HJ, Bettis DB, Traber MG, Neville H, Ringel S, et al. Isolated vitamin E deficiency in the absence of fat malabsorption – familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med. 1988;**111**(5):548-559. DOI: 10.5555/

uri:pii:0022214388900820

[12] Boda V, Finckh B, Durken M, Commentz J, Hellwege HH,

10.1080/00365519850186490

[13] Rizvi S, Raza ST, Faizal

Ahmed AA, Abbas S, Mahdi F. The role of vitamin E in human health and some diseases. Sultan Qaboos University Medical Journal. 2014;**14**(2):e157-e165.

[14] Azzi A, Meydani SN, Meydani M, Zingg JM. The rise, the fall and the renaissance of vitamin E. Arch. Biochem. Biophys. 2016; **595**:100-108.

[15] EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies). Scientific opinion on dietary reference values for vitamin

2015;**13**(7):4149, 72 pp. DOI: 10.2903/j.

DOI: 10.1016/j.abb.2015.11.010

E as α-tocopherol. EFSA J.

efsa.2015.4149

Kohlschutter A. Monitoring erythrocyte free radical resistance in neonatal blood microsamples using a peroxyl radicalmediated haemolysis test. Scand J Clin Lab Invest. 1998;**58**(4):317-322. DOI:

10.1079/PNS19940066

s11356-013-2084-0

*Vitamin E: Recommended Intake DOI: http://dx.doi.org/10.5772/intechopen.97381*

#### **References**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

and improve nutritional recommendations on vitamin E.

subgroups to adjust recommendations for vitamin E intake. However, well-founded recommendations are a reflection of current nutritional science and certainly not a definitive opinion. We are aware that research in the field of nutrition will bring new knowledge and conclusions, and that the nutritional recommendations for vitamin E within the European area will also have their dynamism and development. At present, only expertly based and transparently compiled recommendations can succeed and be applied in practical life. We believe that this emerging knowledge is worth of consideration to improve nutritional recommendations and the criteria to design the next generation of prevention trials on age-related and chronic diseases. More research is needed to understand the molecular action of metabolites and/or their targets in order to further develop therapeutic strategies

, Katarina Fatrcova-Sramkova1

This work has been supported by the grants of the VEGA no. 1/0180/20.

1 Faculty of Agrobiology and Food Sources, Department of Human Nutrition,

2 Faculty of Biotechnology and Food Sciences, Department of Animal Physiology,

3 Faculty Horticulture and Landscape Engineering, Department of Fruit Science,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Viticulture and Enology, Slovak University of Agriculture in Nitra, Nitra,

Slovak University of Agriculture in Nitra, Nitra, Slovak Republic

Slovak University of Agriculture in Nitra, Nitra, Slovak Republic

\*Address all correspondence to: miroslava.kacaniova@gmail.com

provided the original work is properly cited.

\*

The autors declare no conflict of interest.

, Eva Tvrda2

**180**

**Author details**

Slovak Republic

Marianna Schwarzova1

**Acknowledgements**

**Conflict of interest**

and Miroslava Kacaniova3

[1] Galli F, Azzi A, Birringer M, Cook-Mills JM, Eggersdorfer M, Frank J, Cruciani G, Lorkowski S, Özer, K. Vitamin E: Emerging aspects and new directions. Free Radical Biology and Medicine. 2017;**102**:16-36. DOI: 10.1016/j.freeradbiomed.2016.09.017

[2] Wolf G. The discovery of the antioxidant function of vitamin E: the contribution of Henry A. Mattill. J. Nutr. 2005;**135**:363-366.

[3] Traber MG, Jialal I. Measurement of lipid-soluble vitamins – further adjustment needed? Lancet. 2000;**355**(9220):2013-2014. DOI: 10.1016/S0140-6736(00)02345-X

[4] Morsy TA, Alanazi AD. A minioverview of vitamin E. Journal of the Egyptian Society of Parasitology. 2020;**50**(2):247-257.

[5] Traber MG. Vitamin E regulatory mechanisms. Annual Review of Nutrition. 2007;**27**(1):347-362. DOI: 10.1146/annurev.nutr.27.061406.093819

[6] Halliwell B. Oxidants and human diseases: some new concepts 1. The FASEB Journal. 1987;**1**(5):358-364. DOI: 10.1096/fasebj.1.5.2824268

[7] Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview. Methods in Enzymology. 1990;**186**:1-85. DOI: 10.1016/ 0076-6879(90)86093-B

[8] Cheeseman KH, Slater TF. An introduction to free radical biochemistry. British medical bulletin. 1993;**49**(3):481-493. DOI: 10.1093/ oxfordjournals.bmb.a072625

[9] Morrissey PA, Quinn PB, Sheehy PJA. Newer aspects of micronutrients in chronic disease: vitamin E. Proceedings of the Nutrition Society. 1994;**53**(3):571-582. DOI: 10.1079/PNS19940066

[10] Zhang X, Feng M, Liu F, Qin L, Qu R, Li D, et al. Subacute oral toxicity of BDE-15, CDE-15, and HODE-15 in ICR male mice: assessing effects on hepatic oxidative stress and metals status and ascertaining the protective role of vitamin E. Environ Sci Pollut Res Int. 2014;**21**(3):1924-1935. DOI: 10.1007/ s11356-013-2084-0

[11] Sokol RJ, Kayden HJ, Bettis DB, Traber MG, Neville H, Ringel S, et al. Isolated vitamin E deficiency in the absence of fat malabsorption – familial and sporadic cases: characterization and investigation of causes. J Lab Clin Med. 1988;**111**(5):548-559. DOI: 10.5555/ uri:pii:0022214388900820

[12] Boda V, Finckh B, Durken M, Commentz J, Hellwege HH, Kohlschutter A. Monitoring erythrocyte free radical resistance in neonatal blood microsamples using a peroxyl radicalmediated haemolysis test. Scand J Clin Lab Invest. 1998;**58**(4):317-322. DOI: 10.1080/00365519850186490

[13] Rizvi S, Raza ST, Faizal Ahmed AA, Abbas S, Mahdi F. The role of vitamin E in human health and some diseases. Sultan Qaboos University Medical Journal. 2014;**14**(2):e157-e165.

[14] Azzi A, Meydani SN, Meydani M, Zingg JM. The rise, the fall and the renaissance of vitamin E. Arch. Biochem. Biophys. 2016; **595**:100-108. DOI: 10.1016/j.abb.2015.11.010

[15] EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies). Scientific opinion on dietary reference values for vitamin E as α-tocopherol. EFSA J. 2015;**13**(7):4149, 72 pp. DOI: 10.2903/j. efsa.2015.4149

[16] IOM. Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academies Press (US); 2000. p. 186-283. DOI: 10.1179/135100001101535978

[17] Péter S, Eggersdorfer M, Weber P. Vitamin E Intake and Serum Levels in the General Population: A Global Perspective. In: Weber P, Birringer M, Blumberg J, Eggersdorfer M, Frank J, editors. Vitamin E in Human Health. Nutrition and Health. Cham: Humana Press; 2019. p. 175-188. DOI: 10.1007/978-3-030-05315-4\_13

[18] Raederstorff D, Wyss A, Calder PC, Weber P, Eggersdorfer M. Vitamin E function and requirements in relation to PUFA. Br J Nutr. 2015;**114**(8):1113-22. DOI: 10.1017/S000711451500272X

[19] DGE - Deutsche Gesellschaft für Ernährung ÖGfE, Schweizerische Gesellschaft für Ernährung. Referenzwerte für die Nährstoffzufuhr. Neustadt an der Weinstraße: Neuer Umschau Buchverlag; 2008.

[20] Raederstorff D, Szabolcs P, Weber P. The Challenge of Defining Daily Intake Recommendations: Vitamin E and Polyunsaturated Fatty Acids. In: Weber P, Birringer M, Blumberg J, Eggersdorfer M, Frank J, editors. Vitamin E in Human Health. Nutrition and Health. Cham: Humana Press; 2019. p. 163-174. DOI: 10.1007/978-3- 030-05315-4\_12

[21] Sharma S, Kolahdooz F, Butler L, Budd N, Rushovich B, Mukhina G, Gittelsohn J, Caballero B. Assessing dietary intake among infants and toddlers 0-24 months of age in Baltimore, Maryland, USA. Nutr J. 2013;**12**:52. DOI: 10.1186/1475- 2891-12-52

[22] Willett W. Nutritional Epidemiology. 3rd ed. New York: Oxford University Press; 2013: 529 p.

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Thomas AJ, Clayton BE. Selenium and vitamin E status of healthy and institutionalized elderly subjects: analysis of plasma, erythrocytes and platelets. Br J Nutr. 1989;**62**:221-227.

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arr.2011.06.006

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[64] Schuelke M, Elsner A, Finckh B, Kohlschütter A, Hübner C, Brigelius-Flohé R. Urinary alphatocopherol metabolites in

alpha-tocopherol transfer proteindeficient patients. J Lipid Res. 2000;**41**:1543-1551.

[65] Traber MG. Vitamin E regulatory mechanisms. Annual Review of Nutrition. 2007;**27**(1):347-362. DOI: 10.1146/annurev.nutr.27.061406.093819

[66] Valtuena J, Breidenassel C, Folle J, González-Gross M. Retinol, β-carotene, α-tocopherol and vitamin D status in European adolescents; regional differences and variability: A review. Nutr Hosp. 2011;**26**:280-288. DOI: 10.3305/nh.2011.26.2.4971

[67] Jiang T, Christian P, Khatry SK, Wu L, West KP. Micronutrient deficiencies in early pregnancy are common, concurrent, and vary by season among rural Nepali pregnant women. J. Nutr. 2005;**135**:1106-1112. DOI: 10.1093/jn/135.5.1106

[68] Biesalski HK, Bohles H, Esterbauer H, Furst P, Gey F, Hundsdorfer G, Kasper H, Sies H, Weisburger J. Antioxidant vitamins in prevention. Clin. Nutr. 1997;**16**:151-155. DOI: 10.1016/S0261-5614(97)80245-2

[69] Malik A, Eggersdorfer M, Trilok-Kumar G. Vitamin E status in healthy population in Asia: A review of current literature. International Journal for Vitamin and Nutrition Research. 2019;1-14. DOI:10.1024/0300- 9831/a000590

[70] Mangialasche F, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiol Aging. 2012;**33**(10):2282-90. DOI: 10.1016/j. neurobiolaging.2011.11.019

[71] Wright ME, Lawson KA, Weinstein SJ, Pietinen P, Taylor PR, Virtamo J, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and

cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene cancer prevention study. Am J Clin Nutr. 2006;**84**(5):1200-1207. DOI: 10.1093/ ajcn/84.5.1200

[72] Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski R, Thompson C, Pedrosa MC, Diamond RD, Stollar BD. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA. 1997;**277**(17):1380-1386. DOI: 10.1001/jama.277.17.1380

[73] Meydani SN, Lewis ED, Wu D. Perspective: Should vitamin E recommendations for adults be increased? Adv Nutr. 2018;**9**:533-543. DOI: 10.1093/advances/nmy035

[74] Pallast EG, Schouten EG, de Waart FG, Fonk HC, Doekes G, von Blomberg BM, Kok FJ. Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons. Am J Clin Nutr. 1999;**69**(6):1273-1281. DOI: 10.1093/ajcn/69.6.1273

[75] Ohrvall M, Gustafsson IB, Vessby B. The alpha and gamma tocopherol levels in serum are influenced by the dietary fat quality. J Hum Nutr Diet. 2001;**14**: 63-68. DOI: 10.1046/j.1365-277x.2001. 00268.x

[76] Klein EA, Thompson Jr. IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;**306**:1549-1556. DOI: 10.1001/jama.2011.1437

[77] Handelman GJ, Epstein WL, Peerson J, Spiegelman D, Machlin LJ, Dratz EA. Human adipose α-tocopherol and γ-tocopherol kinetics during and after 1 y of α-tocopherol supplementation. Am J Clin Nutr.

1994;**59**(5):1025-1032. DOI: 10.1093/ ajcn/59.5.1025

[78] Ulatowski LM, Manor D. Vitamin E and neurodegeneration. Neurobiol Dis. 2015;**84**:78-83. DOI: 10.1016/j. nbd.2015.04.002

[79] Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr. 1991;**53**(1):194S–200S. DOI: doi.org/10.1093/ajcn/53.1.194S

[80] Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: a meta-analysis. Curr. Aging Sci. 2011;**4**:158-170.

[81] Agudo A, Cabrera L, Amiano P, Ardanaz E, et al. Fruit and vegetable intakes, dietary antioxidant nutrients, and total mortality in Spanish adults: findings from the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Am J Clin Nutr. 2007;**85**(6):1634-1642. DOI: 0.1093/ajcn/85.6.1634

[82] Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013; **33**:87-103. DOI: 10.1146/ annurev-nutr-071812-161252

**187**

**Chapter 10**

**Abstract**

Biosynthesis Pathways of Vitamin E

Naturally occurring vitamin E, comprised of four forms each of tocopherols and tocotrienols, are synthesized solely by photosynthetic organisms and function primarily as antioxidants. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. Tocopherols are lipophilic antioxidants and together with tocotrienols belong to the vitamin-E family. These lipid-soluble compounds are potent antioxidants that protect polyunsaturated fatty acids from lipid peroxidation. Biosynthetic pathways of plants producing a diverse array of natural products that are important for plant function, agriculture, and human nutrition. Edible plant-derived products, notably seed oils, are the main sources of vitamin E in the human diet. The biosynthesis of tocopherols takes place mainly in plastids of higher plants from precursors derived from two metabolic pathways: homogentisic acid, an intermediate of degradation of aromatic amino acids, and phytyldiphosphate, which arises from methylerythritol phosphate pathway. Tocopherols and tocotrienols play an important roles in the oxidative stability of vegetable oils and in the nutritional quality of crop plants for human and livestock diets. Here, we review major biosynthetic pathways, including common precursors and competitive pathways of the vitamin E and its derivatives in plants.

**Keywords:** Vitamin E, Biosynthetic pathways, Tocopherols, Tocochromanol,

Under biotic and abiotic stresses conditions, including pathogens, temperature, drought, salt, and high light, the reactive oxygen species (ROS) resulting the oxidation of cellular components, as proteins, chlorophyll, and lipids [1]. To defend against oxidative stress, the plants have developed two general protective mechanisms, enzymatic and non-enzymatic detoxification, of which the latter involves vitamin E [2]. Plants are a major source of vitamins in the human diet. Due to their significance for human health and development, research has been initiated to understand the biosynthesis of vitamins in plants [3]. Vitamin E is thought to be involved in many essential processes in animals and plants. The function of vitamin E in plants is far from being clear. Likewise, in animal cells, the vitamin E acts as an antioxidant,

Four different forms of tocopherols and tocotrienols occur in nature and differ by the numbers and positions of methyl groups on the aromatic portion of the

Shikimate pathway, Methylerythritol pathway

thus it protects the plant from oxygen toxicity.

chromanol head group (**Figure 1**).

**1. Introduction**

and Its Derivatives in Plants

*Makhlouf Chaalal and Siham Ydjedd*

#### **Chapter 10**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

1994;**59**(5):1025-1032. DOI: 10.1093/

2015;**84**:78-83. DOI: 10.1016/j.

doi.org/10.1093/ajcn/53.1.194S

[80] Abner EL, Schmitt FA,

[78] Ulatowski LM, Manor D. Vitamin E and neurodegeneration. Neurobiol Dis.

[79] Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr. 1991;**53**(1):194S–200S. DOI:

Mendiondo MS, Marcum JL, Kryscio RJ. Vitamin E and all-cause mortality: a meta-analysis. Curr. Aging Sci.

[81] Agudo A, Cabrera L, Amiano P, Ardanaz E, et al. Fruit and vegetable intakes, dietary antioxidant nutrients, and total mortality in Spanish adults: findings from the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Am J Clin Nutr. 2007;**85**(6):1634-1642. DOI:

[82] Ulatowski L, Manor D. Vitamin E trafficking in neurologic health and disease. Annu Rev Nutr. 2013;

ajcn/59.5.1025

nbd.2015.04.002

2011;**4**:158-170.

0.1093/ajcn/85.6.1634

**33**:87-103. DOI: 10.1146/ annurev-nutr-071812-161252

cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene cancer prevention study. Am J Clin Nutr. 2006;**84**(5):1200-1207. DOI: 10.1093/

Pedrosa MC, Diamond RD, Stollar BD. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAMA. 1997;**277**(17):1380-1386. DOI:

[73] Meydani SN, Lewis ED, Wu D. Perspective: Should vitamin E recommendations for adults be increased? Adv Nutr. 2018;**9**:533-543. DOI: 10.1093/advances/nmy035

[74] Pallast EG, Schouten EG, de Waart FG, Fonk HC, Doekes G, von Blomberg BM, Kok FJ. Effect of 50- and 100-mg vitamin E supplements on cellular immune function in

noninstitutionalized elderly persons. Am J Clin Nutr. 1999;**69**(6):1273-1281.

[75] Ohrvall M, Gustafsson IB, Vessby B. The alpha and gamma tocopherol levels in serum are influenced by the dietary fat quality. J Hum Nutr Diet. 2001;**14**: 63-68. DOI: 10.1046/j.1365-277x.2001.

DOI: 10.1093/ajcn/69.6.1273

[76] Klein EA, Thompson Jr. IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;**306**:1549-1556.

DOI: 10.1001/jama.2011.1437

after 1 y of α-tocopherol

[77] Handelman GJ, Epstein WL, Peerson J, Spiegelman D, Machlin LJ, Dratz EA. Human adipose α-tocopherol and γ-tocopherol kinetics during and

supplementation. Am J Clin Nutr.

[72] Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski R, Thompson C,

10.1001/jama.277.17.1380

ajcn/84.5.1200

**186**

00268.x

## Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants

*Makhlouf Chaalal and Siham Ydjedd*

#### **Abstract**

Naturally occurring vitamin E, comprised of four forms each of tocopherols and tocotrienols, are synthesized solely by photosynthetic organisms and function primarily as antioxidants. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. Tocopherols are lipophilic antioxidants and together with tocotrienols belong to the vitamin-E family. These lipid-soluble compounds are potent antioxidants that protect polyunsaturated fatty acids from lipid peroxidation. Biosynthetic pathways of plants producing a diverse array of natural products that are important for plant function, agriculture, and human nutrition. Edible plant-derived products, notably seed oils, are the main sources of vitamin E in the human diet. The biosynthesis of tocopherols takes place mainly in plastids of higher plants from precursors derived from two metabolic pathways: homogentisic acid, an intermediate of degradation of aromatic amino acids, and phytyldiphosphate, which arises from methylerythritol phosphate pathway. Tocopherols and tocotrienols play an important roles in the oxidative stability of vegetable oils and in the nutritional quality of crop plants for human and livestock diets. Here, we review major biosynthetic pathways, including common precursors and competitive pathways of the vitamin E and its derivatives in plants.

**Keywords:** Vitamin E, Biosynthetic pathways, Tocopherols, Tocochromanol, Shikimate pathway, Methylerythritol pathway

#### **1. Introduction**

Under biotic and abiotic stresses conditions, including pathogens, temperature, drought, salt, and high light, the reactive oxygen species (ROS) resulting the oxidation of cellular components, as proteins, chlorophyll, and lipids [1]. To defend against oxidative stress, the plants have developed two general protective mechanisms, enzymatic and non-enzymatic detoxification, of which the latter involves vitamin E [2].

Plants are a major source of vitamins in the human diet. Due to their significance for human health and development, research has been initiated to understand the biosynthesis of vitamins in plants [3]. Vitamin E is thought to be involved in many essential processes in animals and plants. The function of vitamin E in plants is far from being clear. Likewise, in animal cells, the vitamin E acts as an antioxidant, thus it protects the plant from oxygen toxicity.

Four different forms of tocopherols and tocotrienols occur in nature and differ by the numbers and positions of methyl groups on the aromatic portion of the chromanol head group (**Figure 1**).

#### **Figure 1.**

*The eight forms of naturally occurring vitamin E (or tocochromanols) [4].*


**189**

**Figure 2.**

*Cross-points on the biosynthetic pathways of vitamins in plants [13].*

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants*

photosynthetic tissues, γ-tocopherol is the major form [5].

thetic origins of vitamin E biosynthetic precursors in plants.

**2. Biosynthesis of vitamins in plants**

Only plants and some cyanobacteria are able to synthesise vitamin E. α-Tocopherol is the predominant form of vitamin E green parts of higher plants, and is synthesized and localised mainly in plastids, whereas generally in non-

The accumulation of vitamin E was varied in a number of plant species and in different plant parts. Generally, their content was ranged between 100 and 500 mg/kg fresh weight of normal plants with some exceptions. Oil-yielding plants present a higher vitamin E amount. Likewise, the seeds showed a highest total vitamin E content compared to other plant parts. **Table 1** indicates the amount of α-tocopherol in different plant species. In seeds, the vitamins were localized in plastids; however, in some cases it was also observed in cytoplasmic lipid bodies [6]. Commonly, α-Tocopherol was the major form of vitamin E in leaves, while many plants seeds contain γ-Tocopherol. Heowever, β-tocophenrol and δ-Tocophenrol are uncommon in plants [1, 7]. Thus, this work complements highlighted the biosyn-

The biosynthesis of different vitamins in plants has been carried out generally by bacterial pathways, except in the case of vitamin C, which is synthesized exclusively by eukaryotes. The biosynthesis of some vitamins is limited to the compartment as carotenoids (pro-vitamin A), vitamins E and K and water-soluble riboflavin are produced in the plastids of plants [8, 9]. However, some enzymes of phylloquinone biosynthesis have been found in peroxisomes [10] and riboflavin is further converted to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in the cytosol, plastids or mitochondria [11]. Furthermore, the biosynthesis of the water soluble vitamins is split between different compartments, including the mitochondria [12] (**Figure 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.97267*

#### **Table 1.**

*Vitamin E content in different cultivated plant species (reported by Has).*

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants DOI: http://dx.doi.org/10.5772/intechopen.97267*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

**Sources Plant organs Usable Products Vitamin E contents (g/kg)**

Wheat Kerne Germ 1500 Sunflower Seed Oil 610 Sunflower Seed Kernel 351 Almond Kernel Oil 392 Safflower Kernel Oil 450 Canola Seed Oil 270 Walnut Fruit Oil 200 Peanut Seed Edible nut 172 Palm Kernel Oil 150 Olive Seed Oil 120 Soybean Kernel Oil 116 Maize Seed Entire grain 20 Oat Seed Kernel 15 Coconut Seed/fruit Oil 10 Asparagus Shoot Young shoot 15 Spinach Leaf Raw leaf 20 Spinach Leaf Cooked leaf 21 Tomato Fruit Raw fruit 9 Carrot Root Taproot 6 Tobacco Leaf Young leaf 57 Tobacco Leaf Old leaf 180

*The eight forms of naturally occurring vitamin E (or tocochromanols) [4].*

**188**

**Table 1.**

**Figure 1.**

*Vitamin E content in different cultivated plant species (reported by Has).*

Only plants and some cyanobacteria are able to synthesise vitamin E. α-Tocopherol is the predominant form of vitamin E green parts of higher plants, and is synthesized and localised mainly in plastids, whereas generally in nonphotosynthetic tissues, γ-tocopherol is the major form [5].

The accumulation of vitamin E was varied in a number of plant species and in different plant parts. Generally, their content was ranged between 100 and 500 mg/kg fresh weight of normal plants with some exceptions. Oil-yielding plants present a higher vitamin E amount. Likewise, the seeds showed a highest total vitamin E content compared to other plant parts. **Table 1** indicates the amount of α-tocopherol in different plant species. In seeds, the vitamins were localized in plastids; however, in some cases it was also observed in cytoplasmic lipid bodies [6]. Commonly, α-Tocopherol was the major form of vitamin E in leaves, while many plants seeds contain γ-Tocopherol. Heowever, β-tocophenrol and δ-Tocophenrol are uncommon in plants [1, 7]. Thus, this work complements highlighted the biosynthetic origins of vitamin E biosynthetic precursors in plants.

#### **2. Biosynthesis of vitamins in plants**

The biosynthesis of different vitamins in plants has been carried out generally by bacterial pathways, except in the case of vitamin C, which is synthesized exclusively by eukaryotes. The biosynthesis of some vitamins is limited to the compartment as carotenoids (pro-vitamin A), vitamins E and K and water-soluble riboflavin are produced in the plastids of plants [8, 9]. However, some enzymes of phylloquinone biosynthesis have been found in peroxisomes [10] and riboflavin is further converted to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) in the cytosol, plastids or mitochondria [11]. Furthermore, the biosynthesis of the water soluble vitamins is split between different compartments, including the mitochondria [12] (**Figure 2**).

**Figure 2.** *Cross-points on the biosynthetic pathways of vitamins in plants [13].*

The vitamins precursors were coming from carbohydrate metabolism, which regulates the pools of hexoses, pentoses and trioses in the plastids and the cytosol. The pentose and triose pool in the plastids provides: (a) erythrose-P and phosphoenolpyruvate for the synthesis of chorismate, the common intermediary in the biosynthesis of tocochromanols [14, 15]; (b) glyceraldehyde 3-P and pyruvate (from phosphoenolpyruvate), which are required for the synthesis of geranylgeranyl-PP, a key shared precursor of lipid-soluble vitamins [8, 14].

#### **3. Vitamin E structures and biosynthesis**

Plants synthesize eight different molecules with vitamin E antioxidant activity, including α-, β-, γ-, and δ-tocopherols and the corresponding four tocotrienols. These forms were different with respect the number and position of the methyl groups on their chromanol ring. The tocotrienols have an unsaturated tail containing three double bonds, while the four tocopherols have a phytyl tail.

Two main pathways of vitamin E biosynthesis are occurs at the inner envelope of plastids. The shikimate pathway gives rise to the chromanol ring from homogentisate (HGA). While, the methylerytrithol phosphate (MEP) pathway provides the prenyl tail from geranylgeranyl diphosphate (GGDP) for the synthesis of tocotrienol and phytyl diphosphate (phytyl-DP) for the synthesis of tocopherol (**Figure 3**). Furthermore, an additional pathway for phytyl-DP production from chlorophyll degradation, also known as the phytol recycling pathway (**Figure 4**). Seeds and leaves showed 80% and 65% reductions in total tocopherol content, respectively, compared to other plant parts. Chlorophyll synthase and geranylgeranyl diphosphate reductase (GGDR) are also involved in

#### **Figure 3.**

*Vitamin E Chemical Structure and Biosynthesis in Plants [16]. (A) Vitamin E chemical structure. A chromanol head and a prenyl tail constitute the chemical structure of tocopherols and tocotrienols. While tocopherols have a saturated tail, tocochromonals have three unsaturations (orange lines), at 3', 7', and 11'. (B) Biosynthesis of tocopherols and tocotrienols in plants. Tocopherols and tocotrienols are formed from the combination of the methylerythritol phosphate and shikimate pathways.*

**191**

**Figure 4.**

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants*

vitamin E biosynthesis [17]. The identity of the enzymes involved in chlorophyll dephytylation is less clear and the hydrolases such as CLD1 may allow phytol

Tocopherols are found in higher plants, in algae, and in some nonphotosynthetic plants, such as yeasts and mushrooms [20]. Tocopherol biosynthesis was carried out via the condensation of homogentisate, derived from the shikimate pathway, and phytyl pyrophosphate (phytyl-PP), derived from the non-mevalonate pathway, through the action of the homogentisate prenyltransferase (HPT) (**Figure 5**). Subsequent ring cyclization and methylation reactions result in the formation of the four major tocopherol derivatives. The final methylation reaction resulting inα - and β-tocopherol, respectively, is expected to be catalysed by the same methyltransferase (γ-TMT) [21]. Theγ -TMT gene was isolated from the putative 10-gene tocopherol

The shikimate pathway has been found in plants and in some microorganisms serves as a biosynthetic way of aromatic amino acids (phenylalanine (Phe),

remobilization during fruit ripening and seed maturation [18, 19].

**4. Tocopherols biosynthetic pathway**

*Tocopherol Biosynthesis with Chlorophyll Degradation in Plants [16].*

biosynthetic operon in *Synechocystis* sp.

**4.1 Shikimate pathway**

*DOI: http://dx.doi.org/10.5772/intechopen.97267*

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants DOI: http://dx.doi.org/10.5772/intechopen.97267*

**Figure 4.**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

key shared precursor of lipid-soluble vitamins [8, 14].

**3. Vitamin E structures and biosynthesis**

The vitamins precursors were coming from carbohydrate metabolism, which regulates the pools of hexoses, pentoses and trioses in the plastids and the cytosol. The pentose and triose pool in the plastids provides: (a) erythrose-P and phosphoenolpyruvate for the synthesis of chorismate, the common intermediary in the biosynthesis of tocochromanols [14, 15]; (b) glyceraldehyde 3-P and pyruvate (from phosphoenolpyruvate), which are required for the synthesis of geranylgeranyl-PP, a

Plants synthesize eight different molecules with vitamin E antioxidant activity, including α-, β-, γ-, and δ-tocopherols and the corresponding four tocotrienols. These forms were different with respect the number and position of the methyl groups on their chromanol ring. The tocotrienols have an unsaturated tail contain-

Two main pathways of vitamin E biosynthesis are occurs at the inner envelope of plastids. The shikimate pathway gives rise to the chromanol ring from homogentisate (HGA). While, the methylerytrithol phosphate (MEP) pathway provides the prenyl tail from geranylgeranyl diphosphate (GGDP) for the synthesis of tocotrienol and phytyl diphosphate (phytyl-DP) for the synthesis of tocopherol (**Figure 3**). Furthermore, an additional pathway for phytyl-DP production from chlorophyll degradation, also known as the phytol recycling pathway (**Figure 4**). Seeds and leaves showed 80% and 65% reductions in total tocopherol content, respectively, compared to other plant parts. Chlorophyll synthase and geranylgeranyl diphosphate reductase (GGDR) are also involved in

*Vitamin E Chemical Structure and Biosynthesis in Plants [16]. (A) Vitamin E chemical structure. A chromanol head and a prenyl tail constitute the chemical structure of tocopherols and tocotrienols. While tocopherols have a saturated tail, tocochromonals have three unsaturations (orange lines), at 3', 7', and 11'. (B) Biosynthesis of tocopherols and tocotrienols in plants. Tocopherols and tocotrienols are formed from the combination of the* 

ing three double bonds, while the four tocopherols have a phytyl tail.

**190**

**Figure 3.**

*methylerythritol phosphate and shikimate pathways.*

*Tocopherol Biosynthesis with Chlorophyll Degradation in Plants [16].*

vitamin E biosynthesis [17]. The identity of the enzymes involved in chlorophyll dephytylation is less clear and the hydrolases such as CLD1 may allow phytol remobilization during fruit ripening and seed maturation [18, 19].

#### **4. Tocopherols biosynthetic pathway**

Tocopherols are found in higher plants, in algae, and in some nonphotosynthetic plants, such as yeasts and mushrooms [20]. Tocopherol biosynthesis was carried out via the condensation of homogentisate, derived from the shikimate pathway, and phytyl pyrophosphate (phytyl-PP), derived from the non-mevalonate pathway, through the action of the homogentisate prenyltransferase (HPT) (**Figure 5**). Subsequent ring cyclization and methylation reactions result in the formation of the four major tocopherol derivatives. The final methylation reaction resulting inα - and β-tocopherol, respectively, is expected to be catalysed by the same methyltransferase (γ-TMT) [21]. Theγ -TMT gene was isolated from the putative 10-gene tocopherol biosynthetic operon in *Synechocystis* sp.

#### **4.1 Shikimate pathway**

The shikimate pathway has been found in plants and in some microorganisms serves as a biosynthetic way of aromatic amino acids (phenylalanine (Phe),

#### **Figure 5.**

*Vitamin E biosynthetic pathway [21]. The blue box highlights the four naturally occurring tocopherol derivatives in plants.*

**193**

**Figure 6.**

*The shikimate pathway of homogentisate biosynthesis in photosynthetic organisms [23].*

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants*

tyrosine (Tyr) and tryptophan (Trp)), and as precursors for many secondary metabolites, such as pigments, vitamins, etc. [22]. It consists of seven steps where the glycolytic intermediate phosphoenol pyruvate and the pentose phosphate pathway intermediate erythrose-4-phosphate are converted in chorismate (**Figure 6**). Numerous synthases, dehydratases and kinases are involved in this pathway, but their participation in tocopherols biosynthesis is not clear. The limitation step in the shikimate pathway are the reversible formation of

*DOI: http://dx.doi.org/10.5772/intechopen.97267*

#### *Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants DOI: http://dx.doi.org/10.5772/intechopen.97267*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

**192**

**Figure 5.**

*derivatives in plants.*

*Vitamin E biosynthetic pathway [21]. The blue box highlights the four naturally occurring tocopherol* 

tyrosine (Tyr) and tryptophan (Trp)), and as precursors for many secondary metabolites, such as pigments, vitamins, etc. [22]. It consists of seven steps where the glycolytic intermediate phosphoenol pyruvate and the pentose phosphate pathway intermediate erythrose-4-phosphate are converted in chorismate (**Figure 6**). Numerous synthases, dehydratases and kinases are involved in this pathway, but their participation in tocopherols biosynthesis is not clear. The limitation step in the shikimate pathway are the reversible formation of

**Figure 6.** *The shikimate pathway of homogentisate biosynthesis in photosynthetic organisms [23].*

#### *Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

5-enolpyruvylshikimate 3-phosphate (EPSP) and inorganic phosphate from shikimate 3-phosphate and phosphoenolpyruvate. Likewise, the reaction is catalyzed by EPSP synthase (EC 2.5.1.19), which is the unique target for herbicide glyphosate (N-phosphonomethylglycine) [24]. Glyphosate interacts with the binding site of phosphoenolpyruvate and forms a stable ternary complex with the enzyme and shikimate 3-phosphate Likewise, Chorismate is the end product of the shikimate pathway and, at the same time, is a precursor for many primary and secondary metabolites, such as vitamin-K, folates, alkaloids,

**195**

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants*

**4.2 Methyl erythritol phosphate (MEP) synthesis**

conjugates such as chlorophylls and tocopherols.

**5. Tocochromanol biosynthetic pathway**

quinones, tocopherols and three aromatic amino acids (Phe, Tyr and Trp) [23]. *p*-Hydroxyphenylpyruvate (HPP) is the first intermediate in tocopherol biosynthesis. Different ways of HPP synthesis exist in photosynthetic organisms. In higher plants, it is formed from prephenate via arogenate and tyrosine. A portion of fixed carbon is incorporated into Tyr used for biosynthesis of HPP and homogentisate, a tocochromanol (tocopherols and tocotrienols)

The formation of homogentisate from HPP occurs in the reaction catalyzed by HPPD. Homogentisate may either enter the prenylquinone biosynthesis pathway or be metabolized by homogentisate dioxygenase (EC 1.13.11.5) to yield maleylacetoacetate, which further is catabolized to fumarate and acetyl-

The plastidic 2C-methyl-D-erythritol 4-phosphate (MEP) pathway produces isopentenyl diphosphate (IPP) that is used for the biosynthesis of isoprenes, monoterpenes (C10), diterpenes (C20), carotenoids, plastoquinones, and phytol

The first step in the MEP pathway involves a transketolase-type condensation reaction of pyruvate and glyceraldehyde 3-phosphate to form 1-deoxy-D-xylulose-5-phosphate (DOXP) (**Figure 7**), which is also an intermediate in the biosynthesis of thiamin and pyridoxol [26–28]. The formed isopentenyl diphosphate is further isomerized to DMAPP. However, the IPP is suggested to be the final production of the MEP pathway in higher plants [26]. The chlorophyll-derived phytol may be a precursor for the biosynthesis of tocopherols, because, the accumulation of tocopherol negatively correlated with chlorophyll content in some plant species during leaf

According to the degree of methylation of the chromanol ring, four different forms of tocochromanol was obtained (**Figure 8**). Four forms of tocopherol, tocotrienol, and tocomonoenol have been identified in wild-type plant extracts, only the

It has been assumed for a long time that tocochromanol biosynthesis was the exclusive appanage of plants, algae, and some cyanobacteria that are all photosynthetic organisms. Tocochromanol biosynthesis is initiated by the condensation of the polar aromatic head HGA with various lipophilic polyprenyl pyrophosphates that determine the type of tocochromanol. The condensation reaction is catalyzed by three types of HGA prenyltransferases that possess each their substrate specificities. Tocopherol synthesis is initiated by HGA phytyltransferases (HPTs) that condense HGA and PPP. The condensation between HGA and polyprenyl pyrophosphates produces 2-methyl-6-phytyl-1,4-benzoquinol (MPBQ ), 2-methyl-6-geranylgeranyl- 1,4-benzoquinol (MGGBQ ), 2-methyl-6-solanesyl-1,4-benzoquinol (MSBQ ), and 2-methyl-6-tetrahydrogeranylgeranyl-1,4-benzoquinol (MTHGGBQ ) for tocopherols, tocotrienols, PC-8, and for tocomonoenols, respectively (**Figure 8**). Finally, tocochromanol biosynthesis consists of the methylation of γ- and δ-tocochromanols intoα and β-tocochromanols, respectively [31, 32]. In Arabidopsis leaves and seeds, VTE4 converts γ anjdδ -tocopherols intoα - and β-tocopherol, respectively [32].

solanesyl-derived tocochromanol PC-8form is exists in the nature [30].

*DOI: http://dx.doi.org/10.5772/intechopen.97267*

precursor [25].

CoA [23].

senescence [29].

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants DOI: http://dx.doi.org/10.5772/intechopen.97267*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

5-enolpyruvylshikimate 3-phosphate (EPSP) and inorganic phosphate from shikimate 3-phosphate and phosphoenolpyruvate. Likewise, the reaction is catalyzed by EPSP synthase (EC 2.5.1.19), which is the unique target for herbicide glyphosate (N-phosphonomethylglycine) [24]. Glyphosate interacts with the binding site of phosphoenolpyruvate and forms a stable ternary complex with the enzyme and shikimate 3-phosphate Likewise, Chorismate is the end product of the shikimate pathway and, at the same time, is a precursor for many primary and secondary metabolites, such as vitamin-K, folates, alkaloids,

*Methylerythritol pathway of phytyl diphosphate biosynthesis in the plastids of higher plants [23].*

**194**

**Figure 7.**

quinones, tocopherols and three aromatic amino acids (Phe, Tyr and Trp) [23]. *p*-Hydroxyphenylpyruvate (HPP) is the first intermediate in tocopherol biosynthesis. Different ways of HPP synthesis exist in photosynthetic organisms. In higher plants, it is formed from prephenate via arogenate and tyrosine. A portion of fixed carbon is incorporated into Tyr used for biosynthesis of HPP and homogentisate, a tocochromanol (tocopherols and tocotrienols) precursor [25].

The formation of homogentisate from HPP occurs in the reaction catalyzed by HPPD. Homogentisate may either enter the prenylquinone biosynthesis pathway or be metabolized by homogentisate dioxygenase (EC 1.13.11.5) to yield maleylacetoacetate, which further is catabolized to fumarate and acetyl-CoA [23].

#### **4.2 Methyl erythritol phosphate (MEP) synthesis**

The plastidic 2C-methyl-D-erythritol 4-phosphate (MEP) pathway produces isopentenyl diphosphate (IPP) that is used for the biosynthesis of isoprenes, monoterpenes (C10), diterpenes (C20), carotenoids, plastoquinones, and phytol conjugates such as chlorophylls and tocopherols.

The first step in the MEP pathway involves a transketolase-type condensation reaction of pyruvate and glyceraldehyde 3-phosphate to form 1-deoxy-D-xylulose-5-phosphate (DOXP) (**Figure 7**), which is also an intermediate in the biosynthesis of thiamin and pyridoxol [26–28]. The formed isopentenyl diphosphate is further isomerized to DMAPP. However, the IPP is suggested to be the final production of the MEP pathway in higher plants [26]. The chlorophyll-derived phytol may be a precursor for the biosynthesis of tocopherols, because, the accumulation of tocopherol negatively correlated with chlorophyll content in some plant species during leaf senescence [29].

#### **5. Tocochromanol biosynthetic pathway**

According to the degree of methylation of the chromanol ring, four different forms of tocochromanol was obtained (**Figure 8**). Four forms of tocopherol, tocotrienol, and tocomonoenol have been identified in wild-type plant extracts, only the solanesyl-derived tocochromanol PC-8form is exists in the nature [30].

It has been assumed for a long time that tocochromanol biosynthesis was the exclusive appanage of plants, algae, and some cyanobacteria that are all photosynthetic organisms. Tocochromanol biosynthesis is initiated by the condensation of the polar aromatic head HGA with various lipophilic polyprenyl pyrophosphates that determine the type of tocochromanol. The condensation reaction is catalyzed by three types of HGA prenyltransferases that possess each their substrate specificities. Tocopherol synthesis is initiated by HGA phytyltransferases (HPTs) that condense HGA and PPP. The condensation between HGA and polyprenyl pyrophosphates produces 2-methyl-6-phytyl-1,4-benzoquinol (MPBQ ), 2-methyl-6-geranylgeranyl- 1,4-benzoquinol (MGGBQ ), 2-methyl-6-solanesyl-1,4-benzoquinol (MSBQ ), and 2-methyl-6-tetrahydrogeranylgeranyl-1,4-benzoquinol (MTHGGBQ ) for tocopherols, tocotrienols, PC-8, and for tocomonoenols, respectively (**Figure 8**). Finally, tocochromanol biosynthesis consists of the methylation of γ- and δ-tocochromanols intoα and β-tocochromanols, respectively [31, 32]. In Arabidopsis leaves and seeds, VTE4 converts γ anjdδ -tocopherols intoα - and β-tocopherol, respectively [32].

**Figure 8.**

*Tocochromanol (tocopherol, tocotrienol, tocomonoenol, and methyl PC-8) biosynthetic pathways in plants [30].*

In addition, transgenic Arabidopsis lines overexpressing the barley HGGT gene notably produceα -tocotrienol [33].

#### **6. Conclusion**

Vitamin E biosynthesis mobilizes two distinct biosynthetic pathways, the shikimate pathway and the MEP pathway. Indeed, the shikimate pathway gives rise to the chromanol ring from homogentisate (HGA). While, the methylerytrithol phosphate (MEP) pathway provides the prenyl tail from geranylgeranyl diphosphate (GGDP) and phytyl diphosphate (phytyl-DP) for the synthesis of tocotrienol and tocopherol, respectively. An additional pathway for phytyl-DP production from chlorophyll degradation, known as the phytol recycling pathway. Understanding the regulation of vitamin E biosynthesis will imply that we take up the challenges to understand the regulation of each of these numerous events. The fundamental role of this vitamin in human reproduction and its benefit in current widespread diseases such as high cholesterol and neurodegenerative pathologies makes it a candidate of choice to improve human health.

**197**

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants*

AIR 5-aminoimidazole ribonucleotide

DMGGBQ dimethylgeranylgeranylbenzoquinol

GGDR geranylgeranyl diphosphate reductase GGPP geranylgeranyl pyrophosphate GGPS geranylgeranyl diphosphate synthase

HPPD hydroxyphenylpyruvate dioxygenase HPT homogentisate phytyl transferase

HET-P 4-methyl-5-b-hydroxyethyl thiazole phosphate HGGT homogentisate geranylgeranyl transferase

MT 2-methyl-6-phytylhydroquinone methyltransferase

1 Laboratoire de Biochimie Appliquée, Faculté des Sciences de la Nature et de la Vie,

2 Department of Natural Sciences and Life, University of Guelma, Guelma, Algeria

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

3 Institute of Nutrition, Food and Agri-Food Technologies, University of

\*Address all correspondence to: makhlouf.chaalal@yahoo.fr;

HMP-PP 2-methyl-4-amino-5-hydroxymethylpyrimidine diphosphate

*DOI: http://dx.doi.org/10.5772/intechopen.97267*

CLD1 chlorophyll dephytylase 1

HPP hydroxyphenylpyruvate

IMP inosine monophosphate IPP isopentenyl pyrophosphate MEP methylerythritol phosphate MGGBQ methylgeranylgeranylbenzoquinol

MPBQ methylphytylbenzoquinol MPBQ-MT MPBQ methyltransferase

PPRP 5-phosphoribosyl-1pyrophosphate

TMT tocopherol methyltransferase.

PDP phytyl diphosphate phytyl-PP phytyl pyrophosphate

TC tocopherol cyclase

**Author details**

S-AdoMet S-adenosylmethionine. TAT tyrosine aminotransferase

Makhlouf Chaalal1,3\* and Siham Ydjedd1,2

Université de Bejaia, Bejaia, Algeria

Constantine 1, Constantine, Algeria

provided the original work is properly cited.

makhlouf.chaalal@umc.edu.dz

DMPBQ dimethylphytylbenzoquinol DMPP dimethylallyl pyro-phosphate GGDP geranylgeranyl diphosphate

**Acronyms and abbreviations**

*Biosynthesis Pathways of Vitamin E and Its Derivatives in Plants DOI: http://dx.doi.org/10.5772/intechopen.97267*

#### **Acronyms and abbreviations**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

In addition, transgenic Arabidopsis lines overexpressing the barley HGGT gene

*Tocochromanol (tocopherol, tocotrienol, tocomonoenol, and methyl PC-8) biosynthetic pathways in plants [30].*

Vitamin E biosynthesis mobilizes two distinct biosynthetic pathways, the shikimate pathway and the MEP pathway. Indeed, the shikimate pathway gives rise to the chromanol ring from homogentisate (HGA). While, the methylerytrithol phosphate (MEP) pathway provides the prenyl tail from geranylgeranyl diphosphate (GGDP) and phytyl diphosphate (phytyl-DP) for the synthesis of tocotrienol and tocopherol, respectively. An additional pathway for phytyl-DP production from chlorophyll degradation, known as the phytol recycling pathway. Understanding the regulation of vitamin E biosynthesis will imply that we take up the challenges to understand the regulation of each of these numerous events. The fundamental role of this vitamin in human reproduction and its benefit in current widespread diseases such as high cholesterol and neurodegenerative pathologies makes it a candidate of choice to improve human health.

notably produceα -tocotrienol [33].

**6. Conclusion**

**Figure 8.**

**196**


### **Author details**

Makhlouf Chaalal1,3\* and Siham Ydjedd1,2

1 Laboratoire de Biochimie Appliquée, Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, Bejaia, Algeria

2 Department of Natural Sciences and Life, University of Guelma, Guelma, Algeria

3 Institute of Nutrition, Food and Agri-Food Technologies, University of Constantine 1, Constantine, Algeria

\*Address all correspondence to: makhlouf.chaalal@yahoo.fr; makhlouf.chaalal@umc.edu.dz

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[3] Herbers K. Vitamin production in transgenic plants. Journal of Plant Physiology 2003;160:821.

[4] Hunter SC, Cahoon EB. Enhancing Vitamin E in Oilseeds: Unraveling Tocopherol and Tocotrienol Biosynthesis. Lipids 2007; 42:97-108.

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[9] Sandoval FJ, Zhang Y, Roje S. Flavin nucleotide metabolism in plants monofunctional enzymes synthesize

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[11] Sinclair SJ, Murphy KJ, Birch CD, Hamill JD. Molecular characterization of quinolinate phosphoribosyltransferase (QPRTase) in Nicotiana. Plant Molecular Biology 2000;44:603-617.

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[13] Asensi-Fabado MA, Munné-Bosch S. Vitamins in plants: occurrence, biosynthesis and antioxidant function. Trends Plant Science 2010; 15:582-92.

[14] DellaPenna D, Last RL. Progress in the dissection and manipulation of plant vitamin E biosynthesis. Physiologia Plantarum 2006;126:356-368.

[15] Sahr T, Ravanel S, Basset G, Nichols BP, Hanson AD, Rébeillé F. Folate synthesis in plants: purification, kinetic properties, and inhibition of aminodeoxychorismate synthase. Biochemical Journal 2006;396:157-162.

[16] Muñoz P, Munné-Bosch S. Vitamin E in Plants: Biosynthesis, Transport, and Function. Trends Plant Science 2019; 24:1040-1051

[17] Zhang C, Zhang W, Ren G, Li D, Cahoon RE, Chen M, et al. Chlorophyll synthase under epigenetic surveillance is critical for vitamin E synthesis, and altered expression affects tocopherol levels in Arabidopsis. Plant Physiology 2015;168:1503-1511.

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[29] Valentin HE, Lincoln K, Moshiri F, Jensen PK, Qi Q, Venkatesh TV, et al. The Arabidopsis vitamin E pathway gene5-1 mutant reveals a critical role for

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[23] Lushchak VI, Semchuk NM. Tocopherol biosynthesis: chemistry, regulation and effects of environmental factors. Acta Physiologiae Plantarum

[24] Herrmann KM. The shikimate pathway: early steps in the biosynthesis of aromatic compounds. The Plant Cell

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[26] Lichtenthaler HK. Non-mevalonate isoprenoid biosynthesis: enzymes, genes

resistance. Plant Physiology

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2016;28:2974-2990.

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[18] Lin Y-P, Wu M-C, Charng Y. Identification of a chlorophyll dephytylase involved in chlorophyll turnover in Arabidopsis. The Plant Cell 2016;28:2974-2990.

[19] Zhang X, Song J, Shi X, Miao S, Li Y, Wen A. Absorption and metabolism characteristics of rutin in Caco-2 cells. The Scientific World Journal 2013;2013.

[20] Threlfall DR. The biosynthesis of vitamins E and K and related compounds. Vitamins & Hormones, vol. 29, Elsevier; 1971, p. 153-200.

[21] Hofius D, Sonnewald U. Vitamin E biosynthesis: biochemistry meets cell biology. Trends in Plant Science 2003;8:6-8.

[22] Herrmann KM, Weaver LM. The shikimate pathway. Annual Review of Plant Biology 1999;50:473-503.

[23] Lushchak VI, Semchuk NM. Tocopherol biosynthesis: chemistry, regulation and effects of environmental factors. Acta Physiologiae Plantarum 2012;34:1607-1628.

[24] Herrmann KM. The shikimate pathway: early steps in the biosynthesis of aromatic compounds. The Plant Cell 1995;7:907.

[25] Rippert P, Scimemi C, Dubald M, Matringe M. Engineering plant shikimate pathway for production of tocotrienol and improving herbicide resistance. Plant Physiology 2004;134:92-100.

[26] Lichtenthaler HK. Non-mevalonate isoprenoid biosynthesis: enzymes, genes and inhibitors. Portland Press Ltd.; 2000.

[27] Rohmer M. Mevalonateindependent methylerythritol phosphate pathway for isoprenoid biosynthesis. Elucidation and distribution. Pure and Applied Chemistry 2003;75:375-388.

[28] Wanke M, Skorupinska-Tudek K, Swiezewska E. Isoprenoid biosynthesis via 1-deoxy-D-xylulose 5-phosphate/2- C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway. Acta Biochimica Polonica 2001;48:663-672.

[29] Valentin HE, Lincoln K, Moshiri F, Jensen PK, Qi Q, Venkatesh TV, et al. The Arabidopsis vitamin E pathway gene5-1 mutant reveals a critical role for phytol kinase in seed tocopherol biosynthesis. The Plant Cell 2006;18:212-224.

[30] Mène-Saffrané L. Vitamin E biosynthesis and its regulation in plants. Antioxidants 2018;7:2.

[31] Bergmüller E, Porfirova S, Dörmann P. Characterization of an Arabidopsis mutant deficient in γ-tocopherol methyltransferase. Plant Molecular Biology 2003;52:1181-1190.

[32] Shintani D, DellaPenna D. Elevating the vitamin E content of plants through metabolic engineering. Science 1998;282:2098-2100.

[33] Cahoon EB, Hall SE, Ripp KG, Ganzke TS, Hitz WD, Coughlan SJ. Metabolic redesign of vitamin E biosynthesis in plants for tocotrienol production and increased antioxidant content. Nature Biotechnology 2003;21:1082-1087.

**198**

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FAD in plastids. Journal of Biological Chemistry 2008;283:30890-30900.

[10] Babujee L, Wurtz V, Ma C, Lueder F, Soni P, Van Dorsselaer A, et al. The proteome map of spinach leaf peroxisomes indicates partial

compartmentalization of phylloquinone (vitamin K1) biosynthesis in plant peroxisomes. Journal of Experimental

[12] Roje S. Vitamin B biosynthesis in

[13] Asensi-Fabado MA, Munné-Bosch S.

biosynthesis and antioxidant function. Trends Plant Science 2010; 15:582-92.

[14] DellaPenna D, Last RL. Progress in the dissection and manipulation of plant vitamin E biosynthesis. Physiologia Plantarum 2006;126:356-368.

[16] Muñoz P, Munné-Bosch S. Vitamin E in Plants: Biosynthesis, Transport, and Function. Trends Plant Science

[17] Zhang C, Zhang W, Ren G, Li D, Cahoon RE, Chen M, et al. Chlorophyll synthase under epigenetic surveillance is critical for vitamin E synthesis, and altered expression affects tocopherol levels in Arabidopsis. Plant Physiology

2019; 24:1040-1051

2015;168:1503-1511.

Vitamins in plants: occurrence,

[15] Sahr T, Ravanel S, Basset G, Nichols BP, Hanson AD, Rébeillé F. Folate synthesis in plants: purification, kinetic properties, and inhibition of aminodeoxychorismate synthase. Biochemical Journal 2006;396:157-162.

Botany 2010;61:1441-1453.

[11] Sinclair SJ, Murphy KJ, Birch CD, Hamill JD. Molecular characterization of quinolinate phosphoribosyltransferase (QPRTase) in Nicotiana. Plant Molecular Biology

2000;44:603-617.

plants. Phytochemistry 2007;68:1904-1921.

[1] Abbasi A-R, Hajirezaei M, Hofius D, Sonnewald U, Voll LM. Specific roles of α-and γ-tocopherol in abiotic stress responses of transgenic tobacco. Plant Physiology 2007;143:1720-1738.

[2] Alscher RG, Erturk N, Heath LS. Role of superoxide dismutases (SODs) in controlling oxidative stress in plants. Journal of Experimental Botany

[3] Herbers K. Vitamin production in transgenic plants. Journal of Plant

[4] Hunter SC, Cahoon EB. Enhancing Vitamin E in Oilseeds: Unraveling Tocopherol and Tocotrienol

Biosynthesis. Lipids 2007; 42:97-108.

[5] Munné-Bosch S, Alegre L. The function of tocopherols and tocotrienols in plants. Critical Reviews in Plant

[6] White DA, Fisk ID, Gray DA.

[7] Hussain N, Irshad F, Jabeen Z, Shamsi IH, Li Z, Jiang L. Biosynthesis, structural, and functional attributes of tocopherols in planta; past, present, and

future perspectives. Journal of Agricultural and Food Chemistry

[8] Rodríguez-Villalón A, Gas E, Rodríguez-Concepción M. Phytoene synthase activity controls the biosynthesis of carotenoids and the supply of their metabolic precursors in dark-grown Arabidopsis seedlings. The

Plant Journal 2009;60:424-435.

[9] Sandoval FJ, Zhang Y, Roje S. Flavin nucleotide metabolism in plants monofunctional enzymes synthesize

Characterisation of oat (*Avena sativa* L.) oil bodies and intrinsically associated E-vitamers. Journal of Cereal Science

2002;53:1331-1341.

**References**

Physiology 2003;160:821.

Sciences 2002;21:31-s57.

2006;43:244-249.

2013;61:6137-6149.

**201**

**Chapter 11**

**Abstract**

and Diseases

*Ahmad Farouk Musa*

future of vitamin E research.

**1. Introduction**

**Keywords:** vitamin E, tocotrienols, health benefits

Tocotrienol: An Underrated

Isomer of Vitamin E in Health

Vitamin E was first discovered as a fertility factor in 1922 in the laboratory of Herbert McLean Evans, a scientist and anatomist. Following this discovery, it was extensively researched and found to possess a potent antioxidant property. It soon dawned that the family of vitamin E has eight members: four tocopherols, namely α-, β-, δ- and γ-tocopherol; and four tocotrienols in the form of α-, β-, δ- and γ-tocotrienols. This chapter discusses this rather unknown and underrated isomer of vitamin E with unsurpassed health benefits: tocotrienols. Until recently, tocotrienols rarely figured in vitamin E research in spite of their relative superiority to tocopherol coupled with their abundant presence in palm oil. In fact, since palm oil contains about 70% of all tocotrienol homologues, it would be no exaggeration to call it nature's best kept secret, if not the most promising natural substance in influencing health and disease. While highlighting the wonders of tocotrienols as a safe and efficacious product, this chapter offers a panoramic view of recent research into tocotrienols that demonstrates their undeniable benefits in conferring protection against cancer as well as a whole litany of ailments including cardiovascular, metabolic, autoimmune, bone and neurological diseases. Admittedly, many of these researches were conducted in the laboratory, with some preclinical trials translated into clinical trials. Nonetheless, it is hoped that more randomised clinical trials will be carried out on a global scale in the near future. From the vessels in the heart to the neurons in the brain, tocotrienols have the extraordinary potential to be the

Vitamin E, an important nutrient in the human diet that is readily available in lipid-rich plant products, is well known for its antioxidant properties with multiple health benefits. Historically, drug discovery researches have focused on natural products that abound in biological compounds with pharmacologic properties [1]. The discovery of vitamin E began in 1922 when Herbert Evans and Katherine Bishop [2] isolated an uncharacterised fat-soluble compound (which they termed 'substance X') from green leafy vegetables that they imagined might play a role in fertility. When the compound was finally identified in 1924, it was named tocopherol derived from the Greek word tokos meaning childbirth and pheros which means to

#### **Chapter 11**

## Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases

*Ahmad Farouk Musa*

#### **Abstract**

Vitamin E was first discovered as a fertility factor in 1922 in the laboratory of Herbert McLean Evans, a scientist and anatomist. Following this discovery, it was extensively researched and found to possess a potent antioxidant property. It soon dawned that the family of vitamin E has eight members: four tocopherols, namely α-, β-, δ- and γ-tocopherol; and four tocotrienols in the form of α-, β-, δ- and γ-tocotrienols. This chapter discusses this rather unknown and underrated isomer of vitamin E with unsurpassed health benefits: tocotrienols. Until recently, tocotrienols rarely figured in vitamin E research in spite of their relative superiority to tocopherol coupled with their abundant presence in palm oil. In fact, since palm oil contains about 70% of all tocotrienol homologues, it would be no exaggeration to call it nature's best kept secret, if not the most promising natural substance in influencing health and disease. While highlighting the wonders of tocotrienols as a safe and efficacious product, this chapter offers a panoramic view of recent research into tocotrienols that demonstrates their undeniable benefits in conferring protection against cancer as well as a whole litany of ailments including cardiovascular, metabolic, autoimmune, bone and neurological diseases. Admittedly, many of these researches were conducted in the laboratory, with some preclinical trials translated into clinical trials. Nonetheless, it is hoped that more randomised clinical trials will be carried out on a global scale in the near future. From the vessels in the heart to the neurons in the brain, tocotrienols have the extraordinary potential to be the future of vitamin E research.

**Keywords:** vitamin E, tocotrienols, health benefits

#### **1. Introduction**

Vitamin E, an important nutrient in the human diet that is readily available in lipid-rich plant products, is well known for its antioxidant properties with multiple health benefits. Historically, drug discovery researches have focused on natural products that abound in biological compounds with pharmacologic properties [1]. The discovery of vitamin E began in 1922 when Herbert Evans and Katherine Bishop [2] isolated an uncharacterised fat-soluble compound (which they termed 'substance X') from green leafy vegetables that they imagined might play a role in fertility. When the compound was finally identified in 1924, it was named tocopherol derived from the Greek word tokos meaning childbirth and pheros which means to

bring forth [3]. Vitamin E was rediscovered as 'factor 2 antioxidant' in 1965 [4]. Not surprisingly, as the major isoform of Vitamin E ever identified, α-tocopherol was thrust into the limelight while its sisters were ignored. Tocopherol is regarded as the most biologically active and potent antioxidant currently in existence. However, recent studies have shown that tocotrienols may have superior anti-oxidant [5], antiinflammatory [6], anti-cholesterolaemic, [7–11] anti-cancer [12, 13], anti-diabetic [14–16], anti-atherogenic [17, 18], blood pressure lowering, [19, 20] and neuroprotective effects [21–23]. Unfortunately, despite the recent interest in tocotrienols, it comprises only 3% of all vitamin E research papers listed in PubMed [24].

### **2. Biochemical properties of vitamin E isoforms**

Generally, vitamin E is classified into tocopherols and tocotrienols, and there are eight isoforms altogether: α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol. Structurally, they are very similar and possess a chromanol head formed by phenolic and heterocyclic rings, and a phenyl tail [25]. Designation as α-, β-, γ- or δ-tocopherol or tocotrienols is dependent on the methyl substitutions on


**203**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

between the structures of tocopherols and tocotrienols [28].

**4. Bioavailability and pharmacokinetics of vitamin E**

Compelling evidence from recent research prove that tocotrienols are detected at appreciable levels in the plasma after supplementation, whether this was done on a short-term or long-term basis [34]. While both compounds are basically bioavailable, tocotrienol has a shorter plasma half-life [33]. One study showed that the halflife of α-, γ- and δ-tocotrienols in human plasma was estimated to be 2.3, 4.4 and 4.3 hours respectively [35]. However, the half-life of α-tocopherol and γ-tocopherol was 57 and 13 hours respectively [36]. Given that tocotrienols are essentially oil-based compounds, and that emulsions are known to increase the absorption of oil-based compounds based on the new system of self-emulsifying drug delivery system [37], new products such as Tocovid Suprabio™ were developed following this technique. This new product led to a threefold increase in the peak plasma concentration of α-tocotrienol in humans compared to a previous study [38]. It has also been shown that the bioavailability of tocotrienols is dependent on several

the phenolic ring [26]. The main difference between the two groups is that tocopherols have a long-saturated carbon side-chain with chiral centres, whereas tocotrienols possess three unsaturated bonds in the carbon side-chain with one chiral centre [27]. This unique property somehow increases the efficiency of tocotrienols in its metabolic function; it allows a better penetration of saturated fatty layers by tocotrienols as compared to tocopherols. **Figure 1** above illustrates the difference

Vitamin E occurs naturally in vegetables, plants and plant oils. With regard

to tocopherols, α-tocopherol is generally found in green leafy plants while γ-tocopherol occurs in the non-green parts of the plants, notably seeds and fruits [29]. Based on the United States Department of Agriculture nutrient database, α-tocopherol is commonly found in almonds, avocados, hazelnuts, peanuts and sunflower seeds; β-tocopherol in oregano and poppy seeds; γ-tocopherol in pecans, pistachios, sesame seeds and walnuts; and δ-tocopherol in edamame and raspberries. Both α-tocopherol and γ-tocopherol are present in food oils such as corn, peanut and soybean oil. Conversely, tocotrienols are rarely found in food sources or vegetable oils, with rice bran and palm oil being the only known exceptions. This explains the scarcity of scientific literature on tocotrienols compared to tocopherols as a form of vitamin E that is widely accepted by the public. In fact, most people are unaware that up to 70% of vitamin E from crude palm oil consists of tocotrienols [30, 31]. Studies have proven that the extraction of crude palm oil (scientifically known as *Elaeis guineensis*) can yield up to 800 mg/kg of tocotrienols in the form of α-tocotrienol and γ-tocotrienol [32]. Moreover, cereal grains such as barley, oat, rice, rye and wheat contain a higher concentration of tocotrienols than tocopherol in a ratio of 79:21, 77:23, 67:55, 51:49 and 55:45 respectively [24]. However, in food supplements, tocotrienols are often prepared in soft-gel capsules. Even at a dose of 1000 mg daily, this is equivalent to a daily intake of 16.7 mg of tocotrienol/kg/day for a 60-kg person, or about seven times below the level where no adverse effects were observed in rats [33]. Hence, the usual dosage for any experimental use in humans has always been 400 mg daily in two divided doses which is a safe dosage with no observable adverse effects on any

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

**3. Sources of vitamin E**

study patients to date.

**Figure 1.**

*The different structures between tocopherols and tocotrienols.*

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

the phenolic ring [26]. The main difference between the two groups is that tocopherols have a long-saturated carbon side-chain with chiral centres, whereas tocotrienols possess three unsaturated bonds in the carbon side-chain with one chiral centre [27]. This unique property somehow increases the efficiency of tocotrienols in its metabolic function; it allows a better penetration of saturated fatty layers by tocotrienols as compared to tocopherols. **Figure 1** above illustrates the difference between the structures of tocopherols and tocotrienols [28].

#### **3. Sources of vitamin E**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

bring forth [3]. Vitamin E was rediscovered as 'factor 2 antioxidant' in 1965 [4]. Not surprisingly, as the major isoform of Vitamin E ever identified, α-tocopherol was thrust into the limelight while its sisters were ignored. Tocopherol is regarded as the most biologically active and potent antioxidant currently in existence. However, recent studies have shown that tocotrienols may have superior anti-oxidant [5], antiinflammatory [6], anti-cholesterolaemic, [7–11] anti-cancer [12, 13], anti-diabetic [14–16], anti-atherogenic [17, 18], blood pressure lowering, [19, 20] and neuroprotective effects [21–23]. Unfortunately, despite the recent interest in tocotrienols, it

Generally, vitamin E is classified into tocopherols and tocotrienols, and there

are eight isoforms altogether: α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol. Structurally, they are very similar and possess a chromanol head formed by phenolic and heterocyclic rings, and a phenyl tail [25]. Designation as α-, β-, γ- or δ-tocopherol or tocotrienols is dependent on the methyl substitutions on

comprises only 3% of all vitamin E research papers listed in PubMed [24].

**2. Biochemical properties of vitamin E isoforms**

**202**

**Figure 1.**

*The different structures between tocopherols and tocotrienols.*

Vitamin E occurs naturally in vegetables, plants and plant oils. With regard to tocopherols, α-tocopherol is generally found in green leafy plants while γ-tocopherol occurs in the non-green parts of the plants, notably seeds and fruits [29]. Based on the United States Department of Agriculture nutrient database, α-tocopherol is commonly found in almonds, avocados, hazelnuts, peanuts and sunflower seeds; β-tocopherol in oregano and poppy seeds; γ-tocopherol in pecans, pistachios, sesame seeds and walnuts; and δ-tocopherol in edamame and raspberries. Both α-tocopherol and γ-tocopherol are present in food oils such as corn, peanut and soybean oil. Conversely, tocotrienols are rarely found in food sources or vegetable oils, with rice bran and palm oil being the only known exceptions. This explains the scarcity of scientific literature on tocotrienols compared to tocopherols as a form of vitamin E that is widely accepted by the public. In fact, most people are unaware that up to 70% of vitamin E from crude palm oil consists of tocotrienols [30, 31]. Studies have proven that the extraction of crude palm oil (scientifically known as *Elaeis guineensis*) can yield up to 800 mg/kg of tocotrienols in the form of α-tocotrienol and γ-tocotrienol [32]. Moreover, cereal grains such as barley, oat, rice, rye and wheat contain a higher concentration of tocotrienols than tocopherol in a ratio of 79:21, 77:23, 67:55, 51:49 and 55:45 respectively [24]. However, in food supplements, tocotrienols are often prepared in soft-gel capsules. Even at a dose of 1000 mg daily, this is equivalent to a daily intake of 16.7 mg of tocotrienol/kg/day for a 60-kg person, or about seven times below the level where no adverse effects were observed in rats [33]. Hence, the usual dosage for any experimental use in humans has always been 400 mg daily in two divided doses which is a safe dosage with no observable adverse effects on any study patients to date.

#### **4. Bioavailability and pharmacokinetics of vitamin E**

Compelling evidence from recent research prove that tocotrienols are detected at appreciable levels in the plasma after supplementation, whether this was done on a short-term or long-term basis [34]. While both compounds are basically bioavailable, tocotrienol has a shorter plasma half-life [33]. One study showed that the halflife of α-, γ- and δ-tocotrienols in human plasma was estimated to be 2.3, 4.4 and 4.3 hours respectively [35]. However, the half-life of α-tocopherol and γ-tocopherol was 57 and 13 hours respectively [36]. Given that tocotrienols are essentially oil-based compounds, and that emulsions are known to increase the absorption of oil-based compounds based on the new system of self-emulsifying drug delivery system [37], new products such as Tocovid Suprabio™ were developed following this technique. This new product led to a threefold increase in the peak plasma concentration of α-tocotrienol in humans compared to a previous study [38]. It has also been shown that the bioavailability of tocotrienols is dependent on several

factors, food status being one of them. The mean apparent volume of tocotrienol distribution values is lower in the fed state, which means that the absorption is much better than in the fasting state [35]. Undoubtedly, tocotrienols have a very different pharmacokinetics from tocopherols which remain longer in the bloodstream. However, the biodistribution of tocotrienols pointed to the accumulation of the compound in the vital organs [34]. Therefore, tocotrienols would score high in terms of therapeutic efficacy since this requires not only bioavailability but also presence in the target organs.

#### **5. Vitamin E as an anti-oxidant**

One of the most well-known effects of vitamin E is its anti-oxidant capability in inhibiting the peroxidation of lipids after its incorporation into the cellular membranes [39]. It is well documented that tocotrienol scavenges the chain propagating the peroxyl radicals [39]. Indeed, α-tocotrienol has a much stronger anti-oxidant effect than α-tocopherol. This superiority is due to a more even distribution of α-tocotrienol in the plasma membrane as a result of a more efficient collision of α-tocotrienol with the radicals. Compared to tocopherols, tocotrienols also have a higher recycling efficiency thanks to their chromanoxyl radicals [39]. These anti-oxidant properties of tocotrienol have a lasting impact on health in general. For instance, patients with hyperlipidaemia and carotid stenosis have been shown to demonstrate a significant reduction in thiobarbituric-acid-reactive substances that were related to platelet peroxidation. It is also proven that tocotrienols have the ability to scavenge free radicals that cause DNA damage, hence providing protection especially to the older age group [40].

#### **6. Preventing cardiovascular diseases**

One of the most feared ailments is cardiovascular disease, and with 17.9 million deaths every year, the World Health Organization (WHO) considers it the main cause of death globally [41]. WHO estimated that out of five mortalities from cardiovascular diseases, four were caused by heart attacks and strokes, with almost a third of these deaths occurring in people less than 70 years of age [41]. Among the modifiable risk factors of atherosclerosis that cause heart attacks are hyperlipidaemia, hypertension, diabetes mellitus and thrombosis. Given its ability as a lipidlowering, blood pressure-lowering, anti-diabetic and anti-thrombogenic agent, the effects of vitamin E – especially tocotrienol – deserve a thorough investigation.

#### **6.1 Prevention of atherosclerosis**

Atherosclerosis is considered the most important event that leads to heart attack and stroke as a result of abnormal deposits of lipids, cholesterol and plaque build-up. Animal studies have been conducted in rabbits to look at the microscopic development of atherosclerosis and lipid peroxidation. After ten weeks of treatment with tocotrienol-rich fraction (TRF) which normally consists of 80% tocotrienol and 20% tocopherol, the researchers [42] found that the cholesterol-fed rabbits had a lower content of malondialdehyde (MDA) or modified low density lipoprotein – a diagnostic biochemical marker for atherosclerosis. The rabbits also had less intimal thickening, while their internal elastic lamina was better preserved compared to those fed on a normal diet. Another study [43] showed that atherosclerosis is prevented through the modulation of the peroxisome proliferator-activated receptors (PPAR) when TRF is administered. A different study [44] found that, after

**205**

concerned.

**7. Lipid-lowering effect**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

the lipid profiles, thereby preventing atherosclerosis.

being given TRF, subjects undergoing chronic haemodialysis showed improvement in their high-density lipoprotein (HDL), triglycerides and total plasma cholesterol as compared to placebo. All these studies prove that TRF intake essentially improves

Another important issue is related to myocardial ischaemia reperfusion injury. This happens when blood flow is restored to an infarcted myocardium either via percutaneous transluminal coronary angioplasty or bypass surgery. Restoring the blood flow, a process known as reperfusion, could also cause injury to the heart muscles and is therefore termed as myocardial ischaemia reperfusion injury. Reperfusion injury could account for almost 50% of the final size of myocardial infarction [45]. Almost all isoforms of tocotrienol have been shown to have cardioprotective effect. Nonetheless, γ-tocotrienol is demonstrably the most potent in myocardial ischaemic injury model. This particular study [46] shows that the interaction between mitogen-activated protein kinase (MAPK) with caveolin and proteasome plays an important role in the cardioprotective effect of tocotrienol that is achieved by altering the availability of pro-survival and anti-survival proteins.

The discussion on this topic would be incomplete without any mention of thromboembolic events. In one animal study on dogs [47], an injection of intravenous tocotrienols and tocopherols was administered; it was noted that the cyclic flow that measures the acute platelet-mediated thrombus formation and collageninduced platelet aggregation was significantly reduced in those receiving tocotri-

All these data suggest that tocotrienols provide better cardioprotective effect than tocopherols insofar as myocardial infarction, stroke or thrombosis is

Studies on the hypercholesterolaemic properties of tocotrienols have gained traction after it was shown that the addition of tocotrienols significantly lowered the cholesterol level [48]. This effect was mediated by the inhibition of HMG-CoA reductase by post-transcriptional suppression of the enzyme itself by tocotrienols [49]. Indeed, γ-tocotrienol has been observed to have a dramatic 30-fold activity in inhibiting HMG-CoA reductase [50]. A later study further indicated that the American Heart Association Step 1 diet and TRF25 (25–200 mg/day) from rice bran could reduce the total cholesterol, LDL, triglycerides, and also apolipoprotein B in hypercholesterolaemic patients [51]. Another study demonstrated that when 30 mg tocotrienols are mixed with 270 mg flavonoids, the total serum cholesterol level, LDL, triglycerides and apolipoprotein B are also reduced in hypercholesterolaemic patients [52]. Furthermore, hypercholesterolaemic patients with non-alcoholic fatty liver disease who were treated with mixed-tocotrienols showed a higher percentage of normal liver echogenic response [53]. A study on atherogenesis using human monocyte-macrophages showed that α-tocotrienol, like the new compound FeAOX-6 which combines both the anti-oxidant structural features of tocopherols and carotenoids, reduced the cholesterol accumulation in the cells, with

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

**6.2 Protection against reperfusion injury**

**6.3 Reduction of thromboembolic events**

enol compared to those injected with tocopherol.

α-tocotrienol having a more potent effect [54].

#### *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

being given TRF, subjects undergoing chronic haemodialysis showed improvement in their high-density lipoprotein (HDL), triglycerides and total plasma cholesterol as compared to placebo. All these studies prove that TRF intake essentially improves the lipid profiles, thereby preventing atherosclerosis.

#### **6.2 Protection against reperfusion injury**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

presence in the target organs.

**5. Vitamin E as an anti-oxidant**

**6. Preventing cardiovascular diseases**

**6.1 Prevention of atherosclerosis**

factors, food status being one of them. The mean apparent volume of tocotrienol distribution values is lower in the fed state, which means that the absorption is much better than in the fasting state [35]. Undoubtedly, tocotrienols have a very different pharmacokinetics from tocopherols which remain longer in the bloodstream. However, the biodistribution of tocotrienols pointed to the accumulation of the compound in the vital organs [34]. Therefore, tocotrienols would score high in terms of therapeutic efficacy since this requires not only bioavailability but also

One of the most well-known effects of vitamin E is its anti-oxidant capability in inhibiting the peroxidation of lipids after its incorporation into the cellular membranes [39]. It is well documented that tocotrienol scavenges the chain propagating the peroxyl radicals [39]. Indeed, α-tocotrienol has a much stronger anti-oxidant effect than α-tocopherol. This superiority is due to a more even distribution of α-tocotrienol in the plasma membrane as a result of a more efficient collision of α-tocotrienol with the radicals. Compared to tocopherols, tocotrienols also have a higher recycling efficiency thanks to their chromanoxyl radicals [39]. These anti-oxidant properties of tocotrienol have a lasting impact on health in general. For instance, patients with hyperlipidaemia and carotid stenosis have been shown to demonstrate a significant reduction in thiobarbituric-acid-reactive substances that were related to platelet peroxidation. It is also proven that tocotrienols have the ability to scavenge free radicals that cause DNA

damage, hence providing protection especially to the older age group [40].

One of the most feared ailments is cardiovascular disease, and with 17.9 million deaths every year, the World Health Organization (WHO) considers it the main cause of death globally [41]. WHO estimated that out of five mortalities from cardiovascular diseases, four were caused by heart attacks and strokes, with almost a third of these deaths occurring in people less than 70 years of age [41]. Among the modifiable risk factors of atherosclerosis that cause heart attacks are hyperlipidaemia, hypertension, diabetes mellitus and thrombosis. Given its ability as a lipidlowering, blood pressure-lowering, anti-diabetic and anti-thrombogenic agent, the effects of vitamin E – especially tocotrienol – deserve a thorough investigation.

Atherosclerosis is considered the most important event that leads to heart attack and stroke as a result of abnormal deposits of lipids, cholesterol and plaque build-up. Animal studies have been conducted in rabbits to look at the microscopic development of atherosclerosis and lipid peroxidation. After ten weeks of treatment with tocotrienol-rich fraction (TRF) which normally consists of 80% tocotrienol and 20% tocopherol, the researchers [42] found that the cholesterol-fed rabbits had a lower content of malondialdehyde (MDA) or modified low density lipoprotein – a diagnostic biochemical marker for atherosclerosis. The rabbits also had less intimal thickening, while their internal elastic lamina was better preserved compared to those fed on a normal diet. Another study [43] showed that atherosclerosis is prevented through the modulation of the peroxisome proliferator-activated receptors (PPAR) when TRF is administered. A different study [44] found that, after

**204**

Another important issue is related to myocardial ischaemia reperfusion injury. This happens when blood flow is restored to an infarcted myocardium either via percutaneous transluminal coronary angioplasty or bypass surgery. Restoring the blood flow, a process known as reperfusion, could also cause injury to the heart muscles and is therefore termed as myocardial ischaemia reperfusion injury. Reperfusion injury could account for almost 50% of the final size of myocardial infarction [45]. Almost all isoforms of tocotrienol have been shown to have cardioprotective effect. Nonetheless, γ-tocotrienol is demonstrably the most potent in myocardial ischaemic injury model. This particular study [46] shows that the interaction between mitogen-activated protein kinase (MAPK) with caveolin and proteasome plays an important role in the cardioprotective effect of tocotrienol that is achieved by altering the availability of pro-survival and anti-survival proteins.

#### **6.3 Reduction of thromboembolic events**

The discussion on this topic would be incomplete without any mention of thromboembolic events. In one animal study on dogs [47], an injection of intravenous tocotrienols and tocopherols was administered; it was noted that the cyclic flow that measures the acute platelet-mediated thrombus formation and collageninduced platelet aggregation was significantly reduced in those receiving tocotrienol compared to those injected with tocopherol.

All these data suggest that tocotrienols provide better cardioprotective effect than tocopherols insofar as myocardial infarction, stroke or thrombosis is concerned.

#### **7. Lipid-lowering effect**

Studies on the hypercholesterolaemic properties of tocotrienols have gained traction after it was shown that the addition of tocotrienols significantly lowered the cholesterol level [48]. This effect was mediated by the inhibition of HMG-CoA reductase by post-transcriptional suppression of the enzyme itself by tocotrienols [49]. Indeed, γ-tocotrienol has been observed to have a dramatic 30-fold activity in inhibiting HMG-CoA reductase [50]. A later study further indicated that the American Heart Association Step 1 diet and TRF25 (25–200 mg/day) from rice bran could reduce the total cholesterol, LDL, triglycerides, and also apolipoprotein B in hypercholesterolaemic patients [51]. Another study demonstrated that when 30 mg tocotrienols are mixed with 270 mg flavonoids, the total serum cholesterol level, LDL, triglycerides and apolipoprotein B are also reduced in hypercholesterolaemic patients [52]. Furthermore, hypercholesterolaemic patients with non-alcoholic fatty liver disease who were treated with mixed-tocotrienols showed a higher percentage of normal liver echogenic response [53]. A study on atherogenesis using human monocyte-macrophages showed that α-tocotrienol, like the new compound FeAOX-6 which combines both the anti-oxidant structural features of tocopherols and carotenoids, reduced the cholesterol accumulation in the cells, with α-tocotrienol having a more potent effect [54].

#### **8. Anti-diabetic effect**

Diabetes mellitus – which has risen dramatically in all countries irrespective of their income levels – is a chronic metabolic disease characterised by elevated blood sugar level that could affect the eyes, kidneys and nerves in the long run. While Type II diabetes develops when the body becomes resistant to insulin, Type I diabetes arises when the pancreas produces less or no insulin at all. According to current WHO estimates, approximately 422 million people worldwide suffer from diabetes [55]. Indeed, about 1.6 million deaths are attributed to diabetes on a yearly basis [55]. Alarmingly, these dismal numbers have been growing steadily in the last few decades.

Studies on the antidiabetic effects of vitamin E were conducted as early as the 1990s to determine any possible association between vitamin E and diabetic risks [56–58] as well as the correlation between the dietary intake of vitamin E and insulin action [59, 60]. In a 2004 study with a very long follow-up, it was demonstrated that the intake of vitamin E reduces the risk of Type II diabetes onset [61]. It was also found that TRF reduces the total cholesterol level, low-density lipoprotein (LDL) and total plasma lipid in diabetic patients [62]. Patients who were given canola oil enriched with tocotrienol also showed a significant reduction in their urine microalbumin and the serum C-reactive protein (CRP) known for its protective effect on the kidney and against nitrosative stress [63]. In an animal model, it was observed that both TRF and α-tocopherol improved the vascular endothelial function in streptozotocin-induced diabetic rats through their sparing effect on endothelium derived nitric oxide bioavailability [64]. Another study determining the effects of TRF on erythrocyte membranes and leukocyte deoxyribonucleic acid (DNA) damage in streptozotocin-induced diabetic rats revealed that daily supplementation of tocotrienol for four weeks could inhibit lipid peroxidation while increasing the level of antioxidant markers [65]. In an animal study on the cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes, it was shown that the administration of tocotrienol significantly prevented behavioural, biochemical and molecular changes associated with diabetes. This points to the potential benefit of tocotrienol in preventing diabetic encephalopathy [66].

#### **8.1 Preventing diabetic nephropathy**

Diabetic nephropathy is a common complication of both Type I and Type II diabetes. Diabetic nephropathy (also called clinical nephropathy, proteinuria or microalbuminuria) is defined by the presence of protein of >0.5 g/24 h in the urine [67] and it increases the risk of death. In an animal study [68] designed to investigate the impact of tocotrienol in streptozotocin-induced diabetes in terms of renal function and reno-inflammatory cascade, it was found that tocotrienol has a more profound effect than tocopherol in preventing biochemical and molecular changes associated with diabetes [68]. It was concluded from the study [68] that tocotrienol modulates the release of pro-fibrolytic cytokines, apoptosis, the ongoing inflammation, and the associated oxidative stress, which confers a renoprotective effect on the kidneys. Another study [69] was designed to determine whether TRF from palm oil (PO) or rice bran oil (RBO) could improve the renal function of rats as a result of their hypoglycaemic and anti-oxidant effect. The results analysed the fasting blood glucose, glycosylated haemoglobin, renal function biological markers, and oxidative stress in the serum and urine of the rats. It was revealed that both palm-oil TRF (PO-TRF) and rice bran oil TRF (RBO-TRF) significantly improved renal function and glycaemic status, although PO-TRF conferred a better efficacy than RBO-TRF [68]. Hence, it was concluded that PO-TRF was more effective as a neuroprotective

**207**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

count, retinal cell apoptosis and retinal expression of VEGF.

One of the complications faced by almost 26% to 53% of diabetic patients worldwide is diabetic peripheral neuropathy [86, 87] that significantly impairs their quality of life [86]. The total cost of diabetic care [88] is around 4.2-fold higher among diabetic patients with neuropathic pain [89]. The mainstay treatment for managing diabetic neuropathy surely lies in glycaemic control and pain management [88]. To that end, various pharmacological agents [90, 91] have been used, but they are all limited either by their adverse effects or by having no effect at all on the pathway of the neuropathic pain [92]. It is believed that oxidative stress plays a role in the pathogenesis of peripheral neuropathy [93]. One animal study with diabetic rats has shown that neuropathic pain is reversed by tocotrienols via the modulation of oxidative-nitrosative stress, caspase-3, and inflammatory cytokine release [94]. Another prospective study [95] on human subjects was aimed at evaluating the protective effect of mixed tocotrienol on the white matter lesion (WML) that reflects neurodegenerative changes; it was shown that subjects who received 200 mg of mixed tocotrienols twice daily for two years have attenuated progression of WMLs compared to placebo [95]. However, a recent study by the investigators of the

**8.3 Preventing diabetic neuropathy**

and hypoglycaemic agent compared to RBO-TRF [69]. Another study [70] revealed that TRF ameliorated lipid induced nephropathy in type-II diabetes by modulating the TGF-β – besides leveraging on its hypoglycaemic, hypolipidaemic and antioxidant properties – in order to prevent the increased expression of collagen type IV and fibrinogen. A recent prospective, randomized double-blind study [71] that was conducted to assess the effect of tocotrienol-rich vitamin E on diabetic nephropathy found that it attenuates the progression of diabetic nephropathy. It was also observed that a 12-week supplementation with tocotrienol-rich vitamin E led to a statistically significant improvement in renal function despite having no effect on glycaemia [71].

One of the most common complications of diabetes mellitus is diabetic retinopathy which could lead to blindness in severe cases [72]. It is estimated that the prevalence of diabetic retinopathy worldwide is about 35%, with approximately 10% of the world population afflicted with a vision-threatening disease [73, 74]. A strong correlation has been established between chronic hyperglycaemia and poor diabetic control with diabetic retinopathy [75]. Indeed, with the incidence of diabetes mellitus rising worldwide [76], a concomitant increase in diabetic retinopathy is to be expected [77]. A characteristic feature of diabetic retinopathy is retinal microvascular changes accompanied by an earlier neurodegeneration [78]. Oxidative stress, which induces hyperglycaemia, is considered as one of the main factors responsible for microvascular complication in diabetes mellitus [79]. Hyperglycaemia triggers cellular events resulting in inflammatory cytokines reactions that in turn accelerate microvascular changes [80]. Another important event is angiogenesis, an over-expression of vascular endothelial growth factor (VEGF) associated with neurodegeneration and diabetes-induced oxidative stress [81]. As mentioned earlier, antioxidants confer their benefit in oxidative stress-induced diseases, including diabetic retinopathy [82, 83], by scavenging free radicals through the hydrogen atom situated at the chromanol ring [84]. Indeed, a recent study [85] on streptozotocin-induced diabetic retinopathy in rats alluded to the beneficial effect of tocotrienol in preventing retinal neurodegenerative changes; it was shown that TRF prevented diabetic-induced changes in retinal layer thickness, retinal cell

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

**8.2 Preventing diabetic retinopathy**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

and hypoglycaemic agent compared to RBO-TRF [69]. Another study [70] revealed that TRF ameliorated lipid induced nephropathy in type-II diabetes by modulating the TGF-β – besides leveraging on its hypoglycaemic, hypolipidaemic and antioxidant properties – in order to prevent the increased expression of collagen type IV and fibrinogen. A recent prospective, randomized double-blind study [71] that was conducted to assess the effect of tocotrienol-rich vitamin E on diabetic nephropathy found that it attenuates the progression of diabetic nephropathy. It was also observed that a 12-week supplementation with tocotrienol-rich vitamin E led to a statistically significant improvement in renal function despite having no effect on glycaemia [71].

#### **8.2 Preventing diabetic retinopathy**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

Diabetes mellitus – which has risen dramatically in all countries irrespective of their income levels – is a chronic metabolic disease characterised by elevated blood sugar level that could affect the eyes, kidneys and nerves in the long run. While Type II diabetes develops when the body becomes resistant to insulin, Type I diabetes arises when the pancreas produces less or no insulin at all. According to current WHO estimates, approximately 422 million people worldwide suffer from diabetes [55]. Indeed, about 1.6 million deaths are attributed to diabetes on a yearly basis [55]. Alarmingly, these dismal numbers have been growing steadily in the last

Studies on the antidiabetic effects of vitamin E were conducted as early as the 1990s to determine any possible association between vitamin E and diabetic risks [56–58] as well as the correlation between the dietary intake of vitamin E and insulin action [59, 60]. In a 2004 study with a very long follow-up, it was demonstrated that the intake of vitamin E reduces the risk of Type II diabetes onset [61]. It was also found that TRF reduces the total cholesterol level, low-density lipoprotein (LDL) and total plasma lipid in diabetic patients [62]. Patients who were given canola oil enriched with tocotrienol also showed a significant reduction in their urine microalbumin and the serum C-reactive protein (CRP) known for its protective effect on the kidney and against nitrosative stress [63]. In an animal model, it was observed that both TRF and α-tocopherol improved the vascular endothelial function in streptozotocin-induced diabetic rats through their sparing effect on endothelium derived nitric oxide bioavailability [64]. Another study determining the effects of TRF on erythrocyte membranes and leukocyte deoxyribonucleic acid (DNA) damage in streptozotocin-induced diabetic rats revealed that daily supplementation of tocotrienol for four weeks could inhibit lipid peroxidation while increasing the level of antioxidant markers [65]. In an animal study on the cognitive function and neuroinflammatory cascade in streptozotocin-induced diabetes, it was shown that the administration of tocotrienol significantly prevented behavioural, biochemical and molecular changes associated with diabetes. This points to the potential benefit of tocotrienol in preventing diabetic encephalopathy [66].

Diabetic nephropathy is a common complication of both Type I and Type II diabetes. Diabetic nephropathy (also called clinical nephropathy, proteinuria or microalbuminuria) is defined by the presence of protein of >0.5 g/24 h in the urine [67] and it increases the risk of death. In an animal study [68] designed to investigate the impact of tocotrienol in streptozotocin-induced diabetes in terms of renal function and reno-inflammatory cascade, it was found that tocotrienol has a more profound effect than tocopherol in preventing biochemical and molecular changes associated with diabetes [68]. It was concluded from the study [68] that tocotrienol modulates the release of pro-fibrolytic cytokines, apoptosis, the ongoing inflammation, and the associated oxidative stress, which confers a renoprotective effect on the kidneys. Another study [69] was designed to determine whether TRF from palm oil (PO) or rice bran oil (RBO) could improve the renal function of rats as a result of their hypoglycaemic and anti-oxidant effect. The results analysed the fasting blood glucose, glycosylated haemoglobin, renal function biological markers, and oxidative stress in the serum and urine of the rats. It was revealed that both palm-oil TRF (PO-TRF) and rice bran oil TRF (RBO-TRF) significantly improved renal function and glycaemic status, although PO-TRF conferred a better efficacy than RBO-TRF [68]. Hence, it was concluded that PO-TRF was more effective as a neuroprotective

**8. Anti-diabetic effect**

**8.1 Preventing diabetic nephropathy**

few decades.

**206**

One of the most common complications of diabetes mellitus is diabetic retinopathy which could lead to blindness in severe cases [72]. It is estimated that the prevalence of diabetic retinopathy worldwide is about 35%, with approximately 10% of the world population afflicted with a vision-threatening disease [73, 74]. A strong correlation has been established between chronic hyperglycaemia and poor diabetic control with diabetic retinopathy [75]. Indeed, with the incidence of diabetes mellitus rising worldwide [76], a concomitant increase in diabetic retinopathy is to be expected [77]. A characteristic feature of diabetic retinopathy is retinal microvascular changes accompanied by an earlier neurodegeneration [78]. Oxidative stress, which induces hyperglycaemia, is considered as one of the main factors responsible for microvascular complication in diabetes mellitus [79]. Hyperglycaemia triggers cellular events resulting in inflammatory cytokines reactions that in turn accelerate microvascular changes [80]. Another important event is angiogenesis, an over-expression of vascular endothelial growth factor (VEGF) associated with neurodegeneration and diabetes-induced oxidative stress [81]. As mentioned earlier, antioxidants confer their benefit in oxidative stress-induced diseases, including diabetic retinopathy [82, 83], by scavenging free radicals through the hydrogen atom situated at the chromanol ring [84]. Indeed, a recent study [85] on streptozotocin-induced diabetic retinopathy in rats alluded to the beneficial effect of tocotrienol in preventing retinal neurodegenerative changes; it was shown that TRF prevented diabetic-induced changes in retinal layer thickness, retinal cell count, retinal cell apoptosis and retinal expression of VEGF.

#### **8.3 Preventing diabetic neuropathy**

One of the complications faced by almost 26% to 53% of diabetic patients worldwide is diabetic peripheral neuropathy [86, 87] that significantly impairs their quality of life [86]. The total cost of diabetic care [88] is around 4.2-fold higher among diabetic patients with neuropathic pain [89]. The mainstay treatment for managing diabetic neuropathy surely lies in glycaemic control and pain management [88]. To that end, various pharmacological agents [90, 91] have been used, but they are all limited either by their adverse effects or by having no effect at all on the pathway of the neuropathic pain [92]. It is believed that oxidative stress plays a role in the pathogenesis of peripheral neuropathy [93]. One animal study with diabetic rats has shown that neuropathic pain is reversed by tocotrienols via the modulation of oxidative-nitrosative stress, caspase-3, and inflammatory cytokine release [94]. Another prospective study [95] on human subjects was aimed at evaluating the protective effect of mixed tocotrienol on the white matter lesion (WML) that reflects neurodegenerative changes; it was shown that subjects who received 200 mg of mixed tocotrienols twice daily for two years have attenuated progression of WMLs compared to placebo [95]. However, a recent study by the investigators of the

Vitamin E in Neuroprotective Study (VENUS) [96] found that the supplementation of oral mixed tocotrienols of 400 mg daily on diabetic patients with neuropathic pain did not show any remarkable improvement in alleviating the neuropathic symptoms. Nonetheless, the researchers qualified their statement by saying that their observation on the lancinating pain among the subsets of patients studied would require further exploration. More optimistically, a more recent randomizedcontrolled study [97] on the effects of tocotrienol on diabetic neuropathy showed that supplementation of tocotrienol-rich vitamin E of 200 mg twice daily led to a higher serum nerve growth factor (NGF) and improved the nerve conduction velocity for all nerves tested after eight weeks of supplementation. The researchers concluded that TRF could be a disease-modifying agent that targets the NGF in improving nerve conduction velocity [97].

#### **9. Preventing neurological diseases**

Neurodegenerative diseases have been widely believed to be caused by oxidative damage due to reactive oxygen species [98]. Indeed, the increased levels of oxidative stress have been associated with numerous pathophysiological conditions together with derangements in mitochondrial complex I activity [99, 100]. Since vitamin E is a potent anti-oxidative agent, it is hypothesised that the neuroprotective effects of vitamin E is mediated via its anti-oxidative property [101]. A growing body of evidence supports the view that tocotrienol is a potent neuroprotective agent against Alzheimer's disease [102]. However, as it stands today, the pathogenesis of Alzheimer's disease remains unclear with a few different hypotheses [103]. Nonetheless, the ability of tocotrienol in reducing oxidative stress and promoting cellular repair contributes to its positive and beneficial effect in protecting the neurons. Admittedly, no clinical trials are available to support the hypothesis that tocotrienol could prevent Alzheimer's disease, with available data based on only four human epidemiological studies [104–107]. With more studies in the future, this research gap could certainly be narrowed. **Figure 2** below summarizes the possible pathways for the neuroprotective actions of tocotrienol.

#### **Figure 2.**

*A summary of the current in vitro evidence of neuroprotective actions of tocotrienol. Legend: Solid line represents beneficial effects of tocotrienol on neurons. Dotted line represents potential adverse effects of tocotrienol on neurons.*

**209**

**Figure 3.**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

tocotrienol on the bone are summarised below in **Figure 3** [125].

*The effects of tocotrienol on bone histomorphometry, bone mineral and bone calcium content.*

Osteoporosis, a metabolic bone disease requiring extensive healthcare, is common in both men and women, though women suffer fragility fracture from osteoporosis at a ratio of 6:1 to men [108]. Osteoporosis is caused by an imbalance in bone remodelling, where the rate of bone resorption is faster than bone formation [109]. While it is known that menopause in women leads to oestrogen deficiency, in men, however, it is due to late-onset testosterone deficiency [110, 111]. The existing therapies for osteoporosis include bisphosphonates, teriparatide and strontium ranelate, all of which increase bone mineral density [112]. Recent studies have tried to explore the use of natural products to cure osteoporosis. With its inherent antioxidative and anti-inflammatory properties that are implicated in the pathogenesis of osteoporosis, tocotrienol is an agent of choice for such studies [113, 114]. Oxidative stress is known to damage osteoblasts by affecting both its differentiation and survival [115]. Oxidative stress also affects the signalling of osteoclasts and promotes the differentiation process [116]. Similarly, proinflammatory cytokines such as tumour necrosis factor (TNF), interleukin 1 (IL-1), and interleukin-6 (IL-6) promote osteoclasts differentiation [117]. The expression of proinflammatory cytokines is also suppressed by tocotrienol [118]. Hence, it is reasonable to assume that by reducing both oxidative stress and inflammation, the process of osteoporosis could be mitigated, if not prevented, by tocotrienol. A study on bone histomorphometry [119] that describes the bone volume and trabecular number, thickness and separation showed that palm tocotrienol preserved the trabecular bone structure, volume, and trabecular separation in rats with ovarian deficiency from ovariectomy. It was also demonstrated in another study [120] that in the bone loss model of rats, palm tocotrienol decreased the eroded surface and increased the osteoblast number, osteoid surface and osteoid volume in the supplemented study animal as compared to the other arm of the study. In another experiment on ovariectomised rats [121], the group that was treated with palm vitamin E showed significantly higher bone mineral density at the femur and vertebrae compared to the untreated group. The bone calcium level at the femur and vertebra of orchidectomised and ovariectomised was also found to be restored with palm vitamin E supplementation [122, 123]. Nonetheless, while tocotrienol has been proven to improve bone density and microarchitecture, and enhance bone biomechanical strength, the study [124] done was not convincing enough to show any statistical difference. The effects of

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

**10. Preventing bone diseases**

### **10. Preventing bone diseases**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

possible pathways for the neuroprotective actions of tocotrienol.

*A summary of the current in vitro evidence of neuroprotective actions of tocotrienol. Legend: Solid line represents beneficial effects of tocotrienol on neurons. Dotted line represents potential adverse effects of* 

improving nerve conduction velocity [97].

**9. Preventing neurological diseases**

Vitamin E in Neuroprotective Study (VENUS) [96] found that the supplementation of oral mixed tocotrienols of 400 mg daily on diabetic patients with neuropathic pain did not show any remarkable improvement in alleviating the neuropathic symptoms. Nonetheless, the researchers qualified their statement by saying that their observation on the lancinating pain among the subsets of patients studied would require further exploration. More optimistically, a more recent randomizedcontrolled study [97] on the effects of tocotrienol on diabetic neuropathy showed that supplementation of tocotrienol-rich vitamin E of 200 mg twice daily led to a higher serum nerve growth factor (NGF) and improved the nerve conduction velocity for all nerves tested after eight weeks of supplementation. The researchers concluded that TRF could be a disease-modifying agent that targets the NGF in

Neurodegenerative diseases have been widely believed to be caused by oxidative damage due to reactive oxygen species [98]. Indeed, the increased levels of oxidative stress have been associated with numerous pathophysiological conditions together with derangements in mitochondrial complex I activity [99, 100]. Since vitamin E is a potent anti-oxidative agent, it is hypothesised that the neuroprotective effects of vitamin E is mediated via its anti-oxidative property [101]. A growing body of evidence supports the view that tocotrienol is a potent neuroprotective agent against Alzheimer's disease [102]. However, as it stands today, the pathogenesis of Alzheimer's disease remains unclear with a few different hypotheses [103]. Nonetheless, the ability of tocotrienol in reducing oxidative stress and promoting cellular repair contributes to its positive and beneficial effect in protecting the neurons. Admittedly, no clinical trials are available to support the hypothesis that tocotrienol could prevent Alzheimer's disease, with available data based on only four human epidemiological studies [104–107]. With more studies in the future, this research gap could certainly be narrowed. **Figure 2** below summarizes the

**208**

**Figure 2.**

*tocotrienol on neurons.*

Osteoporosis, a metabolic bone disease requiring extensive healthcare, is common in both men and women, though women suffer fragility fracture from osteoporosis at a ratio of 6:1 to men [108]. Osteoporosis is caused by an imbalance in bone remodelling, where the rate of bone resorption is faster than bone formation [109]. While it is known that menopause in women leads to oestrogen deficiency, in men, however, it is due to late-onset testosterone deficiency [110, 111]. The existing therapies for osteoporosis include bisphosphonates, teriparatide and strontium ranelate, all of which increase bone mineral density [112]. Recent studies have tried to explore the use of natural products to cure osteoporosis. With its inherent antioxidative and anti-inflammatory properties that are implicated in the pathogenesis of osteoporosis, tocotrienol is an agent of choice for such studies [113, 114]. Oxidative stress is known to damage osteoblasts by affecting both its differentiation and survival [115]. Oxidative stress also affects the signalling of osteoclasts and promotes the differentiation process [116]. Similarly, proinflammatory cytokines such as tumour necrosis factor (TNF), interleukin 1 (IL-1), and interleukin-6 (IL-6) promote osteoclasts differentiation [117]. The expression of proinflammatory cytokines is also suppressed by tocotrienol [118]. Hence, it is reasonable to assume that by reducing both oxidative stress and inflammation, the process of osteoporosis could be mitigated, if not prevented, by tocotrienol. A study on bone histomorphometry [119] that describes the bone volume and trabecular number, thickness and separation showed that palm tocotrienol preserved the trabecular bone structure, volume, and trabecular separation in rats with ovarian deficiency from ovariectomy. It was also demonstrated in another study [120] that in the bone loss model of rats, palm tocotrienol decreased the eroded surface and increased the osteoblast number, osteoid surface and osteoid volume in the supplemented study animal as compared to the other arm of the study. In another experiment on ovariectomised rats [121], the group that was treated with palm vitamin E showed significantly higher bone mineral density at the femur and vertebrae compared to the untreated group. The bone calcium level at the femur and vertebra of orchidectomised and ovariectomised was also found to be restored with palm vitamin E supplementation [122, 123]. Nonetheless, while tocotrienol has been proven to improve bone density and microarchitecture, and enhance bone biomechanical strength, the study [124] done was not convincing enough to show any statistical difference. The effects of tocotrienol on the bone are summarised below in **Figure 3** [125].

Let us now look at the mechanism of actions of tocotrienol in the prevention of osteoporosis. Studies have revealed that oxidative stress plays a major role in the development of osteoporosis [126, 127]. Any increase in the oxidative stress process would lead to a decrease in differentiation of osteoclasts [128] as well as the bone resorption activity [129], which would subsequently impair the musculoskeletal system. Some in vivo studies [124, 130] which supplemented the study rats with tocotrienol showed a reduction in oxidative stress and anti-oxidant enzyme activities such as malondialdehyde. Additionally, an in vitro study [131] showed that γ-tocotrienol homologue decreased the oxidative damage on primary osteoblast culture. Tocotrienol exerts its effect by preserving the antioxidant enzyme activities in bone cells affected with oxidative stress [132]. Another effect is via the mevalonate pathway which is known to regulate osteoblastogenesis and osteoclastogenesis [133]. Tocotrienol suppresses the mevalonate pathway via the hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that is also involved in cholesterol synthesis [134]. Another study [135] further revealed that tocotrienol, in combination with statins, enhances bone static histomorphometry and remodeling markers in the ovariectomised rats although it could not be confirmed whether this was via the mevalonate pathway alone or if it involved some other pathways as well. The anti-inflammatory effect of tocotrienol in preventing proinflammatory cytokines such as IL-1 and IL-6 has also been shown to preserve bone health in rats [120, 136, 137]. It is worth noting that the differentiation and activity of osteoclasts and osteoblast are governed by some genes [138] and that supplementation of palm vitamin E has been shown to significantly enhance the gene expression [139]. Another study [140] demonstrated that tocotrienol could enhance the gene expression related to bone formation and osteoblast activity. All the above-mentioned studies confirmed that tocotrienol possesses some promising bone-protective effect: it increases the osteoblast number, mineral deposition and bone formation; and it reduces the osteoclast number, thereby preventing the bone resorption, erosion, and degeneration of bone mineral density and microarchitecture. The summary of the whole mechanism is illustrated in **Figure 4** below.

**211**

asthmatic patients.

**12. Gastroprotective effect**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

be used in the management of TMJ rheumatoid arthritis.

It is also pertinent to look at another common ailment: bronchiole asthma. This chronic respiratory problem with a female preponderance afflicts more than 339 million people worldwide, according to a WHO estimate [155]. An increase in antinuclear antibodies and autoantibodies against bronchial epithelial antigens or endothelial antigens suggest that asthma is an autoimmune disease [156]. As the first experiment to demonstrate the effectiveness of tocotrienol in preventing asthma, a study [157] on rats showed that γ-tocotrienol possesses better free radicalneutralizing activity in vitro; reduces the eosinophil and neutrophil counts in vivo; and promotes lung-endogenous antioxidant activity. Another study investigated the effect of tocotrienol on airway remodelling [158], undoubtedly one of the characteristic features of asthma. It was shown that several inflammatory mediators were involved in airway remodelling [159, 160] and the most important among them is transforming growth factor beta1 TGF-β1 [161, 162]. The researchers convincingly proved the effect of γ-tocotrienol on the TGF-β1 induced differentiation of human airway smooth muscle and the extracellular deposition and the down-signaling of the airway smooth muscle cells activated by TGF-β1 [158]. This study suggested that γ-tocotrienol could play a therapeutic role in regulating airway remodelling in

Non-steroidal anti-inflammatory drugs (NSAIDs) are probably the most frequently used therapeutic agents in the world [163] for the treatment of pain, arthritis and trauma, besides many other indications. Achieving more than 73 million prescriptions per year [164], NSAIDs have been notoriously associated with gastrointestinal bleeding [165]. In an earlier study on a rat model of three different study groups [166], it was found that both TRF and tocopherol were equally

One of the most common autoimmune diseases is rheumatoid arthritis. With a prevalence of about 0.5 to 1.0% worldwide [141], it is presented as a typical systemic autoimmune disease of unknown aetiology that affects many joints [142]. The joint inflammation is characterised by some marked changes in the cartilage from the effects of proinflammatory mediators such as cytokines and C-reactive protein [143]. These include destruction of cartilage [144], leukocytes infiltration [145], and bone erosion [146]. The proinflammatory cytokines such as tumour necrosis factor-α (TNF-α), Interleukin-1α (IL-1α) and IL-1β [147] play a role in modulating inflammatory responses in the affected joints [148]. These cytokines have been shown to be involved in the pathogenesis of rheumatoid arthritis in animal studies. Since such studies closely mimic human disease [149], the development of biological agents that have the potential to modulate the cytokine mediators could yield an effective prevention against rheumatoid arthritis [150]. It has been demonstrated in an animal study [151] that palm γ-tocotrienol exerts an effect against both oxidative stress and joint pathology. In another study [152], it was discovered that palm δ-tocotrienol somehow reduced inflammation in arthritic rats. This should not be surprising given that palm tocotrienol has been shown to downregulate proinflammatory cytokines such as TNF-α, IL-1α, IL-β, IL-6 and IL-8 [153]. In another recent study [154] on the temporomandibular joint (TMJ) of a rat model, it was observed that in the group fed with TRF, the bone mineral density was notably increased. The researchers concluded that the concomitant decrease of plasma level of inflammatory cytokines with the increased bone density is sufficient evidence that TRF could

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

**11. Preventing autoimmune diseases**

**Figure 4.** *The bone protective mechanism of Tocotrienol.*

#### **11. Preventing autoimmune diseases**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

Let us now look at the mechanism of actions of tocotrienol in the prevention of osteoporosis. Studies have revealed that oxidative stress plays a major role in the development of osteoporosis [126, 127]. Any increase in the oxidative stress process would lead to a decrease in differentiation of osteoclasts [128] as well as the bone resorption activity [129], which would subsequently impair the musculoskeletal system. Some in vivo studies [124, 130] which supplemented the study rats with tocotrienol showed a reduction in oxidative stress and anti-oxidant enzyme activities such as malondialdehyde. Additionally, an in vitro study [131] showed that γ-tocotrienol homologue decreased the oxidative damage on primary osteoblast culture. Tocotrienol exerts its effect by preserving the antioxidant enzyme activities in bone cells affected with oxidative stress [132]. Another effect is via the mevalonate pathway which is known to regulate osteoblastogenesis and osteoclastogenesis [133]. Tocotrienol suppresses the mevalonate pathway via the hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that is also involved in cholesterol synthesis [134]. Another study [135] further revealed that tocotrienol, in combination with statins, enhances bone static histomorphometry and remodeling markers in the ovariectomised rats although it could not be confirmed whether this was via the mevalonate pathway alone or if it involved some other pathways as well. The anti-inflammatory effect of tocotrienol in preventing proinflammatory cytokines such as IL-1 and IL-6 has also been shown to preserve bone health in rats [120, 136, 137]. It is worth noting that the differentiation and activity of osteoclasts and osteoblast are governed by some genes [138] and that supplementation of palm vitamin E has been shown to significantly enhance the gene expression [139]. Another study [140] demonstrated that tocotrienol could enhance the gene expression related to bone formation and osteoblast activity. All the above-mentioned studies confirmed that tocotrienol possesses some promising bone-protective effect: it increases the osteoblast number, mineral deposition and bone formation; and it reduces the osteoclast number, thereby preventing the bone resorption, erosion, and degeneration of bone mineral density and microarchitecture. The summary of the whole mechanism is illustrated in **Figure 4** below.

**210**

**Figure 4.**

*The bone protective mechanism of Tocotrienol.*

One of the most common autoimmune diseases is rheumatoid arthritis. With a prevalence of about 0.5 to 1.0% worldwide [141], it is presented as a typical systemic autoimmune disease of unknown aetiology that affects many joints [142]. The joint inflammation is characterised by some marked changes in the cartilage from the effects of proinflammatory mediators such as cytokines and C-reactive protein [143]. These include destruction of cartilage [144], leukocytes infiltration [145], and bone erosion [146]. The proinflammatory cytokines such as tumour necrosis factor-α (TNF-α), Interleukin-1α (IL-1α) and IL-1β [147] play a role in modulating inflammatory responses in the affected joints [148]. These cytokines have been shown to be involved in the pathogenesis of rheumatoid arthritis in animal studies. Since such studies closely mimic human disease [149], the development of biological agents that have the potential to modulate the cytokine mediators could yield an effective prevention against rheumatoid arthritis [150]. It has been demonstrated in an animal study [151] that palm γ-tocotrienol exerts an effect against both oxidative stress and joint pathology. In another study [152], it was discovered that palm δ-tocotrienol somehow reduced inflammation in arthritic rats. This should not be surprising given that palm tocotrienol has been shown to downregulate proinflammatory cytokines such as TNF-α, IL-1α, IL-β, IL-6 and IL-8 [153]. In another recent study [154] on the temporomandibular joint (TMJ) of a rat model, it was observed that in the group fed with TRF, the bone mineral density was notably increased. The researchers concluded that the concomitant decrease of plasma level of inflammatory cytokines with the increased bone density is sufficient evidence that TRF could be used in the management of TMJ rheumatoid arthritis.

It is also pertinent to look at another common ailment: bronchiole asthma. This chronic respiratory problem with a female preponderance afflicts more than 339 million people worldwide, according to a WHO estimate [155]. An increase in antinuclear antibodies and autoantibodies against bronchial epithelial antigens or endothelial antigens suggest that asthma is an autoimmune disease [156]. As the first experiment to demonstrate the effectiveness of tocotrienol in preventing asthma, a study [157] on rats showed that γ-tocotrienol possesses better free radicalneutralizing activity in vitro; reduces the eosinophil and neutrophil counts in vivo; and promotes lung-endogenous antioxidant activity. Another study investigated the effect of tocotrienol on airway remodelling [158], undoubtedly one of the characteristic features of asthma. It was shown that several inflammatory mediators were involved in airway remodelling [159, 160] and the most important among them is transforming growth factor beta1 TGF-β1 [161, 162]. The researchers convincingly proved the effect of γ-tocotrienol on the TGF-β1 induced differentiation of human airway smooth muscle and the extracellular deposition and the down-signaling of the airway smooth muscle cells activated by TGF-β1 [158]. This study suggested that γ-tocotrienol could play a therapeutic role in regulating airway remodelling in asthmatic patients.

#### **12. Gastroprotective effect**

Non-steroidal anti-inflammatory drugs (NSAIDs) are probably the most frequently used therapeutic agents in the world [163] for the treatment of pain, arthritis and trauma, besides many other indications. Achieving more than 73 million prescriptions per year [164], NSAIDs have been notoriously associated with gastrointestinal bleeding [165]. In an earlier study on a rat model of three different study groups [166], it was found that both TRF and tocopherol were equally

effective in preventing aspirin-induced gastric ulcer. In another recent study [167] on a rat model comparing control to a group fed with omeprazole and another group with tocotrienol, it was discovered that while both groups were effective against gastric ulcer, the tocotrienol group displayed various modes in its protective effect – via the nitric oxide (NO) pathway and superoxide dismutase (SOD) activity – and in reducing TNF-α activity.

#### **13. Radioprotective effect**

With the increasing adoption of radiation in both clinical and non-clinical applications [168], human exposure to radiation is set for an exponential increase. Radiation toxicity is manifested in oxidative stress and DNA damage [169], inflammatory changes [170] and cell apoptosis [171]. Studies were carried out to examine the potential benefits of naturally occurring products such as vitamin E, a potent anti-oxidant with the capacity to neutralize free radicals from radiation exposure by donating H atoms [172]. It was shown that exposure to ionizing radiation yields reactive oxygen species (ROS) and nitrogen species (RNS), hydroxyl radical, superoxide, peroxynitrite and hydrogen peroxide. These reactive species of ROS and RNS with radiation-induced radicals damage proteins, DNA and lipids, besides activating intracellular signalling pathways that release cytochrome C from the mitochondria, eventually leading to cell apoptosis [173–175]. Thanks to its potent anti-oxidant properties, tocotrienol has been a subject of several studies and has been reported to be radioprotective [176–178]. Studies on a rat model [176, 179] have showed the protective effect of γ-tocotrienol against radiation-induced DNA damage through the activation of haematopoietic progenitors, red and white blood cells including platelets, and also through the inhibition of 3-hydroxy-3-methylglutaryl-CoA Reductase (HMG-CoA Reductase) – a protein-coding gene-mediated nitrosative stress [180]. It is also proven that γ-tocotrienol increases serum IL-6 and granulocyte colony stimulating factor (G-CSF), both of which induce haematopoiesis and are protective against radiation-induced neutropenia and thrombocytopenia in mice [181].

#### **14. Anti-cancer effect**

Cancer (also known as malignant tumours or neoplasms) is the second leading cause of mortality globally according to WHO [182], with an estimated 9.6 million deaths in 2018. The cancer burden keeps on growing inexorably, exerting its pressure emotionally and financially on individuals and families, not to mention the community and health system. While chemotherapy has been the mainstay of treatment, it is limited by a few factors such as tumour immune evasion [183, 184], drug toxicity and resistance, and inappropriate cancer metabolism [185], all of which lead to possible metastases and recurrence. Hence the search for a more effective and potent anti-cancer agent. Buoyed by the earlier success in extracting anti-cancer agents from plants, the search has been on for a natural product. Tocotrienol became the choice of study due to its multitargeted actions in destroying cancer cells, promoting cancer cells apoptosis and inhibiting angiogenesis and metastases [186–188]. It is certainly beyond the scope of this writing to discuss all the research conducted on the effects of tocotrienol on cancer. Notable among the most recent research papers on this subject are "Tocotrienols and Cancer: From the State of Art to Promising Novel Patents" [189] and "Tocotrienols Modulate a Life or

**213**

**14.1 Apoptosis**

*Anti-cancer mechanism of actions of tocotrienol.*

**Figure 5.**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

Death Decision in Cancers" [190]. For our purpose, it suffices to understand how tocotrienol exerts its anti-cancer effect. The mechanism of action is illustrated in **Figure 5**. Indeed, the effect of tocotrienol in suppressing the growth of different form of malignancies, including that of the uterine, ovary, prostate, liver, gastric, breast and brain, is well documented [191, 192]. **Figure 5** below depicts the possible

As an innate defence mechanism against cancer, apoptosis is considered critical [194, 195]. Natural molecules have the potential to exert their apoptosis-inducing quality [196–199] and tocotrienols are one of those compounds that could exert the anti-neoplastic activity via this apoptosis mechanism [200]. One study [201] demonstrated that γ-tocotrienol caused substantial apoptosis in tumour cells by down-regulating several oncogenic gene products' expression. It also displayed chemosensitisation and anti-invasive properties against prostate cells [202], and induced apoptosis in gastric cancer cells [203]. In another study [204], both α-tocopherol and γ-tocotrienol showed anti-proliferative activities and apoptosis on both the cervical carcinoma and hepatoma cell lines. Tocotrienols were also found to induce apoptosis in breast cancer cell lines [205] and effected both apoptosis and antiangiogenic activity of murine mammary cancer cells in mice [206]. A different study revealed that δ-tocotrienol is more efficacious than both α- and γ-tocotrienol in exerting its apoptosis effect on both human lung adenocarcinoma and glioblastoma [207]. In a study [208] on human bladder cancer cells, δ-tocotrienol was observed to have effectively induced apoptosis and chemosensitization, in addition to arresting the growth of human bladder cells. A study conducted on human chronic myeloid leukaemia cells [209] found that γ-tocotrienol was an effective inducer of apoptosis in the myeloid leukaemia cells. TRF mixture is also found to prevent cell proliferation, migration, and tumour cell invasiveness by inducing apoptosis in non-small cell lung cancer

mechanism of actions of tocotrienols in exerting its anti-cancer effect [193].

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

Death Decision in Cancers" [190]. For our purpose, it suffices to understand how tocotrienol exerts its anti-cancer effect. The mechanism of action is illustrated in **Figure 5**. Indeed, the effect of tocotrienol in suppressing the growth of different form of malignancies, including that of the uterine, ovary, prostate, liver, gastric, breast and brain, is well documented [191, 192]. **Figure 5** below depicts the possible mechanism of actions of tocotrienols in exerting its anti-cancer effect [193].

**Figure 5.** *Anti-cancer mechanism of actions of tocotrienol.*

#### **14.1 Apoptosis**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

activity – and in reducing TNF-α activity.

**13. Radioprotective effect**

effective in preventing aspirin-induced gastric ulcer. In another recent study [167] on a rat model comparing control to a group fed with omeprazole and another group with tocotrienol, it was discovered that while both groups were effective against gastric ulcer, the tocotrienol group displayed various modes in its protective effect – via the nitric oxide (NO) pathway and superoxide dismutase (SOD)

With the increasing adoption of radiation in both clinical and non-clinical applications [168], human exposure to radiation is set for an exponential increase. Radiation toxicity is manifested in oxidative stress and DNA damage [169], inflammatory changes [170] and cell apoptosis [171]. Studies were carried out to examine the potential benefits of naturally occurring products such as vitamin E, a potent anti-oxidant with the capacity to neutralize free radicals from radiation exposure by donating H atoms [172]. It was shown that exposure to ionizing radiation yields reactive oxygen species (ROS) and nitrogen species (RNS), hydroxyl radical, superoxide, peroxynitrite and hydrogen peroxide. These reactive species of ROS and RNS with radiation-induced radicals damage proteins, DNA and lipids, besides activating intracellular signalling pathways that release cytochrome C from the mitochondria, eventually leading to cell apoptosis [173–175]. Thanks to its potent anti-oxidant properties, tocotrienol has been a subject of several studies and has been reported to be radioprotective [176–178]. Studies on a rat model [176, 179] have showed the protective effect of γ-tocotrienol against radiation-induced DNA damage through the activation of haematopoietic progenitors, red and white blood cells including platelets, and also through the inhibition of 3-hydroxy-3-methylglutaryl-CoA Reductase (HMG-CoA Reductase) – a protein-coding gene-mediated nitrosative stress [180]. It is also proven that γ-tocotrienol increases serum IL-6 and granulocyte colony stimulating factor (G-CSF), both of which induce haematopoiesis and are protective against radiation-induced neutropenia and thrombocytopenia

Cancer (also known as malignant tumours or neoplasms) is the second leading cause of mortality globally according to WHO [182], with an estimated 9.6 million deaths in 2018. The cancer burden keeps on growing inexorably, exerting its pressure emotionally and financially on individuals and families, not to mention the community and health system. While chemotherapy has been the mainstay of treatment, it is limited by a few factors such as tumour immune evasion [183, 184], drug toxicity and resistance, and inappropriate cancer metabolism [185], all of which lead to possible metastases and recurrence. Hence the search for a more effective and potent anti-cancer agent. Buoyed by the earlier success in extracting anti-cancer agents from plants, the search has been on for a natural product. Tocotrienol became the choice of study due to its multitargeted actions in destroying cancer cells, promoting cancer cells apoptosis and inhibiting angiogenesis and metastases [186–188]. It is certainly beyond the scope of this writing to discuss all the research conducted on the effects of tocotrienol on cancer. Notable among the most recent research papers on this subject are "Tocotrienols and Cancer: From the State of Art to Promising Novel Patents" [189] and "Tocotrienols Modulate a Life or

**212**

in mice [181].

**14. Anti-cancer effect**

As an innate defence mechanism against cancer, apoptosis is considered critical [194, 195]. Natural molecules have the potential to exert their apoptosis-inducing quality [196–199] and tocotrienols are one of those compounds that could exert the anti-neoplastic activity via this apoptosis mechanism [200]. One study [201] demonstrated that γ-tocotrienol caused substantial apoptosis in tumour cells by down-regulating several oncogenic gene products' expression. It also displayed chemosensitisation and anti-invasive properties against prostate cells [202], and induced apoptosis in gastric cancer cells [203]. In another study [204], both α-tocopherol and γ-tocotrienol showed anti-proliferative activities and apoptosis on both the cervical carcinoma and hepatoma cell lines. Tocotrienols were also found to induce apoptosis in breast cancer cell lines [205] and effected both apoptosis and antiangiogenic activity of murine mammary cancer cells in mice [206]. A different study revealed that δ-tocotrienol is more efficacious than both α- and γ-tocotrienol in exerting its apoptosis effect on both human lung adenocarcinoma and glioblastoma [207]. In a study [208] on human bladder cancer cells, δ-tocotrienol was observed to have effectively induced apoptosis and chemosensitization, in addition to arresting the growth of human bladder cells. A study conducted on human chronic myeloid leukaemia cells [209] found that γ-tocotrienol was an effective inducer of apoptosis in the myeloid leukaemia cells. TRF mixture is also found to prevent cell proliferation, migration, and tumour cell invasiveness by inducing apoptosis in non-small cell lung cancer

cells (NSCLC) [210]. Furthermore, γ-tocotrienol exerted its anti-proliferative effect and induced apoptosis in human cervical cancer cells [211].

#### **14.2 Cell cycle arrest**

Cell cycle has its checkpoints from one phase to another, and any aberrant activation may lead to the proliferation of tumour cells. Hence, it is imperative to target these checkpoints in cancer therapy [212]. The cell cycle and its checkpoints are illustrated in **Figure 6** below [213].

#### **Figure 6.**

*The cell cycle and its checkpoints. There are four phases in the cell cycle – G1 phase, S-phase, G2-phase, and M-phase. The checkpoints control the progression of the cell cycle which is unidirectional in nature.*

It is worthy of note that γ-tocotrienol had an effect on the G2/M arrest and apoptosis of breast cancer cells, with the potential to reverse multi-drug resistance [214]. Another study on brain cancer cells [215] documented the anti-proliferative effect of γ-tocotrienol in combination with another agent, jerantinine (an indole alkaloid obtained from leaves extract) which led to G0/G1 cell cycle arrest. The combination effect of γ-tocopherol and δ-tocotrienol was also cited in successfully arresting the G1 phase and G2/M phase in the cell cycle of prostate cancer cells [216], besides inhibiting prostate cancer cell growth. A synergistic effect was observed between δ-tocotrienol and geranylgeraniol (a compound synthesised endogenously in the human body via mevalonate pathway) in arresting G1 phase activity in prostate carcinoma cells [217]. With the addition of γ-tocotrienol, the cell cycle at G0/G1 phase was also arrested while the S phase was reduced in cervical cancer HeLa cells [211]. In short, tocotrienols, whether alone or in combination with other agents, are capable of exerting their inhibitory effects through the checkpoints in the cell cycle. This promising evidence supports their future development as therapeutic agents in modulating the checkpoints of the cell cycle.

#### **14.3 Anti-angiogenesis**

Angiogenesis, defined as the formation of new blood vessels, is an important process for tumour growth and metastases [218] triggered by chemical signals from tumour

**215**

**14.4 Anti-metastasis**

*assemble as lumen-bearing cords.*

**Figure 7.**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

cells. Researchers have identified more than a dozen angiogenic activators, including vascular endothelial growth factor (VEGF) which is a powerful angiogenic factor in neoplasms as well as normal tissue [219]. Therefore, targeting these angiogenic factors seemed to be the most rational intervention to combat tumour growth [220, 221]. Several trials [222–224] have shown the effectiveness of tocotrienol in inhibiting angiogenesis in various cancers, with the process illustrated in **Figure 7** below [225].

A study has shown that both δ- and γ-tocotrienol inhibit angiogenesis and proliferation in human hepatocellular carcinoma cells [226]. In another study, it was demonstrated that δ-tocotrienol inhibited tumour angiogenesis via VEGF and MMP-9 in pancreatic cancer cells; it also decreased the expression of cell surface markers in cancer stem cells [227]. Another study revealed that δ-tocotrienol exhibited potential against both melanoma and its associated stem cells [228, 229], while displaying suppressive action on prostate cancer stem-like cells [230]. Recent findings also indicated that tocotrienols displayed antiangiogenic protein expression of VEGF in colorectal cancer [231], malignant mesothelioma [232], breast cancer [233], ovarian carcinoma [234], and head and neck squamous cell carcinoma [235]. All these studies provide ample evidence of the role of tocotrienol in arresting tumour growth by inhibiting angiogenesis.

*The angiogenic cascade. (A) During the process of angiogenesis, stable vessels undergo (B) a vascular permeability increase which allows extravasation of plasma proteins. (C) Degradation of the ECM by matrix metalloproteases (MMPs) relieves pericyte-endothelial cells (EC) contacts and liberates extracellular matrix (ECM)-sequestered growth factors. (D) ECs then proliferate and migrate to their final destination and (E)* 

The morbidity and mortality from cancer are mainly caused by cancer metastases; in fact, almost 90% mortality is thought to be due to metastases [236]. Cancer metastasis starts at the primary tumour with the detachment of metastatic cells which then travel to different parts of the body either through the bloodstream or lymphatic drainage, and thereafter settle and start growing at the distal site [237]. To put it simply, the process of metastasis involves four essential steps: detachment, migration, invasion and adhesion. This is illustrated in **Figure 8** below [238].

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

cells. Researchers have identified more than a dozen angiogenic activators, including vascular endothelial growth factor (VEGF) which is a powerful angiogenic factor in neoplasms as well as normal tissue [219]. Therefore, targeting these angiogenic factors seemed to be the most rational intervention to combat tumour growth [220, 221]. Several trials [222–224] have shown the effectiveness of tocotrienol in inhibiting angiogenesis in various cancers, with the process illustrated in **Figure 7** below [225].

#### **Figure 7.**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

and induced apoptosis in human cervical cancer cells [211].

**14.2 Cell cycle arrest**

are illustrated in **Figure 6** below [213].

cells (NSCLC) [210]. Furthermore, γ-tocotrienol exerted its anti-proliferative effect

Cell cycle has its checkpoints from one phase to another, and any aberrant activation may lead to the proliferation of tumour cells. Hence, it is imperative to target these checkpoints in cancer therapy [212]. The cell cycle and its checkpoints

It is worthy of note that γ-tocotrienol had an effect on the G2/M arrest and apoptosis of breast cancer cells, with the potential to reverse multi-drug resistance [214]. Another study on brain cancer cells [215] documented the anti-proliferative effect of γ-tocotrienol in combination with another agent, jerantinine (an indole alkaloid obtained from leaves extract) which led to G0/G1 cell cycle arrest. The combination effect of γ-tocopherol and δ-tocotrienol was also cited in successfully arresting the G1 phase and G2/M phase in the cell cycle of prostate cancer cells [216], besides inhibiting prostate cancer cell growth. A synergistic effect was observed between δ-tocotrienol and geranylgeraniol (a compound synthesised endogenously in the human body via mevalonate pathway) in arresting G1 phase activity in prostate carcinoma cells [217]. With the addition of γ-tocotrienol, the cell cycle at G0/G1 phase was also arrested while the S phase was reduced in cervical cancer HeLa cells [211]. In short, tocotrienols, whether alone or in combination with other agents, are capable of exerting their inhibitory effects through the checkpoints in the cell cycle. This promising evidence supports their future development as therapeutic agents in

*The cell cycle and its checkpoints. There are four phases in the cell cycle – G1 phase, S-phase, G2-phase, and M-phase. The checkpoints control the progression of the cell cycle which is unidirectional in nature.*

Angiogenesis, defined as the formation of new blood vessels, is an important process for tumour growth and metastases [218] triggered by chemical signals from tumour

**214**

**Figure 6.**

modulating the checkpoints of the cell cycle.

**14.3 Anti-angiogenesis**

*The angiogenic cascade. (A) During the process of angiogenesis, stable vessels undergo (B) a vascular permeability increase which allows extravasation of plasma proteins. (C) Degradation of the ECM by matrix metalloproteases (MMPs) relieves pericyte-endothelial cells (EC) contacts and liberates extracellular matrix (ECM)-sequestered growth factors. (D) ECs then proliferate and migrate to their final destination and (E) assemble as lumen-bearing cords.*

A study has shown that both δ- and γ-tocotrienol inhibit angiogenesis and proliferation in human hepatocellular carcinoma cells [226]. In another study, it was demonstrated that δ-tocotrienol inhibited tumour angiogenesis via VEGF and MMP-9 in pancreatic cancer cells; it also decreased the expression of cell surface markers in cancer stem cells [227]. Another study revealed that δ-tocotrienol exhibited potential against both melanoma and its associated stem cells [228, 229], while displaying suppressive action on prostate cancer stem-like cells [230]. Recent findings also indicated that tocotrienols displayed antiangiogenic protein expression of VEGF in colorectal cancer [231], malignant mesothelioma [232], breast cancer [233], ovarian carcinoma [234], and head and neck squamous cell carcinoma [235]. All these studies provide ample evidence of the role of tocotrienol in arresting tumour growth by inhibiting angiogenesis.

#### **14.4 Anti-metastasis**

The morbidity and mortality from cancer are mainly caused by cancer metastases; in fact, almost 90% mortality is thought to be due to metastases [236]. Cancer metastasis starts at the primary tumour with the detachment of metastatic cells which then travel to different parts of the body either through the bloodstream or lymphatic drainage, and thereafter settle and start growing at the distal site [237]. To put it simply, the process of metastasis involves four essential steps: detachment, migration, invasion and adhesion. This is illustrated in **Figure 8** below [238].

#### **Figure 8.**

*A schematic representation of the four stages of metastatic dissemination of cancer cells from the primary tumour into the blood circulation, involving detachment, migration, invasion and adhesion.*

Cancer survival rate has improved significantly over the years from early diagnosis and inhibition of cancer growth. Nevertheless, the mainstay of cancer treatment for metastasis remains chemotherapy or radiotherapy. Tocotrienols have gained prominence in the last several years due to their anti-proliferative, antiangiogenic, anti-migratory and anti-metastatic properties as exhibited in vivo and in vitro data [239]. Indeed, for metastasis to occur, cancer cells need to detach and migrate to a distant target organ, a process followed by adhesion and local invasion [240]. The ability of tocotrienol in halting cell migration has been demonstrated in several studies [224, 241–243]. In one study on human umbilical vein endothelial cells (HUVEC), treatment with δ-tocotrienol suppressed VEGF-induced migration by 50% [224]. Another study proved a dose-dependent inhibition of non-small cell lung cancer (NCSLC) cells migration [241], while a different one demonstrated the ability of γ-tocotrienol in inhibiting in-vitro human gastric cells migration [242]. In another study on VEGF-stimulated HUVEC migration essay, it was found that γ-tocotrienol suppressed the migratory potential of the HUVEC cells [243]. After the cancer cells migration, the subsequent event in the process of metastases is cell adhesion and invasion; this is preventable by suppressing the tumour cell invasion after adhesion [242]. An in vitro study has shown that after being treated with δ-tocotrienol, a pancreatic cancer mouse model no longer displayed any signs of invasive cancer [244]. A previous study has also showcased the ability of γ-tocotrienol in halting the invasion of the prostatic cancer cells in the control group [202], thereby suppressing the main process in the perpetuation of metastasis.

#### **14.5 Anti-oxidant**

Oxidative stress refers to an imbalance of free radicals or reactive oxygen species (ROS) and antioxidants in the body [245]. This imbalance has been linked to a litany of chronic conditions including neurodegenerative disease, cardiovascular disease, diabetes mellitus, and many other pathologies such as cancer [246]. A variety of

**217**

**15. Discussion**

**Figure 9.**

*condition.*

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

deleterious modifications of macromolecular components such as DNA, lipids and proteins were due to this chronic oxidative stress [247]. There is also a possibility that ROS mediates an indirect attack on DNA, resulting in secondary reactive intermediates that would couple with the DNA bases to form DNA adducts [248]. This formation is central to what is known as carcinogenesis [249]. Oxidative lesions have been implicated in the aetiology of cancer due to the oxidative DNA damage [250–254]. It is now clear how carcinogenesis is perpetuated by this oxidative stress

Evidence from clinical and laboratory studies have showed that the elevated level of ROS contributed to both cancer initiation and cancer progression. Consequently, the most rational, if not preventive, approach is to use antioxidants for combating ROS [256]. Although the results regarding the use of dietary antioxidants were promising, research on this topic is still inconclusive and controversial [257]. Moreover, while studies have indicated that anti-oxidant supplementation resulted in an increase in survival rates and tumour response, with fewer toxicities than controls, a systematic review previously done on this topic showed no evidence of interference by antioxidants on chemotherapy mechanisms that conclusively proves that antioxidants (such as vitamin E) improve tumour response rate or the patients' survival [258]. Despite promising results on improving the side effects from chemotherapy or radiotherapy treatment of cancer, further research into anti-oxidants [259], especially vitamin E in general and tocotrienol in particular, is highly warranted.

*Oxidative stress mediating cancer development. Biological, chemical and physical factors mediated free radicals (ROS) which damage the biomolecules that initiate the neoplastic cells through the up-regulation of transcriptional factors and inactivation of tumour suppressor genes. They also alter the functions of DNA repair proteins, apoptotic modulators, metabolic enzymes and signalling pathways that induce the neoplastic* 

Long ignored despite being close yet superior to its related isomer tocopherol, tocotrienol is increasingly becoming a subject of interest in vitamin E research

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

process, as illustrated in **Figure 9** below [255].

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

deleterious modifications of macromolecular components such as DNA, lipids and proteins were due to this chronic oxidative stress [247]. There is also a possibility that ROS mediates an indirect attack on DNA, resulting in secondary reactive intermediates that would couple with the DNA bases to form DNA adducts [248]. This formation is central to what is known as carcinogenesis [249]. Oxidative lesions have been implicated in the aetiology of cancer due to the oxidative DNA damage [250–254]. It is now clear how carcinogenesis is perpetuated by this oxidative stress process, as illustrated in **Figure 9** below [255].

#### **Figure 9.**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

Cancer survival rate has improved significantly over the years from early diagnosis and inhibition of cancer growth. Nevertheless, the mainstay of cancer treatment for metastasis remains chemotherapy or radiotherapy. Tocotrienols have gained prominence in the last several years due to their anti-proliferative, antiangiogenic, anti-migratory and anti-metastatic properties as exhibited in vivo and in vitro data [239]. Indeed, for metastasis to occur, cancer cells need to detach and migrate to a distant target organ, a process followed by adhesion and local invasion [240]. The ability of tocotrienol in halting cell migration has been demonstrated in several studies [224, 241–243]. In one study on human umbilical vein endothelial cells (HUVEC), treatment with δ-tocotrienol suppressed VEGF-induced migration by 50% [224]. Another study proved a dose-dependent inhibition of non-small cell lung cancer (NCSLC) cells migration [241], while a different one demonstrated the ability of γ-tocotrienol in inhibiting in-vitro human gastric cells migration [242]. In another study on VEGF-stimulated HUVEC migration essay, it was found that γ-tocotrienol suppressed the migratory potential of the HUVEC cells [243]. After the cancer cells migration, the subsequent event in the process of metastases is cell adhesion and invasion; this is preventable by suppressing the tumour cell invasion after adhesion [242]. An in vitro study has shown that after being treated with δ-tocotrienol, a pancreatic cancer mouse model no longer displayed any signs of invasive cancer [244]. A previous study has also showcased the ability of γ-tocotrienol in halting the invasion of the prostatic cancer cells in the control group [202], thereby suppressing the main process in the perpetuation of metastasis.

*A schematic representation of the four stages of metastatic dissemination of cancer cells from the primary* 

*tumour into the blood circulation, involving detachment, migration, invasion and adhesion.*

Oxidative stress refers to an imbalance of free radicals or reactive oxygen species (ROS) and antioxidants in the body [245]. This imbalance has been linked to a litany of chronic conditions including neurodegenerative disease, cardiovascular disease, diabetes mellitus, and many other pathologies such as cancer [246]. A variety of

**216**

**14.5 Anti-oxidant**

**Figure 8.**

*Oxidative stress mediating cancer development. Biological, chemical and physical factors mediated free radicals (ROS) which damage the biomolecules that initiate the neoplastic cells through the up-regulation of transcriptional factors and inactivation of tumour suppressor genes. They also alter the functions of DNA repair proteins, apoptotic modulators, metabolic enzymes and signalling pathways that induce the neoplastic condition.*

Evidence from clinical and laboratory studies have showed that the elevated level of ROS contributed to both cancer initiation and cancer progression. Consequently, the most rational, if not preventive, approach is to use antioxidants for combating ROS [256]. Although the results regarding the use of dietary antioxidants were promising, research on this topic is still inconclusive and controversial [257]. Moreover, while studies have indicated that anti-oxidant supplementation resulted in an increase in survival rates and tumour response, with fewer toxicities than controls, a systematic review previously done on this topic showed no evidence of interference by antioxidants on chemotherapy mechanisms that conclusively proves that antioxidants (such as vitamin E) improve tumour response rate or the patients' survival [258]. Despite promising results on improving the side effects from chemotherapy or radiotherapy treatment of cancer, further research into anti-oxidants [259], especially vitamin E in general and tocotrienol in particular, is highly warranted.

#### **15. Discussion**

Long ignored despite being close yet superior to its related isomer tocopherol, tocotrienol is increasingly becoming a subject of interest in vitamin E research

among the scientific community. One of the main reasons why it was understudied could be due to its abundant presence in palm oil, itself a much maligned product that had to bear the full brunt of a damaging smear campaign for decades. In fact, palm oil contains about 70% of all tocotrienol homologues namely α-, β-, δ- and γ-tocotrienols. Consequently, it would be no exaggeration to say that palm oil is nature's best kept secret, if not the most promising natural substance in influencing health and disease.

Growing interest in tocotrienols has led to research exploring the molecular basis of their action in health. This chapter has highlighted the recent advances in this rapidly developing field of study. Indeed, recent studies have shown that tocotrienols may have superior chemopreventive or chemotherapeutic effects when used either alone or in combination with tocopherols. Indeed, tocotrienols are well adapted for their biochemical function. Thanks to their organic structure featuring a long-saturated carbon side-chain, they are able to penetrate more efficiently in the lipid membrane and in the intermembrane of tissues containing saturated fatty layers. This ability contributes immensely to their therapeutic efficacy.

Without doubt, the beneficial health effects of tocotrienols are partly related to their anti-oxidant activity. Though both tocotrienol and tocopherol have the ability to scavenge the free radicals directly by donating the phenolic hydrogen of their chromanol ring, tocotrienol is considered a better anti-oxidant due to its generally uniform distribution in the membrane bilayer coupled with a stronger disordering of its membrane lipid structure. Vitamin E, in particular tocotrienol, was shown to play a vital role in maintaining the integrity of the central nervous system through its anti-oxidant property. Indeed, as an organ with very high metabolic needs in terms of oxygen consumption, the brain is extremely susceptible to any forms of oxidative stress. However, current evidence is largely focused on Alzheimer's disease – an age-related inflammatory neurodegenerative disease characterised by the presence of pathognomonic amyloid plaques and neurofibrillary tangles. It is postulated that the main mechanism of action of tocotrienol in attenuating the neurodegenerative changes is via its anti-oxidant action, either by inhibiting the production of ROS or by reducing the lipid peroxidation by-products. Admittedly, a gap still persists in this area insofar as other neurodegenerative conditions (such as Parkinson's disease) are concerned. Notwithstanding the fact that some recent studies have reported contradicting outcomes on the relationship between tocotrienol and Parkinson's disease, it is hoped that future studies will shed more light in this area.

Given the potential of tocotrienol in preventing auto-immune diseases, especially through its anti-inflammatory properties, the evidence available warrants further investigation into its molecular action. That would enable the development of drug targets to combat inflammatory diseases. Nevertheless, the therapeutic potential of tocotrienol as an anti-inflammatory agent cannot be denied. On the one hand, δ-tocotrienol somehow lessened joint inflammation in arthritic rats by reducing the level of proinflammatory cytokines. On the other hand, in a human study, γ-tocotrienol improved airway remodelling that characterises bronchiole asthma which is essentially an inflammatory disorder. Another rat model also showed that tocotrienol is effective against gastric ulcer. The gastroprotective effect of tocotrienol was mainly modulated through a reduction in inflammatory response, besides its anti-oxidative properties. Though this protective effect was witnessed in various animal models of gastric ulcer, clinical studies on the use of tocotrienol in patients with peptic ulcer disease or even gastritis are yet to be conducted.

As one of its health benefits, tocotrienol – through its ability to improve the lipid profiles – has been shown to confer a cardioprotective effect, at least with respect to atherosclerosis, myocardial infarction and thrombosis. There is sufficient evidence

**219**

tract from injury.

disorders.

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

to prove that tocotrienol, especially in the form of γ-tocotrienol, is anti-cholesterolaemic; this is achieved by inhibiting the mevalonate pathway responsible for the synthesis of cholesterol and other isoprenoids. Overall, the potential of tocotrienol as a potential hypocholesterolaemic agent is evidenced by in-vitro, in-vivo and human clinical trials. Thus, tocotrienol supplementation is highly recommended for

In fact, human studies on the effects of tocotrienol on cardiovascular disease have been limited to its anti-hypercholesterolaemic property. The only exception is an ongoing clinical study at the National Heart Institute of Kuala Lumpur, Malaysia. Conducted by this author, it investigates the ability of tocotrienol in preventing atrial fibrillation in post-coronary artery bypass grafting surgery. Indeed, while tocotrienol has been shown to be protective against cardiovascular disease in animal models, its direct effects on humans are inconsistent. Our current evidence serves as a basis for further clinical trials aimed at validating the positive effects of tocotri-

enol especially among patients susceptible to cardiovascular complications.

The potency of α-tocotrienol as an anti-atherogenic agent, besides being a bulwark against cerebrovascular disease, is well documented. Several animal models have demonstrated that tocotrienol protects against ischaemic stroke by attenuating brain lesion volume. A similar scenario was observed during clinical trials where it was shown to attenuate the progression of brain white matter lesion. Consequently, it could be safely concluded that tocotrienol protects against cerebrovascular

Tocotrinol-rich vitamin E (TRF) has been observed to ameliorate diabetes in animal studies through its superior antioxidant, anti-hyperglycaemic and antiinflammatory properties. A recent clinical trial also showed that TRF significantly reduced serum creatinine level, and therefore has the potential to be used as a supplement in the treatment of diabetic nephropathy. Moreover, the anti-diabetic properties of tocotrienol in preventing nephropathy, retinopathy and neuropathy

Studies conducted on animal models have demonstrated that tocotrienol can mitigate, if not prevent, osteoporosis in rats by reducing oxidative stress and inflammation. Indeed, tocotrienol has been proposed to counter osteoporosis which leads to fragility fracture, a leading cause of morbidity and mortality worldwide. It is postulated that tocotrienol mediated bone protection via its anti-oxidant, antiinflammatory, mevalonate suppression and gene-modulating properties. Despite strong evidence in animal models showing improved bone structure and strength after tocotrienol supplementation, limited human clinical trials on the effects of tocotrienol on bone health has been a serious impediment to its clinical use. The role of γ-tocotrienol in protecting against radiation toxicity has been a subject of numerous animal studies, and the results are very promising. With the widespread use of ionising radiation in various non-clinical applications such as construction, sterilization of food products and engineering, exposure to radiation – whether intentional or unintentional – is very high. Studies have shown that γ-tocotrienol has a protective effect against radiation injury by increasing haematopoietic progenitors, neutrophils, platelets, white blood cells and reticulocytes. It has also been demonstrated that γ-tocotrienol protects against vascular injury by inhibiting HMG-CoA reductase. Since tocotrienols accumulate in the small intestine and colon at a higher level than tocopherols, they could protect the gastrointestinal

Last, but certainly not least, with cancer being one of the leading causes of death

worldwide, the role of tocotrienol as an anti-cancer agent cannot be underestimated. Tocotrienol has been shown to modulate intracellular signalling pathways; it induces apoptosis and cell cycle arrest, and inhibits angiogenesis, cell proliferation

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

patients suffering from hypercholesterolaemia.

have been proven in several other studies.

#### *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

health and disease.

among the scientific community. One of the main reasons why it was understudied could be due to its abundant presence in palm oil, itself a much maligned product that had to bear the full brunt of a damaging smear campaign for decades. In fact, palm oil contains about 70% of all tocotrienol homologues namely α-, β-, δ- and γ-tocotrienols. Consequently, it would be no exaggeration to say that palm oil is nature's best kept secret, if not the most promising natural substance in influencing

Growing interest in tocotrienols has led to research exploring the molecular basis of their action in health. This chapter has highlighted the recent advances in this rapidly developing field of study. Indeed, recent studies have shown that tocotrienols may have superior chemopreventive or chemotherapeutic effects when used either alone or in combination with tocopherols. Indeed, tocotrienols are well adapted for their biochemical function. Thanks to their organic structure featuring a long-saturated carbon side-chain, they are able to penetrate more efficiently in the lipid membrane and in the intermembrane of tissues containing saturated fatty

Without doubt, the beneficial health effects of tocotrienols are partly related to their anti-oxidant activity. Though both tocotrienol and tocopherol have the ability to scavenge the free radicals directly by donating the phenolic hydrogen of their chromanol ring, tocotrienol is considered a better anti-oxidant due to its generally uniform distribution in the membrane bilayer coupled with a stronger disordering of its membrane lipid structure. Vitamin E, in particular tocotrienol, was shown to play a vital role in maintaining the integrity of the central nervous system through its anti-oxidant property. Indeed, as an organ with very high metabolic needs in terms of oxygen consumption, the brain is extremely susceptible to any forms of oxidative stress. However, current evidence is largely focused on Alzheimer's disease – an age-related inflammatory neurodegenerative disease characterised by the presence of pathognomonic amyloid plaques and neurofibrillary tangles. It is postulated that the main mechanism of action of tocotrienol in attenuating the neurodegenerative changes is via its anti-oxidant action, either by inhibiting the production of ROS or by reducing the lipid peroxidation by-products. Admittedly, a gap still persists in this area insofar as other neurodegenerative conditions (such as Parkinson's disease) are concerned. Notwithstanding the fact that some recent studies have reported contradicting outcomes on the relationship between tocotrienol and Parkinson's disease, it is hoped that future studies will shed more light in

Given the potential of tocotrienol in preventing auto-immune diseases, especially through its anti-inflammatory properties, the evidence available warrants further investigation into its molecular action. That would enable the development of drug targets to combat inflammatory diseases. Nevertheless, the therapeutic potential of tocotrienol as an anti-inflammatory agent cannot be denied. On the one hand, δ-tocotrienol somehow lessened joint inflammation in arthritic rats by reducing the level of proinflammatory cytokines. On the other hand, in a human study, γ-tocotrienol improved airway remodelling that characterises bronchiole asthma which is essentially an inflammatory disorder. Another rat model also showed that tocotrienol is effective against gastric ulcer. The gastroprotective effect of tocotrienol was mainly modulated through a reduction in inflammatory response, besides its anti-oxidative properties. Though this protective effect was witnessed in various animal models of gastric ulcer, clinical studies on the use of tocotrienol in patients

As one of its health benefits, tocotrienol – through its ability to improve the lipid profiles – has been shown to confer a cardioprotective effect, at least with respect to atherosclerosis, myocardial infarction and thrombosis. There is sufficient evidence

with peptic ulcer disease or even gastritis are yet to be conducted.

layers. This ability contributes immensely to their therapeutic efficacy.

**218**

this area.

to prove that tocotrienol, especially in the form of γ-tocotrienol, is anti-cholesterolaemic; this is achieved by inhibiting the mevalonate pathway responsible for the synthesis of cholesterol and other isoprenoids. Overall, the potential of tocotrienol as a potential hypocholesterolaemic agent is evidenced by in-vitro, in-vivo and human clinical trials. Thus, tocotrienol supplementation is highly recommended for patients suffering from hypercholesterolaemia.

In fact, human studies on the effects of tocotrienol on cardiovascular disease have been limited to its anti-hypercholesterolaemic property. The only exception is an ongoing clinical study at the National Heart Institute of Kuala Lumpur, Malaysia. Conducted by this author, it investigates the ability of tocotrienol in preventing atrial fibrillation in post-coronary artery bypass grafting surgery. Indeed, while tocotrienol has been shown to be protective against cardiovascular disease in animal models, its direct effects on humans are inconsistent. Our current evidence serves as a basis for further clinical trials aimed at validating the positive effects of tocotrienol especially among patients susceptible to cardiovascular complications.

The potency of α-tocotrienol as an anti-atherogenic agent, besides being a bulwark against cerebrovascular disease, is well documented. Several animal models have demonstrated that tocotrienol protects against ischaemic stroke by attenuating brain lesion volume. A similar scenario was observed during clinical trials where it was shown to attenuate the progression of brain white matter lesion. Consequently, it could be safely concluded that tocotrienol protects against cerebrovascular disorders.

Tocotrinol-rich vitamin E (TRF) has been observed to ameliorate diabetes in animal studies through its superior antioxidant, anti-hyperglycaemic and antiinflammatory properties. A recent clinical trial also showed that TRF significantly reduced serum creatinine level, and therefore has the potential to be used as a supplement in the treatment of diabetic nephropathy. Moreover, the anti-diabetic properties of tocotrienol in preventing nephropathy, retinopathy and neuropathy have been proven in several other studies.

Studies conducted on animal models have demonstrated that tocotrienol can mitigate, if not prevent, osteoporosis in rats by reducing oxidative stress and inflammation. Indeed, tocotrienol has been proposed to counter osteoporosis which leads to fragility fracture, a leading cause of morbidity and mortality worldwide. It is postulated that tocotrienol mediated bone protection via its anti-oxidant, antiinflammatory, mevalonate suppression and gene-modulating properties. Despite strong evidence in animal models showing improved bone structure and strength after tocotrienol supplementation, limited human clinical trials on the effects of tocotrienol on bone health has been a serious impediment to its clinical use.

The role of γ-tocotrienol in protecting against radiation toxicity has been a subject of numerous animal studies, and the results are very promising. With the widespread use of ionising radiation in various non-clinical applications such as construction, sterilization of food products and engineering, exposure to radiation – whether intentional or unintentional – is very high. Studies have shown that γ-tocotrienol has a protective effect against radiation injury by increasing haematopoietic progenitors, neutrophils, platelets, white blood cells and reticulocytes. It has also been demonstrated that γ-tocotrienol protects against vascular injury by inhibiting HMG-CoA reductase. Since tocotrienols accumulate in the small intestine and colon at a higher level than tocopherols, they could protect the gastrointestinal tract from injury.

Last, but certainly not least, with cancer being one of the leading causes of death worldwide, the role of tocotrienol as an anti-cancer agent cannot be underestimated. Tocotrienol has been shown to modulate intracellular signalling pathways; it induces apoptosis and cell cycle arrest, and inhibits angiogenesis, cell proliferation

and metastases. Compared to its isoform tocopherol, tocotrienol displayed superior activities in anti-cancer studies. Indeed, in a structural-activity relationship study, the chromanol ring and phytyl carbon tail played a major role in inducing cancer cell apoptosis. However, despite the abundance of cell and animal studies investigating the role of tocotrienol, evidence regarding its preventive effects on cancer remain inconclusive, with most trials still at the preliminary stage. Nonetheless, our improved understanding of the mechanism of actions of tocotrienol in the suppression of cancer cell growth by inhibiting proliferation, migration, and invasion should not be discounted; it will inform more targeted research into cancer therapy in the future.

#### **16. Conclusion and future direction**

This chapter has highlighted the wonders of tocotrienols which, thanks to their efficacy and safety profile, are attracting increased attention. Examining the latest research into tocotrienols, it has demonstrated the undeniable benefits of tocotrienols in conferring protection against cancer as well as a whole litany of diseases including cardiovascular, metabolic, autoimmune, bone and neurological diseases. Admittedly, many of the researches were conducted in the laboratory, with some preclinical trials translated into clinical trials. Nonetheless, it is hoped that more randomised clinical trials will be carried out on a global scale in the near future. From the vessels in the heart to neurons in the brain, tocotrienols have the extraordinary potential to be the future of vitamin E research.

#### **Acknowledgements**

The author is the recipient of HOVID the Malaysian Palm Oil Board research grant for his randomised controlled study on the 'Prevention of Atrial Fibrillation after Coronary Artery Bypass Grafting Surgery using Tocotrienol-rich Vitamin E, Tocovid, derived from Palm Oil' which is being conducted at the National Heart Institute (IJN), Kuala Lumpur. However, the funders had no role in the preparation of this manuscript. The author would like to express his gratitude to Imad Jihadi Ahmad Farouk for illustrating the diagrams, and Nageeb Gounjaria for proofreading and editing the manuscript.

#### **Author details**

#### Ahmad Farouk Musa

Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, Malaysia

\*Address all correspondence to: farouk@monash.edu

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**221**

37:526-541.

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

[10] Parker RA, Pearce BC, Clark RW, et al. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3- methylglutaryl-coenzyme

hyperlipidemias. Am J Clin Nutr. 1991;

[12] Wada S. Chemoprevention of tocotrienols: the mechanism of antiproliferative effects. Forum Nutr.

[13] Constantinou C, Papas A,

J Cancer. 2008; 123:739-752.

[14] Budin SB, Othman F, Louis SR, et al. The effects of palm oil tocotrienolrich fraction supplementation on biochemical parameters, oxidative stress and the vascular wall of streptozotocininduced diabetic rats. Clinics. 2009;

[15] Montenen J, Knekt P, Jarvinen R, et al. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004;

[16] Wan Nazaimoon WM, Khalid BAK.

[17] Qureshi AA, Peterson D, Mhasler-Rapacz JO, et al. Novel tocotrienols of

Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycaemic control in streptozotocininduced diabetic rats. Malays J Pathol

Constantinou AI. Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogues. Int

A reductase. J Biol Chem. 1993;

[11] Qureshi AA, Qureshi N, Hasler-Rapacz JO, et al. Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited

53(Suppl):S1042–S1046.

2009; 61:204-216.

64:235-244.

27:362-366.

2002; 24(2):77-82.

268:11230-11238.

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

[2] Evan HM & Bishop KS. Unrecognized dietary factor essential for reproduction.

[3] Sen CK, Khanna S, Rink C, Roy S. Tocotrienols: the emerging face of natural vitamin E. Vitam Horm 2007;

[4] Schwarz, K. Role of vitamin E, selenium, and related factors in experimental nutritional liver disease.

[5] Serbinova E, Kagan V, Han D, et al. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-

tocopherol and alpha- tocotrienol. Free Radic Biol Med. 1991; 10:263-275.

[6] Zaiden N, Yap WN, Xu CH, et al. Gamma delta tocotrienols reduce hepatic tri- glycerides synthesis and VLDL secretion. J Atheroscler Thromb.

[7] Zaiden N, Yap WN, Xu CH, et al. Gamma delta tocotrienols reduce hepatic tri- glycerides synthesis and VLDL secretion. J Atheroscler Thromb.

[8] Song BL, Debose-Boyd RA. Insig-dependent ubiquitination and degradation of 3-hydroxy-3 methylglutaryl coenzyme A reductase stimulated by delta- and gammatocotrienols. J Biol Chem. 2006;

[9] Pearce BC, Parker RA, Deason ME, et al. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J Med Chem. 1994;

Fed Proc 1965; 24:58-67.

2010; 17:1019-1032.

2010; 17:1019-1032.

281:25054-25061.

[1] Butler MS. The role of natural product chemistry in drug discovery. J

Nat Prod. 2004; 67:2141-2153.

Science 1922; 56(1458):650-651.

76:203-261.

**References**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

#### **References**

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

and metastases. Compared to its isoform tocopherol, tocotrienol displayed superior activities in anti-cancer studies. Indeed, in a structural-activity relationship study, the chromanol ring and phytyl carbon tail played a major role in inducing cancer cell apoptosis. However, despite the abundance of cell and animal studies investigating the role of tocotrienol, evidence regarding its preventive effects on cancer remain inconclusive, with most trials still at the preliminary stage. Nonetheless, our improved understanding of the mechanism of actions of tocotrienol in the suppression of cancer cell growth by inhibiting proliferation, migration, and invasion should not be discounted; it will inform more targeted research into cancer therapy

This chapter has highlighted the wonders of tocotrienols which, thanks to their efficacy and safety profile, are attracting increased attention. Examining the latest research into tocotrienols, it has demonstrated the undeniable benefits of tocotrienols in conferring protection against cancer as well as a whole litany of diseases including cardiovascular, metabolic, autoimmune, bone and neurological diseases. Admittedly, many of the researches were conducted in the laboratory, with some preclinical trials translated into clinical trials. Nonetheless, it is hoped that more randomised clinical trials will be carried out on a global scale in the near future. From the vessels in the heart to neurons in the brain, tocotrienols have the

The author is the recipient of HOVID the Malaysian Palm Oil Board research grant for his randomised controlled study on the 'Prevention of Atrial Fibrillation after Coronary Artery Bypass Grafting Surgery using Tocotrienol-rich Vitamin E, Tocovid, derived from Palm Oil' which is being conducted at the National Heart Institute (IJN), Kuala Lumpur. However, the funders had no role in the preparation of this manuscript. The author would like to express his gratitude to Imad Jihadi Ahmad Farouk for illustrating the diagrams, and Nageeb Gounjaria for proofreading

extraordinary potential to be the future of vitamin E research.

**220**

**Author details**

in the future.

**16. Conclusion and future direction**

Ahmad Farouk Musa

and editing the manuscript.

**Acknowledgements**

Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, Malaysia

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: farouk@monash.edu

provided the original work is properly cited.

[1] Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod. 2004; 67:2141-2153.

[2] Evan HM & Bishop KS. Unrecognized dietary factor essential for reproduction. Science 1922; 56(1458):650-651.

[3] Sen CK, Khanna S, Rink C, Roy S. Tocotrienols: the emerging face of natural vitamin E. Vitam Horm 2007; 76:203-261.

[4] Schwarz, K. Role of vitamin E, selenium, and related factors in experimental nutritional liver disease. Fed Proc 1965; 24:58-67.

[5] Serbinova E, Kagan V, Han D, et al. Free radical recycling and intramembrane mobility in the antioxidant properties of alphatocopherol and alpha- tocotrienol. Free Radic Biol Med. 1991; 10:263-275.

[6] Zaiden N, Yap WN, Xu CH, et al. Gamma delta tocotrienols reduce hepatic tri- glycerides synthesis and VLDL secretion. J Atheroscler Thromb. 2010; 17:1019-1032.

[7] Zaiden N, Yap WN, Xu CH, et al. Gamma delta tocotrienols reduce hepatic tri- glycerides synthesis and VLDL secretion. J Atheroscler Thromb. 2010; 17:1019-1032.

[8] Song BL, Debose-Boyd RA. Insig-dependent ubiquitination and degradation of 3-hydroxy-3 methylglutaryl coenzyme A reductase stimulated by delta- and gammatocotrienols. J Biol Chem. 2006; 281:25054-25061.

[9] Pearce BC, Parker RA, Deason ME, et al. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J Med Chem. 1994; 37:526-541.

[10] Parker RA, Pearce BC, Clark RW, et al. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3- methylglutaryl-coenzyme A reductase. J Biol Chem. 1993; 268:11230-11238.

[11] Qureshi AA, Qureshi N, Hasler-Rapacz JO, et al. Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias. Am J Clin Nutr. 1991; 53(Suppl):S1042–S1046.

[12] Wada S. Chemoprevention of tocotrienols: the mechanism of antiproliferative effects. Forum Nutr. 2009; 61:204-216.

[13] Constantinou C, Papas A, Constantinou AI. Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogues. Int J Cancer. 2008; 123:739-752.

[14] Budin SB, Othman F, Louis SR, et al. The effects of palm oil tocotrienolrich fraction supplementation on biochemical parameters, oxidative stress and the vascular wall of streptozotocininduced diabetic rats. Clinics. 2009; 64:235-244.

[15] Montenen J, Knekt P, Jarvinen R, et al. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004; 27:362-366.

[16] Wan Nazaimoon WM, Khalid BAK. Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycaemic control in streptozotocininduced diabetic rats. Malays J Pathol 2002; 24(2):77-82.

[17] Qureshi AA, Peterson D, Mhasler-Rapacz JO, et al. Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 ApoE-deficient mice. J Nutr. 2001; 131:2606-2618.

[18] Tomeo AC, Geller M, Watkins TR, et al. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids. 1995; 30:1179-1183.

[19] Newaz MA, Nawal NN. Effect of gamma-tocotrienol on blood pressure, lipid oxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens. 1999; 21:1297-1313.

[20] Koba K, Abe K, Ikeda I, et al. Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the spontaneously hypertensive rat (SHR). Biosc Biotech Biochem. 1992; 56:1420-1423.

[21] Sen CK, Rink C, Khanna S. Palm oil–derived natural vitamin E α-tocotrienol in brain health and disease. J Am Coll Nutr. 2010; 29 (Suppl 1):S314–S323.

[22] Mishima K, Tanaka T, Pu F, et al. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosc Lett. 2003; 337:56-60.

[23] Sen CK, Khanna S, Roy S, et al. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamateinduced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem. 2000; 275:13049-13055.

[24] Peh HY, Tan WSD, Liao W, Wong F. Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol. Pharmacol Ther 2016; 162:152-169.

[25] Kamal-Eldin A & Appelqvist L. The chemistry and antioxidant properties of tocopherol and tocotrienols. Lipid 1996; 31:671-701.

[26] Hood RL. Tocotrienols inmetabolism. *In* Phytochemicals – A new paradigm. Bidlack WR, ED. Technomic Publishing Company: Lancaster; 1998:33-51.

[27] Drotleff AM & Ternes W. Determination of RS, E/Z-tocotrienols by HPLC. J Chromatogr A 2001; 901:215-223.

[28] Wong RSY & Radhakrishnan AK. Tocotrienol research: past and present. Nutr Rev 2012; 70(9):483-490.

[29] Zelinski H. Tocotrienols: distribution and source cereals – role in human health. *In* Tocotrienols: vitamin E beyond tocopherols. Boca Raton: CRC Press Vol 1; 2008:23-42.

[30] Choo YM, Ma AN, Chuah CH, Khor HT, Bong SC: A developmental study on the appearance of tocopherols and tocotrienols in developing palm mesocarp (*Elaeis guineensis*). Lipids 2004; 39(6):561-564.

[31] Ng MH, Choo YM, Ma AN, Chuah CH, Hashim MA: Separation of vitamin E (tocopherol, tocotrienol, and tocomonoenol) in palm oil. Lipids 2004; 39(10):1031-1035.

[32] Theriault A, Chao JT, Wang Q, Gapor A, Adell K. Tocotrienol: a review of its therapeutic potential. Clin Biochem 1999; 32: 309-319.

[33] European Food Safety Authority. Scientific opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food on a request from the Commission on Mixed Tocopherols, Tocotrienol Tocopherol and Tocotrienols as Sources for Vitamin E. EFSA J. 2008; 640:1–

[34] 34.Fu JY, Che HL, Yee DM, Teng KT. Bioavailability of tocotrienols: evidence in human studies. Nutr Met 2014; 11(5):1-10.

**223**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

in the aorta of rabbits. Malays J Pathol

[43] Li F, Tan W, Kang Z, Wong CW. Tocotrienol rich palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferationactivated receptors. Atherosclerosis

[44] Daud ZA, Tubie B, Sheyman M, Osia R, Adams J, Tubie S, Khosla P. Vitamin E tocotrienol supplementation improved lipid profile in chronic

haemodialysis patients. Vasc Health Risk

[45] Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T. Myocardial ischaemia reperfusion injury – from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 2012; 16(3):123-132.

[46] Das M, Das S, Wang P, Powell Sr, Das DK. Caveolin and proteasome in tocotrienol mediated muocardial protection. Cell Physiol Biochem 2008;

Qureshi N, Papasian CJ, Morrison DC,

[48] Qureshi AA, Bradlow BA, Brace L, Manganello J, Peterson DM, Pearce BC, Wright JJK, Gapor A, Elson CE. Lipids

[49] Parker RA, Perace BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional

methylglutaryl-coenzyme A reductase. J Biol Chem 1993; 268(15):11230-11238.

[50] Teoh MK, Chong JM, Mohamed J, Phang KS. Protection by tocotrienols

[47] Qureshi AA, Karpen CW,

Folts JD. Tocotrienols-induced inhibition of platelet thrombus formation an platelet aggregation in stenosed canine coronary arteries. Lipids Health Dis 2011; 14:10-58.

1995; 30(12):1171-1177.

suppression of 3-hydroxy-3-

2001; 23:17-25.

2010; 211(1):278-282.

Manag 2013; 9:746-761.

22(1-4):287-294.

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

Pharmacokinetics and bioavailability of alpha-, gamma-, and delta-tocotrienols under different food status. J Pharm

[35] Yap SP, Yuen KH, Wong JW.

Pharmacol 2001; 53:67-71.

[36] Leonard SW, Paterson E, Atkinson JK, Ramakrishnan R, Cross CE, Traber MG. Studies in humans using deuterium-labelled αand γ-tocopherols demonstrate faster plasma γ-tocopherol disappearance and greater γ-metabolite production. Free Radic Biol Med 2005; 38:857-866.

[37] Gao P & Morozowich W. Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin Drug Deliv 2005; 3:97-110.

[38] Khosla P, Patel V, Whinter JM, Khanna S, Rakhkovskova M, Roy S et al. Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal

[39] Packer L, Weber SU, Rimbach G. Molecular aspect of α-tocotrienol antioxidant action and cell signalling. J

[40] Chin SF, Hamid NAA, Latiff AA, Xakaria Z, Mazlan M, Yusof YAM, Karim AA, Ibrahim J, Hamid Z,

Ngah WZW. Reduction of DNA damage in older healthy adults by Tri E® Tocotrienol supplementation. J Nutr

[41] World Health Organization. *Cardiovascular diseases* 2020. Available at: https://www.who.int/en/news-room/ fact-sheets/detail/cardiovasculardiseases-(cvds)/. Accessed 12

[42] Nafeeza MI, Norzana AG,

Jalaluddin HK, Gapor MT. The effects of a tocotrienol-rich fraction on experimentally induced atherosclerosis

2006; 8:1059-1068.

2008; 24(1):1-10.

November 2020.

Nutr 2001; 131:3695-3735.

#### *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

[35] Yap SP, Yuen KH, Wong JW. Pharmacokinetics and bioavailability of alpha-, gamma-, and delta-tocotrienols under different food status. J Pharm Pharmacol 2001; 53:67-71.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[26] Hood RL. Tocotrienols

[27] Drotleff AM & Ternes W.

Nutr Rev 2012; 70(9):483-490.

[29] Zelinski H. Tocotrienols:

Press Vol 1; 2008:23-42.

2004; 39(6):561-564.

39(10):1031-1035.

11(5):1-10.

Lancaster; 1998:33-51.

901:215-223.

inmetabolism. *In* Phytochemicals – A new paradigm. Bidlack WR, ED. Technomic Publishing Company:

Determination of RS, E/Z-tocotrienols by HPLC. J Chromatogr A 2001;

[28] Wong RSY & Radhakrishnan AK. Tocotrienol research: past and present.

distribution and source cereals – role in human health. *In* Tocotrienols: vitamin E beyond tocopherols. Boca Raton: CRC

[30] Choo YM, Ma AN, Chuah CH, Khor HT, Bong SC: A developmental study on the appearance of tocopherols and tocotrienols in developing palm mesocarp (*Elaeis guineensis*). Lipids

[31] Ng MH, Choo YM, Ma AN, Chuah CH, Hashim MA: Separation of vitamin E (tocopherol, tocotrienol, and tocomonoenol) in palm oil. Lipids 2004;

[32] Theriault A, Chao JT, Wang Q, Gapor A, Adell K. Tocotrienol: a review of its therapeutic potential. Clin

[33] European Food Safety Authority. Scientific opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food on a request from the Commission on Mixed Tocopherols, Tocotrienol Tocopherol and Tocotrienols as Sources for Vitamin E. EFSA J. 2008; 640:1–

[34] 34.Fu JY, Che HL, Yee DM, Teng KT. Bioavailability of tocotrienols: evidence in human studies. Nutr Met 2014;

Biochem 1999; 32: 309-319.

rice bran inhibit atherosclerotic lesions in C57BL/6 ApoE-deficient mice. J Nutr.

[18] Tomeo AC, Geller M, Watkins TR, et al. Antioxidant effects of tocotrienols

[19] Newaz MA, Nawal NN. Effect of gamma-tocotrienol on blood pressure, lipid oxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens. 1999;

[20] Koba K, Abe K, Ikeda I, et al. Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the spontaneously hypertensive rat (SHR). Biosc Biotech

Biochem. 1992; 56:1420-1423.

[21] Sen CK, Rink C, Khanna S. Palm oil–derived natural vitamin E α-tocotrienol in brain health and disease. J Am Coll Nutr. 2010; 29

[22] Mishima K, Tanaka T, Pu F, et al. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosc Lett. 2003;

[23] Sen CK, Khanna S, Roy S, et al. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamateinduced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol

Chem. 2000; 275:13049-13055.

[24] Peh HY, Tan WSD, Liao W, Wong F. Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol. Pharmacol Ther 2016; 162:152-169.

[25] Kamal-Eldin A & Appelqvist L. The chemistry and antioxidant properties of tocopherol and tocotrienols. Lipid 1996;

(Suppl 1):S314–S323.

337:56-60.

in patients with hyperlipidemia and carotid stenosis. Lipids. 1995;

2001; 131:2606-2618.

30:1179-1183.

21:1297-1313.

**222**

31:671-701.

[36] Leonard SW, Paterson E, Atkinson JK, Ramakrishnan R, Cross CE, Traber MG. Studies in humans using deuterium-labelled αand γ-tocopherols demonstrate faster plasma γ-tocopherol disappearance and greater γ-metabolite production. Free Radic Biol Med 2005; 38:857-866.

[37] Gao P & Morozowich W. Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin Drug Deliv 2005; 3:97-110.

[38] Khosla P, Patel V, Whinter JM, Khanna S, Rakhkovskova M, Roy S et al. Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal 2006; 8:1059-1068.

[39] Packer L, Weber SU, Rimbach G. Molecular aspect of α-tocotrienol antioxidant action and cell signalling. J Nutr 2001; 131:3695-3735.

[40] Chin SF, Hamid NAA, Latiff AA, Xakaria Z, Mazlan M, Yusof YAM, Karim AA, Ibrahim J, Hamid Z, Ngah WZW. Reduction of DNA damage in older healthy adults by Tri E® Tocotrienol supplementation. J Nutr 2008; 24(1):1-10.

[41] World Health Organization. *Cardiovascular diseases* 2020. Available at: https://www.who.int/en/news-room/ fact-sheets/detail/cardiovasculardiseases-(cvds)/. Accessed 12 November 2020.

[42] Nafeeza MI, Norzana AG, Jalaluddin HK, Gapor MT. The effects of a tocotrienol-rich fraction on experimentally induced atherosclerosis in the aorta of rabbits. Malays J Pathol 2001; 23:17-25.

[43] Li F, Tan W, Kang Z, Wong CW. Tocotrienol rich palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferationactivated receptors. Atherosclerosis 2010; 211(1):278-282.

[44] Daud ZA, Tubie B, Sheyman M, Osia R, Adams J, Tubie S, Khosla P. Vitamin E tocotrienol supplementation improved lipid profile in chronic haemodialysis patients. Vasc Health Risk Manag 2013; 9:746-761.

[45] Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T. Myocardial ischaemia reperfusion injury – from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 2012; 16(3):123-132.

[46] Das M, Das S, Wang P, Powell Sr, Das DK. Caveolin and proteasome in tocotrienol mediated muocardial protection. Cell Physiol Biochem 2008; 22(1-4):287-294.

[47] Qureshi AA, Karpen CW, Qureshi N, Papasian CJ, Morrison DC, Folts JD. Tocotrienols-induced inhibition of platelet thrombus formation an platelet aggregation in stenosed canine coronary arteries. Lipids Health Dis 2011; 14:10-58.

[48] Qureshi AA, Bradlow BA, Brace L, Manganello J, Peterson DM, Pearce BC, Wright JJK, Gapor A, Elson CE. Lipids 1995; 30(12):1171-1177.

[49] Parker RA, Perace BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3 methylglutaryl-coenzyme A reductase. J Biol Chem 1993; 268(15):11230-11238.

[50] Teoh MK, Chong JM, Mohamed J, Phang KS. Protection by tocotrienols

against hypercholesterolaemia and atheroma. Med J Malaysia 1994; 49(3):255-262.

[51] Qureshi AA, Sami SA, Salser WA, Khan FA. Dose-dependent suppression of serum cholesterol by tocotrienolrich fraction (TRF25) of rice bran in hypercholesterolaemic humans. Atherosclerosis 2002; 161(1):199-207.

[52] Roza JM, Xian-Liu Z, Guthrie N. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolaemic patients. Altern Ther Health Med 2007; 13(6):44-48.

[53] Magosso E, Ansari MA, Gopalan MA, Shuaib IL, Wong JW, Khan NAK, Bakar MRA. Ng BH, Yuen KH. Tocotrienols for normalisation of hepatic echogenic response in non-alcoholic fatty liver: a randomised placebo controlled clinical trial. Nutr J 2013; 12(1):166

[54] Napolitano M, Avanzi L, Manfredini S, Bravo E. Effects of new combinative antioxidant FeAOX-6 and α-tocotrienol on macrophage atherogenesis-related functions. Vasc Pharmacol 2007; 46(6):394-405.

[55] World Health Organization. *Diabetes* 2020. Available at: https:// www.who.int/health-topics/diabetes. Accessed 18 November 2020.

[56] Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ,Bell RA, IRAS. Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care 2002; 25(12):2172-2177.

[57] Knekt P, Reunanen A, Marniemi J, Leino A, Aromaa A. Low vitamin E status is a potential risk factor for insulin-dependent diabetes mellitus. J Intern Med 1999; 245(1):99-102.

[58] Salonen JT, Nyyssönen K, Tuomainen TP, Mäenpää PH, Korpela H, Kaplan GA, Lynch J, Helmrich SP, Salonen R. Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. Br Med J 1995; 311(7013):1124-1127.

[59] Paolisso G, D'Amaro G, Giugliano D, Ceriello A, Varricchio M, D'Onofrio F. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin dependent diabetic patients. Am J Clin Nutr 1993; 57(5):650-656.

[60] Paolisso G, D'Amaro G, Galzerano D, Cacciapuoti F, Varricchio M, Varricchio G, D'Onofrio F. Pharmacological doses of vitamin E and insulin action in elderly subjects. Am J Clin Nutr 1994; 59(6):1291-1296.

[61] Montonen J, Knekt P, Järniven R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care 2004; 27(2):362-366.

[62] Baliarsingh S, Beg ZH, Ahmad J. The therapeutic impacts of tocotrienol in type 2 diabetic patients with hyperlipidaemia. Atherosclerosis 2005; 182(2):367-374.

[63] Haghighat N, Vafa M, Eghtasadi S, Heidari R, Hosseini A, Rostami A. The effects of tocotrienols added to canola oil on microalbuminurea, inflammation, and nitrosative stress in patients with type 2 diabetes: A randomised, doubleblind, placebo-controlled trial. Int J Prev Med 2014; 5(5):617-623.

[64] Muharis SP, Top AGM, Murugan D, Mustafa MR. Palm oil tocotrienol fractions restore endothelium dependent relaxation in aortic rings of streptozotocin-induced diabetic and spontaneously hypertensive rats. Nutr Res 2010; 30(3):209-216.

**225**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis. Lancet Glob

Health 2017; 5(12):e1221–e1234

[74] Sayres R, Taly A, Rahimy E, Blumer K, Coz D, Hammel N, Krause J, Narayanaswamy A, Rastegar Z, Wu D, Xu S, Barb S, Joseph A, Shumski M, Smith J, Sood AB, Corrado GS, Peng L, Webster DR. Using a deep learning algorithm and integrated gradients explanation to assist grading for diabetic retinopathy. Ophthalmology 2019;

35(3):556-564

126(4):552-564.

[75] Abougalambou SSI,

Abougalambou AS. Risk factors associated with diabetic retinopathy among type 2 diabetes patients at teaching hospital in Malaysia. Diabetes

Metab Syndr 2015; 9(2):98-103.

[76] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol

[77] Kowluru, R.A. Mitochondrial stability in diabetic retinopathy: Lessons Learned from epigenetics. Diabetes

2018; 14(2):88-98.

2019; 68(2):241-247.

113(19):E2655–E2664.

Longev 2019; 5:1-17.

[79] Bigagli E, Lodovici M. Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications. Oxidative Med Cell

[78] Sohn EH, van Dijk HW, Jiao C, Kok PHB, et al. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc Natl Acad Sci USA 2016;

[73] Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

[65] Matough SA, Budin SB, Hamid ZA, Abdul-Rahman M, Al-Wahaibi N, Mohammed J. Tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats. Sultan Qaboos Univ Med J 2014; 14(1):495-e103.

[66] Kuhad A, Bishnoi M, Tiwari V, Chopra K. Suppression of NF-kappabeta signalling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav

2009; 92(2):251-9.

[67] Gross J, de-Azevedo MJ,

Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 2005; 28(1):164-176.

[68] Kuhad A & Chopra K. Attenuation of diabetic nephropathy by tocotrienol: Involvement of NFkB signalling pathway.

Siddiqui A. Comparative hypoglycaemic

hyperglycaemia induced nephropathy in type I diabetic rats. Chem Biol Interact

[70] Siddiqui S, Ahsan H, Khan MR, Siddiqui WA. Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by the modulation in TGF-β expression. Toxicol Appl Pharmacol

[71] Tan GCJ, Tan SMQ, Phang SCW,

Life Sci 2009; 84(9-10):206-301.

[69] Siddiqui S, Rashid-Khan M,

and nephroprotective effects of tocotrienol rich fraction (TRF) from palm oil and rice bran oil against

2010; 188(3):651-658.

2013; 273(2):314-324.

Ng YT, Ng EY, Ahmad B, Palamisamy UDM, Kadir KA. Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomised controlled trial. Ther Adv Endocrino Metab 2019; 10:1-16.

[72] Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, et al. Global *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

[65] Matough SA, Budin SB, Hamid ZA, Abdul-Rahman M, Al-Wahaibi N, Mohammed J. Tocotrienol-rich fraction from palm oil prevents oxidative damage in diabetic rats. Sultan Qaboos Univ Med J 2014; 14(1):495-e103.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[58] Salonen JT, Nyyssönen K, Tuomainen TP, Mäenpää PH, Korpela H, Kaplan GA, Lynch J, Helmrich SP, Salonen R. Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. Br Med J 1995;

311(7013):1124-1127.

[59] Paolisso G, D'Amaro G,

Nutr 1993; 57(5):650-656.

59(6):1291-1296.

182(2):367-374.

Med 2014; 5(5):617-623.

Res 2010; 30(3):209-216.

[60] Paolisso G, D'Amaro G, Galzerano D, Cacciapuoti F, Varricchio M, Varricchio G,

D'Onofrio F. Pharmacological doses of vitamin E and insulin action in elderly subjects. Am J Clin Nutr 1994;

[61] Montonen J, Knekt P, Järniven R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes

[62] Baliarsingh S, Beg ZH, Ahmad J. The therapeutic impacts of tocotrienol

hyperlipidaemia. Atherosclerosis 2005;

[63] Haghighat N, Vafa M, Eghtasadi S, Heidari R, Hosseini A, Rostami A. The effects of tocotrienols added to canola oil on microalbuminurea, inflammation, and nitrosative stress in patients with type 2 diabetes: A randomised, doubleblind, placebo-controlled trial. Int J Prev

[64] Muharis SP, Top AGM, Murugan D, Mustafa MR. Palm oil tocotrienol fractions restore endothelium

dependent relaxation in aortic rings of streptozotocin-induced diabetic and spontaneously hypertensive rats. Nutr

in type 2 diabetic patients with

Care 2004; 27(2):362-366.

Giugliano D, Ceriello A, Varricchio M, D'Onofrio F. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin dependent diabetic patients. Am J Clin

against hypercholesterolaemia and atheroma. Med J Malaysia 1994;

[51] Qureshi AA, Sami SA, Salser WA, Khan FA. Dose-dependent suppression of serum cholesterol by tocotrienolrich fraction (TRF25) of rice bran in hypercholesterolaemic humans. Atherosclerosis 2002; 161(1):199-207.

[52] Roza JM, Xian-Liu Z, Guthrie N. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolaemic

patients. Altern Ther Health Med 2007;

Gopalan MA, Shuaib IL, Wong JW, Khan NAK, Bakar MRA. Ng BH,

of hepatic echogenic response in non-alcoholic fatty liver: a randomised placebo controlled clinical trial. Nutr J

[54] Napolitano M, Avanzi L,

[55] World Health Organization. *Diabetes* 2020. Available at: https:// www.who.int/health-topics/diabetes.

[56] Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ,Bell RA, IRAS. Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care 2002;

[57] Knekt P, Reunanen A, Marniemi J, Leino A, Aromaa A. Low vitamin E status is a potential risk factor for insulin-dependent diabetes mellitus. J Intern Med 1999; 245(1):99-102.

Accessed 18 November 2020.

25(12):2172-2177.

Manfredini S, Bravo E. Effects of new combinative antioxidant FeAOX-6 and α-tocotrienol on macrophage atherogenesis-related functions. Vasc Pharmacol 2007; 46(6):394-405.

Yuen KH. Tocotrienols for normalisation

[53] Magosso E, Ansari MA,

49(3):255-262.

13(6):44-48.

2013; 12(1):166

**224**

[66] Kuhad A, Bishnoi M, Tiwari V, Chopra K. Suppression of NF-kappabeta signalling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 2009; 92(2):251-9.

[67] Gross J, de-Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care 2005; 28(1):164-176.

[68] Kuhad A & Chopra K. Attenuation of diabetic nephropathy by tocotrienol: Involvement of NFkB signalling pathway. Life Sci 2009; 84(9-10):206-301.

[69] Siddiqui S, Rashid-Khan M, Siddiqui A. Comparative hypoglycaemic and nephroprotective effects of tocotrienol rich fraction (TRF) from palm oil and rice bran oil against hyperglycaemia induced nephropathy in type I diabetic rats. Chem Biol Interact 2010; 188(3):651-658.

[70] Siddiqui S, Ahsan H, Khan MR, Siddiqui WA. Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by the modulation in TGF-β expression. Toxicol Appl Pharmacol 2013; 273(2):314-324.

[71] Tan GCJ, Tan SMQ, Phang SCW, Ng YT, Ng EY, Ahmad B, Palamisamy UDM, Kadir KA. Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomised controlled trial. Ther Adv Endocrino Metab 2019; 10:1-16.

[72] Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, et al. Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis. Lancet Glob Health 2017; 5(12):e1221–e1234

[73] Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3):556-564

[74] Sayres R, Taly A, Rahimy E, Blumer K, Coz D, Hammel N, Krause J, Narayanaswamy A, Rastegar Z, Wu D, Xu S, Barb S, Joseph A, Shumski M, Smith J, Sood AB, Corrado GS, Peng L, Webster DR. Using a deep learning algorithm and integrated gradients explanation to assist grading for diabetic retinopathy. Ophthalmology 2019; 126(4):552-564.

[75] Abougalambou SSI, Abougalambou AS. Risk factors associated with diabetic retinopathy among type 2 diabetes patients at teaching hospital in Malaysia. Diabetes Metab Syndr 2015; 9(2):98-103.

[76] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14(2):88-98.

[77] Kowluru, R.A. Mitochondrial stability in diabetic retinopathy: Lessons Learned from epigenetics. Diabetes 2019; 68(2):241-247.

[78] Sohn EH, van Dijk HW, Jiao C, Kok PHB, et al. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc Natl Acad Sci USA 2016; 113(19):E2655–E2664.

[79] Bigagli E, Lodovici M. Circulating Oxidative Stress Biomarkers in Clinical Studies on Type 2 Diabetes and Its Complications. Oxidative Med Cell Longev 2019; 5:1-17.

[80] Liu XF, Zhou DD, Xie T, Hao JL, Malik TH, Lu CB, Qi, J Pant OP, Lu CB. Qi J, Pant OP, Lu CW. The Nrf2 Signalling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases. Int J Biol Sci 2018; 14(9):1090-1098.

[81] Zhang D, Lv FL, Wang GH. Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression. Eur Rev Med Pharmacol Sci 2018; 22(16):5071-5076.

[82] Kowluru RA & Kennedy A. Therapeutic potential of anti-oxidants and diabetic retinopathy. Expert Opin Investig Drugs 2001; 10(9):1665-1676.

[83] Kowluru RA & Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta 2015; 1852(11):2474-2483.

[84] Ahmadi K, Kumalaningsih S, Wijana S, Santoso I. Antioxidative effect of tocotrienol rich fraction from palm fatty acid distillate on oxidative stress. Food and Public Health 2013; 3(3):130-136.

[85] Sadikan MZ, Nasir NMA, Agarwal R, Ismail NM. Protective effect of palm oil-derived tocotrienol-rich fraction against neurodegenerative changes in rats with streptozotocininduced diabetic retinopathy. Biomolecules 2020; 10(4):556.

[86] Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, Chappell AS. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: A review. Pain Med 2007; 8 (Suppl 2): S50–S63.

[87] Sobhani S, Asayesh H, Sharifi F, Djalalinia S, Baradaran HR, Arzhagi SM, Mansourian M, Rezapoor A, Ansari H, Masoud MR, Qorbani M. Prevalence of diabetic peripheral neuropathy in Iran: A

systematic review and meta-analysis. J Diabetes Metab Disord 2014; 13(1):97.

[88] Callaghan BC, Cheng H, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: Clinical manifestations and current treatment. Lancet Neurol 2012; 11(6):521-534.

[89] Sadosky A, Mardekian J, Parsons B, Hopps M, Bienan EJ, Markman J. Healthcare utilization and costs in diabetic relative to the clinical spectrum of painful peripheral diabetic neuropathy. J Diabetes Complications 2015; 29(2):212-217.

[90] Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T, European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17(9):1113-1e88.

[91] Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic neuropathy in older adults. Clin Geriatr Med 2008; 24(3):407-435.

[92] Ziegler D, Low PA, Litchy WJ, Boulton AJM et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 2011; 34(9):2054-2060.

[93] Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44(11):1973-1988.

[94] Kuhad A, Chopra K. Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 2009; 57(4):456-462.

[95] Gopalan Y, Shuaib IL, Magosso E, Ansari MA et al. Clinical investigation of the protective effects of palm vitamin

**227**

10(7):881.

2007; 2(3);34759.

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

impairment. Neurobiol Aging 2012;

[105] Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, Fratiglioni L. High plasma levels of Vitamin E forms and reduced Alzheimer's disease risk in advanced age. J. Alzheimers Dis. 2010;

[106] Mangialasche F, Solomon A, Kareholt I, Hooshmand B,

[107] Mangialasche F, Westman E,

Baglioni M, Tarducci R, Gobbi G, Floridi P, Soininen H et al. Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of alpha−/gammatocotrienols and gamma-tocopherol. J

Intern Med 2013; 273:602-621.

2011; 6:121-145.

Kivipelto M, Muehlboeck JS, Cecchetti R,

[108] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17(12):1726-1733.

[109] Feng X, McDonald JM. Disorders of bone remodelling. Annu Rev Pathol

[110] Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002; 23(3):279-302.

[111] Chin KY, Ima-Nirwana S. Sex steroids and bone health status in men. Int J Endocrinol 2012; 2012:208719.

[112] Hough FS, Brown SL, Cassim B, Davey MR et al. National Osteoporosis Foundation of South Africa. The safety of osteoporosis medication. S Afr Med J

2014; 104(4):279-282.

Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M. Serum levels of Vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol 2013; 48:1428-1435.

33:2282-2290.

20:1029-1037.

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

E tocotrienols on brain white matter.

[96] VENUS Investigators, Hor CP, Fung WY, Ang HA, Lim SC et al. Efficacy of oral mixed tocotrienols in diabetic peripheral neuropathy: A randomized clinical trial. JAMA Neurol

[97] Ng Yt, Phang SCW, Tan GCJ, Ng EY, Henien NPB, Palanisamy UMD, Ahmad B, Kadir KA. The effects of tocotrienol-rich vitamin E (Tocovid) on Diabetic neuropathy: A phase II Randomised controlled trial. Nutrients

[98] Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;

[99] Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem

[100] Zhang Y, Dawson VL, Dawson TM. Oxidative stress and genetics in the pathogenesis of Parkinson's disease. Neurobiol Dis 2000; 7(4):240-250.

2000; 267(16):4904-4911.

[101] Sen CK, Khanna S, Roy S. Tocotrienol: The natural vitamin E to defend the nervous system? Ann N Y

Acad Sci 2004; 1031:127-142.

[102] Chin KY, Tay SS. A review on the relationship between tocotrienol and Alzheimer's disease. Nutrients 2018;

[103] Swerdlow RH. Pathogenesis of Alzheimer's disease. Clin Interven Aging

Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, Cecchetti R, Baglioni M,

[104] Mangialasche F, Xu W,

Simmons A, Soininen H et al. Tocopherols and tocotrienols plasma levels are associated with cognitive

Stroke 2014; 45(5):1422-1428.

2018; 75(4):444-452.

2020; 12(5):1522

222(3):236-245.

#### *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

E tocotrienols on brain white matter. Stroke 2014; 45(5):1422-1428.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

systematic review and meta-analysis. J Diabetes Metab Disord 2014; 13(1):97.

[88] Callaghan BC, Cheng H, Stables CL,

[89] Sadosky A, Mardekian J, Parsons B, Hopps M, Bienan EJ, Markman J. Healthcare utilization and costs in diabetic relative to the clinical spectrum of painful peripheral diabetic neuropathy. J Diabetes Complications

Smith AL, Feldman EL. Diabetic neuropathy: Clinical manifestations and current treatment. Lancet Neurol 2012;

[90] Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, Nurmikko T, European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J

Neurol 2010; 17(9):1113-1e88.

[91] Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Diabetic

Med 2008; 24(3):407-435.

2011; 34(9):2054-2060.

57(4):456-462.

[93] Cameron NE, Eaton SE,

Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44(11):1973-1988.

[94] Kuhad A, Chopra K. Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 2009;

[95] Gopalan Y, Shuaib IL, Magosso E, Ansari MA et al. Clinical investigation of the protective effects of palm vitamin

neuropathy in older adults. Clin Geriatr

[92] Ziegler D, Low PA, Litchy WJ, Boulton AJM et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care

11(6):521-534.

2015; 29(2):212-217.

[80] Liu XF, Zhou DD, Xie T, Hao JL, Malik TH, Lu CB, Qi, J Pant OP, Lu CB. Qi J, Pant OP, Lu CW. The Nrf2 Signalling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases. Int J Biol

[81] Zhang D, Lv FL, Wang GH. Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression. Eur Rev Med Pharmacol Sci 2018;

[83] Kowluru RA & Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys

[82] Kowluru RA & Kennedy A. Therapeutic potential of anti-oxidants and diabetic retinopathy. Expert Opin Investig Drugs 2001; 10(9):1665-1676.

Acta 2015; 1852(11):2474-2483.

[85] Sadikan MZ, Nasir NMA,

[86] Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, Chappell AS. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: A review. Pain Med 2007; 8 (Suppl 2):

[87] Sobhani S, Asayesh H, Sharifi F,

Rezapoor A, Ansari H, Masoud MR, Qorbani M. Prevalence of diabetic peripheral neuropathy in Iran: A

Djalalinia S, Baradaran HR, Arzhagi SM, Mansourian M,

Agarwal R, Ismail NM. Protective effect of palm oil-derived tocotrienol-rich fraction against neurodegenerative changes in rats with streptozotocininduced diabetic retinopathy. Biomolecules 2020; 10(4):556.

[84] Ahmadi K, Kumalaningsih S, Wijana S, Santoso I. Antioxidative effect of tocotrienol rich fraction from palm fatty acid distillate on oxidative stress. Food and Public Health 2013;

Sci 2018; 14(9):1090-1098.

22(16):5071-5076.

3(3):130-136.

**226**

S50–S63.

[96] VENUS Investigators, Hor CP, Fung WY, Ang HA, Lim SC et al. Efficacy of oral mixed tocotrienols in diabetic peripheral neuropathy: A randomized clinical trial. JAMA Neurol 2018; 75(4):444-452.

[97] Ng Yt, Phang SCW, Tan GCJ, Ng EY, Henien NPB, Palanisamy UMD, Ahmad B, Kadir KA. The effects of tocotrienol-rich vitamin E (Tocovid) on Diabetic neuropathy: A phase II Randomised controlled trial. Nutrients 2020; 12(5):1522

[98] Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999; 222(3):236-245.

[99] Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 2000; 267(16):4904-4911.

[100] Zhang Y, Dawson VL, Dawson TM. Oxidative stress and genetics in the pathogenesis of Parkinson's disease. Neurobiol Dis 2000; 7(4):240-250.

[101] Sen CK, Khanna S, Roy S. Tocotrienol: The natural vitamin E to defend the nervous system? Ann N Y Acad Sci 2004; 1031:127-142.

[102] Chin KY, Tay SS. A review on the relationship between tocotrienol and Alzheimer's disease. Nutrients 2018; 10(7):881.

[103] Swerdlow RH. Pathogenesis of Alzheimer's disease. Clin Interven Aging 2007; 2(3);34759.

[104] Mangialasche F, Xu W, Kivipelto M, Costanzi E, Ercolani S, Pigliautile M, Cecchetti R, Baglioni M, Simmons A, Soininen H et al. Tocopherols and tocotrienols plasma levels are associated with cognitive

impairment. Neurobiol Aging 2012; 33:2282-2290.

[105] Mangialasche F, Kivipelto M, Mecocci P, Rizzuto D, Palmer K, Winblad B, Fratiglioni L. High plasma levels of Vitamin E forms and reduced Alzheimer's disease risk in advanced age. J. Alzheimers Dis. 2010; 20:1029-1037.

[106] Mangialasche F, Solomon A, Kareholt I, Hooshmand B, Cecchetti R, Fratiglioni L, Soininen H, Laatikainen T, Mecocci P, Kivipelto M. Serum levels of Vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Exp Gerontol 2013; 48:1428-1435.

[107] Mangialasche F, Westman E, Kivipelto M, Muehlboeck JS, Cecchetti R, Baglioni M, Tarducci R, Gobbi G, Floridi P, Soininen H et al. Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of alpha−/gammatocotrienols and gamma-tocopherol. J Intern Med 2013; 273:602-621.

[108] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17(12):1726-1733.

[109] Feng X, McDonald JM. Disorders of bone remodelling. Annu Rev Pathol 2011; 6:121-145.

[110] Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002; 23(3):279-302.

[111] Chin KY, Ima-Nirwana S. Sex steroids and bone health status in men. Int J Endocrinol 2012; 2012:208719.

[112] Hough FS, Brown SL, Cassim B, Davey MR et al. National Osteoporosis Foundation of South Africa. The safety of osteoporosis medication. S Afr Med J 2014; 104(4):279-282.

[113] Ginaldi L, Di Benedetto MC, De Martinis M. Osteoporosis, inflammation and ageing. Immun Ageing 2005; 2:14.

[114] Manolagas SC. From estrogencentric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 2010; 31(3):266-300.

[115] Fatokun AA, Stone TW, Smith RA. Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species. Eur J Pharmacol 2008; 587(1-3):35-41.

[116] Ha H, Kwak HB, Lee SW, Jin HM, Kim HM, Kim HH, Lee ZH. Reactive oxygen species mediate RANK signalling in osteoclasts. Exp Cell Res 2004; 301(2):119-127.

[117] McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep 2009; 7(4):134-139.

[118] Kaileh M, Sen R. Role of NF-kappaB in the anti-inflammatory effects of tocotrienols. J Am Coll Nutr 2010; 29(3 Suppl):334S–339S.

[119] Muhammad N, Luke DA, Shuid AN, Mohamed N, Soelaiman IN. Two different isomers of vitamin Eprevent bone loss in post-menopausal osteoporosis rat model. Evid Based Complement Alternate Med 2012; 2012:161527.

[120] Ahmad NS, Khalid BA, Luke DA, Ima-Nirwana S. Tocotrienol offers better protection than tocopherol from free radical-induced damage of rat bone. Clin Exp Pharmacol Physiol 2005; 32(9):761-770.

[121] Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BA. Palm vitamin E is comparable to alpha-tocopherol in maintaining bone mineral density in ovariectomised female rats. Exp Clin Endocrinol Diabetes 2000; 108:305-310. [122] Ima-Nirwana S, Kiftiah A, Zainal AG, Norazlina M, Gapor MT, Khalid BAK. Palm vitamin E prevents osteoporosis in orchidectomized growing male rats. Natural Product Sciences 2000; 6(4):155-160.

[123] Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BA. Palm vitamin E is comparable to alpha-tocopherol in maintaining bone mineral density in ovariectomised female rats. Exp Clin Endocrinol Diabetes 2000; 108:305-310.

[124] Nazrun A, Khairunnur A, Norliza M, Norazlina M, Ima-Nirwana S. Effects of palm tocotrienol on oxidative stress and bone strength in ovariectomised rats. Med Health 2008; 3(2):83-90.

[125] Chin KY, Ima-Nirwana S. The biological effects of tocotrienol on bone: A review on evidence from rodent models. Drugs Des Devel Ther 2015; 9:2049-2061.

[126] Cervellati C, Bonaccorsi G, Cremonini E, Romani A, Fila E, Castaldini MC, Ferrazzini S, Giganti M, Massari L. Oxidative stress and bone resorption interplay as a possible trigger for postmenopausal osteoporosis. Biomed Res Int 2014; 2014:569563.

[127] Ibáñez L, Ferrándiz ML, Brines R, Guede D, Cuadrado A, Alcaraz MJ. Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis. Oxid Med Cell Longev 2014; 2014:726590.

[128] Yang Y, Su Y, Wang D, Chen Y, Wu T, Li G, Sun X, Cui L. Tanshinol attenuates the deleterious effects of oxidative stress on osteoblastic differentiation via Wnt/FoxO3a signaling. Oxid Med Cell Longev 2013; 2013:351895.

[129] Baek KH, Oh KW, Lee WY, Lee SS, Kim MK, Kwn HS, Rhee EJ, Han JH,

**229**

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases*

vitamin E supplementation on bone metabolism in nicotine-treated rats. Singapore Med J 2007; 48(3):195-199.

[137] Norazlina M, Hermizi H, Faizah O, Nazrun AS, Norliza M, Ima-Nirwana S. Vitamin E reversed nicotine-induced toxic effects on bone biochemical markers in male rats. Arch Med Sci

[138] Bruzzaniti A, Baron R. Molecular regulation of osteoclast activity. Rev Endocr Metab Disord 2006;

[139] Abukhadir SS, Mohamed N, Makpol S, Muhammad N. Effects of palm vitamin e on bone-formationrelated gene expression in nicotinetreated rats. Evid Based Complement Alternat Med 2012; 2012:656025.

[140] Chin KY, Ima-Nirwana S. Effects of annatto-derived tocotrienol supplementation in osteoporosis induced by testosterone deficiency in rats. Clin Interv Aging 2014; 9:1247-1259.

[141] Neidhart S & Neidhart M. Rheumatoid arthritis and the concept of autoimmune disease. Int J Clin Rheumatol 2019; 14(2):75-79.

376(9746):1094-1108.

2015; 6(9):e1887.

[142] Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet 2010;

[143] Clementi MS, Triggianese P, Conigliaro P, Candi E, Melino G, Perricone R. The interplay between inflammation and metabolism in rheumatoid arthritis. Cell Death Dis

[144] Harre U & Schett G. Cellular and molecular pathways of structural damage in rheumatoid arthritis. Semin Immunopathol 2017; 39(4):355-363.

[145] Udalova IA, Mantovani A,

Feldmann M. Macrophage heterogeneity

2010; 6(4):505-512.

7(1-2):123-139.

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

Song KH, Cha BY, Lee KW, Kang MI. Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int

2010; 87(3):226-235.

103(1):55-60.

[130] Maniam S, Mohamed N, Shuid AN, Soelaiman IN. Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol. Basic Clin Pharmacol Toxicol 2008;

[131] Nizar AM, Nazrun AS,

Ter 2011; 162(6):533-538.

2012; 2012:680834.

14(13):1579-1590.

2012:960742.

[132] Abd Manan N, Mohamed N, Shuid AN. Effects of low-dose versus high-dose γ-tocotrienol on the bone cells exposed to the hydrogen peroxideinduced oxidative stress and apoptosis. Evid Based Complement Alternat Med

[133] Mo H, Yeganehjoo H, Shah A, Mo WK, Soelaiman IN, Shen CL. Mevalonate-suppressive dietary isoprenoids for bone health. J Nutr Biochem 2012; 23(12):1543-1551.

[134] Abdul-Majeed S, Mohamed N, Soelaiman IN. A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis. Curr Drug Targets 2013;

[135] Abdul-Majeed S, Mohamed N, Soelaiman IN. Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. Evid Based Complement Alternat Med 2012;

[136] Norazlina M, Lee PL, Lukman HI, Nazrun AS, Ima-Nirwana S. Effects of

Norazlina M, Norliza M, Ima Nirwana S. Low dose of tocotrienols protects osteoblasts against oxidative stress. Clin

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

Song KH, Cha BY, Lee KW, Kang MI. Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int 2010; 87(3):226-235.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[122] Ima-Nirwana S, Kiftiah A, Zainal AG, Norazlina M, Gapor MT, Khalid BAK. Palm vitamin E prevents osteoporosis in orchidectomized growing male rats. Natural Product Sciences 2000; 6(4):155-160.

[123] Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BA. Palm vitamin E is comparable to alpha-tocopherol in maintaining bone mineral density in ovariectomised female rats. Exp Clin Endocrinol Diabetes 2000; 108:305-310.

[124] Nazrun A, Khairunnur A, Norliza M, Norazlina M, Ima-

3(2):83-90.

9:2049-2061.

Nirwana S. Effects of palm tocotrienol on oxidative stress and bone strength in ovariectomised rats. Med Health 2008;

[125] Chin KY, Ima-Nirwana S. The biological effects of tocotrienol on bone: A review on evidence from rodent models. Drugs Des Devel Ther 2015;

[126] Cervellati C, Bonaccorsi G, Cremonini E, Romani A, Fila E,

Castaldini MC, Ferrazzini S, Giganti M, Massari L. Oxidative stress and bone resorption interplay as a possible trigger for postmenopausal osteoporosis. Biomed Res Int 2014; 2014:569563.

[127] Ibáñez L, Ferrándiz ML, Brines R, Guede D, Cuadrado A, Alcaraz MJ. Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis. Oxid Med Cell

[128] Yang Y, Su Y, Wang D, Chen Y, Wu T, Li G, Sun X, Cui L. Tanshinol attenuates the deleterious effects of oxidative stress on osteoblastic differentiation via Wnt/FoxO3a signaling. Oxid Med Cell Longev 2013;

[129] Baek KH, Oh KW, Lee WY, Lee SS, Kim MK, Kwn HS, Rhee EJ, Han JH,

Longev 2014; 2014:726590.

2013:351895.

[113] Ginaldi L, Di Benedetto MC, De Martinis M. Osteoporosis, inflammation and ageing. Immun Ageing 2005; 2:14.

[114] Manolagas SC. From estrogencentric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 2010;

[115] Fatokun AA, Stone TW, Smith RA. Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species. Eur J Pharmacol 2008;

[116] Ha H, Kwak HB, Lee SW, Jin HM, Kim HM, Kim HH, Lee ZH. Reactive oxygen species mediate RANK signalling in osteoclasts. Exp Cell Res

[117] McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep 2009; 7(4):134-139.

NF-kappaB in the anti-inflammatory effects of tocotrienols. J Am Coll Nutr

Shuid AN, Mohamed N, Soelaiman IN. Two different isomers of vitamin Eprevent bone loss in post-menopausal osteoporosis rat model. Evid Based Complement Alternate Med 2012;

[120] Ahmad NS, Khalid BA, Luke DA, Ima-Nirwana S. Tocotrienol offers better protection than tocopherol from free radical-induced damage of rat bone. Clin Exp Pharmacol Physiol 2005;

[121] Norazlina M, Ima-Nirwana S, Gapor MT, Khalid BA. Palm vitamin E is comparable to alpha-tocopherol in maintaining bone mineral density in ovariectomised female rats. Exp Clin Endocrinol Diabetes 2000; 108:305-310.

[118] Kaileh M, Sen R. Role of

2010; 29(3 Suppl):334S–339S.

[119] Muhammad N, Luke DA,

2012:161527.

32(9):761-770.

31(3):266-300.

587(1-3):35-41.

2004; 301(2):119-127.

**228**

[130] Maniam S, Mohamed N, Shuid AN, Soelaiman IN. Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol. Basic Clin Pharmacol Toxicol 2008; 103(1):55-60.

[131] Nizar AM, Nazrun AS, Norazlina M, Norliza M, Ima Nirwana S. Low dose of tocotrienols protects osteoblasts against oxidative stress. Clin Ter 2011; 162(6):533-538.

[132] Abd Manan N, Mohamed N, Shuid AN. Effects of low-dose versus high-dose γ-tocotrienol on the bone cells exposed to the hydrogen peroxideinduced oxidative stress and apoptosis. Evid Based Complement Alternat Med 2012; 2012:680834.

[133] Mo H, Yeganehjoo H, Shah A, Mo WK, Soelaiman IN, Shen CL. Mevalonate-suppressive dietary isoprenoids for bone health. J Nutr Biochem 2012; 23(12):1543-1551.

[134] Abdul-Majeed S, Mohamed N, Soelaiman IN. A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis. Curr Drug Targets 2013; 14(13):1579-1590.

[135] Abdul-Majeed S, Mohamed N, Soelaiman IN. Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. Evid Based Complement Alternat Med 2012; 2012:960742.

[136] Norazlina M, Lee PL, Lukman HI, Nazrun AS, Ima-Nirwana S. Effects of

vitamin E supplementation on bone metabolism in nicotine-treated rats. Singapore Med J 2007; 48(3):195-199.

[137] Norazlina M, Hermizi H, Faizah O, Nazrun AS, Norliza M, Ima-Nirwana S. Vitamin E reversed nicotine-induced toxic effects on bone biochemical markers in male rats. Arch Med Sci 2010; 6(4):505-512.

[138] Bruzzaniti A, Baron R. Molecular regulation of osteoclast activity. Rev Endocr Metab Disord 2006; 7(1-2):123-139.

[139] Abukhadir SS, Mohamed N, Makpol S, Muhammad N. Effects of palm vitamin e on bone-formationrelated gene expression in nicotinetreated rats. Evid Based Complement Alternat Med 2012; 2012:656025.

[140] Chin KY, Ima-Nirwana S. Effects of annatto-derived tocotrienol supplementation in osteoporosis induced by testosterone deficiency in rats. Clin Interv Aging 2014; 9:1247-1259.

[141] Neidhart S & Neidhart M. Rheumatoid arthritis and the concept of autoimmune disease. Int J Clin Rheumatol 2019; 14(2):75-79.

[142] Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet 2010; 376(9746):1094-1108.

[143] Clementi MS, Triggianese P, Conigliaro P, Candi E, Melino G, Perricone R. The interplay between inflammation and metabolism in rheumatoid arthritis. Cell Death Dis 2015; 6(9):e1887.

[144] Harre U & Schett G. Cellular and molecular pathways of structural damage in rheumatoid arthritis. Semin Immunopathol 2017; 39(4):355-363.

[145] Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12(8):472-485.

[146] Schett G & Gravellese E. Bone erosion in rheumatoid arthritis: Mechanism, diagnosis, and treatment. Nat Rev Rheumatol 2012; 8(11):656-664.

[147] Brennan FM & McInnes IB. Evidence that cytokines paly a role in rheumatoid arthritis. J Clin Invest 2018; 118(11):3537-3545.

[148] Zhang JM & An J. Cytokines, inflammation and pain. Int Anaesthesiol Clin 2007; 45(2):27-37.

[149] Alves CH, Farrell E, Vis M, Colin EM, Lubberts E. Animal models of bone loss in inflammatory arthritis: From cytokines in the bench to novel treatments for bone loss In the bedside – A comprehensive review. Clin Rev Allergy Immunol 2016; 51(1):27-47.

[150] Kukar M, Petryna O, Efthimiou P. Biological targets in the treatment of rheumatoid arthritis: A comprehensive review of current and in-development biological disease modifying antirheumatic drugs. Biologics 2009; 3:443-457.

[151] Radhakrishnan A, Tudawe D, Chakravarthi S, Chew GS, Haleagrahara N. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats. Exp Ther Med 2014; 7(5):1408-1414.

[152] Haleagrahara N, Swaminathan N, Chakravarthi S, Radhakrishnan AK. Therapeutic efficacy of vitamin E δ-tocotrienol in collagen-induced ratmodel of arthritis. J Biomed Biotechnol 2014; 2:539540.

[153] Zainal Z, Rahim AA, Radhakrishnan AK, Chang SK, Khaza'ai H. Investigation of the curative effects of palm vitamin E tocotrienols on

autoimmune arthritis disease in vivo. Sci Rep 2019; 9:16973.

[154] Ahmed AAS. Tocotrienol rich fraction of palm oil attenuates Type II collagen-induced temporomandibular joint rheumatoid arthritis in rats for future clinical application. Eur Sci J 2020; 16(24):124.

[155] World Health Organization. *Chronic respiratory diseases – Asthma* 2020. Available at: https://www.who. int/news-room/q-a-detail/chronicrespiratory-diseases-asthma. Accessed 1 December 2020.

[156] Tedeschi A & Asero R. Asthma and autoimmunity: A complex but intriguing relation. Expert Rev Clin 2008; 4(6):767-776.

[157] Peh HY, Ho WE, Cheng C, Chan TK, Seow AC, Fong CW, Seng KY, Ong CN, Wong WS. Vitamin E isoform γ-tocotrienol down-regulates house dust mite-induced asthma. J Immunol 2015; 195(2):437-444.

[158] Fukushima T, Yamasaki A, Harada T, Chikui H, Watanabe M, Okazaki R, Takata M, Hasegawa Y, Kurai J, Yueda Y, Halayko AJ, Shimizu E. γ-tocotrienol inhibits TGF-β1-induced contractile phenotype expression of human airway smooth muscle cells. Yanogo Acta Med 2017; 60:16-23.

[159] Clarke DL, Dakshinamuri S, Larsson AK, Ward JE, Yamasaki A. Lipid metabolites as regulators of airway smooth muscle function. Pulm Pharmacol Ther 2009; 22:426-35/

[160] Finiasz M, Otero C, Bezrodnik L, Fink S. The role of cytokinesis in atopic asthma. Curr Med Chem 2011; 18:1476-1487.

[161] Al-Alawi M, Hassan T, Chotirmall SH. Transforming growth factor beta and severe asthma: A perfect storm. Respir Med 2014; 108:1409-1423.

**231**

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[170] Multoff G & Radons J. Radiation, inflammation, and immune responses in

[171] Roos WP & Kaina B. DNA damageinduced cell death by apoptosis. Trends

[172] Nukala U, Thakkar S, Krager KJ, Breen PJ, Compadre CM, Aykin-

Burns N. Antioxidant tocols as radiation countermeasures (Challenges to be addressed to use tocols as radiation countermeasures in human). Antioxidants (Basel) 2018; 7(2):33.

Suzuki K, Yamashita S, Mori H. Ionizing radiation-induced cell death is partly caused by increase in mitochondrial reactive oxygen species in normal human fibroblast cells. Radiat Res 2015;

cancer. Front Oncol 2012; 2:58.

Mol Med 2006; 12(9):440-450.

[173] Kobashigawa S, Kashino G,

[174] Redza-Dutordoir M & Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016;

[175] Chen Q, Chai YC, Mazumder S, Jiang C, Macklis RM, Chisolm GM, Almasan A. The late increase in

intracellular free radical oxygen species during apoptosis is associated with cytochrome C release, capase activation, and mitochondrial dysfunction. Cell Death Differ 2003; 10(3):323-334.

[176] Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS. Gammatocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol

183(4):455-464.

1863(12):2977-2992.

2009; 85(7):598-606.

2014; 75(1):10-22.

[177] Compadre CM, Singh A, Thakkar S, Zheng G, Breen PJ, Ghosh SP, Kiaei M, Varughese KI, Hauer-Jensen M. Molecular dynamics guided design of tocoflexol: A new radioprotectant tocotrienol with enhanced bioavailability. Drug Dev Res

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

[163] Gómez-Acebo I, Dierssen-Sotos T, de-Pedro M, Pèrez-Gómez B et al. Epidemiology of non-steroidal antiinflammatory drugs consumption in Spain. The MCC-Spain study. BMC

[162] Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q. Role of transforming growth factor-beta In airway remodelling in asthma. Am J Respir Cell Mol Biol 2011; 44:127-133.

Public Health 2018; 18:1134.

[164] Vaishnavi PRR, Gaikwad N, Dhaneria SP. Assessment of nonsteroidal anti-inflammatory drug use pattern using World Health Organization indicators: A crosssectional study in a tertiary care teaching hospital in Chhattisgargh. Indian J Pharmacol 2017; 49(6):445-450.

[165] Scarpignato C & Hunt RH. Nonsteroidal anti-inflammatory drugrelated injury to the gastrointestinal tract: Clinical picture, pathogenesis, and prevention. Gastroenterol Clin North

Am 2010; 39(3):433-464.

11(4):309-313.

[166] Nafeeza MI, Fauzee AM, Kamsiah J, Gapor MT. Comparative effects of a tocotrienol-rich fraction in aspirin-induced gastric lesions in rats. Asia Pacific J Clin Nutr 2012;

[167] Azlina MFN, Kamisah Y,

2015; 10(10):e0139348.

Biol 1992; 61(6):712-720.

Chua KH, Ibrahim IAA, Qadriyah HMS. Preventive effect of tocotrienol on stress-induced gastric mucosal lesions and its relation to oxidative and inflammatory biomarkers. PLoS One

[168] Singh PK & Krishnan S. Vitamin E analogues as radiation response modifiers. Evid Based Complement Alternat Med 2015; 2015:741301.

[169] Arrand JE & Michael BD. Recent advances in the study in ionizing

radiation damage and repair. Int J Radiat

#### *Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

[162] Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q. Role of transforming growth factor-beta In airway remodelling in asthma. Am J Respir Cell Mol Biol 2011; 44:127-133.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

autoimmune arthritis disease in vivo. Sci

[154] Ahmed AAS. Tocotrienol rich fraction of palm oil attenuates Type II collagen-induced temporomandibular joint rheumatoid arthritis in rats for future clinical application. Eur Sci J

[155] World Health Organization. *Chronic respiratory diseases – Asthma* 2020. Available at: https://www.who. int/news-room/q-a-detail/chronicrespiratory-diseases-asthma. Accessed 1

[156] Tedeschi A & Asero R. Asthma and autoimmunity: A complex but intriguing relation. Expert Rev Clin

[157] Peh HY, Ho WE, Cheng C,

[158] Fukushima T, Yamasaki A, Harada T, Chikui H, Watanabe M, Okazaki R, Takata M, Hasegawa Y, Kurai J, Yueda Y, Halayko AJ, Shimizu E. γ-tocotrienol inhibits TGF-β1-induced contractile phenotype expression of human airway smooth muscle cells. Yanogo Acta Med 2017; 60:16-23.

[159] Clarke DL, Dakshinamuri S, Larsson AK, Ward JE, Yamasaki A. Lipid metabolites as regulators of airway smooth muscle function. Pulm Pharmacol Ther 2009; 22:426-35/

[160] Finiasz M, Otero C, Bezrodnik L, Fink S. The role of cytokinesis in atopic asthma. Curr Med Chem 2011;

Chotirmall SH. Transforming growth factor beta and severe asthma: A perfect storm. Respir Med 2014; 108:1409-1423.

[161] Al-Alawi M, Hassan T,

Chan TK, Seow AC, Fong CW, Seng KY, Ong CN, Wong WS. Vitamin E isoform γ-tocotrienol down-regulates house dust mite-induced asthma. J Immunol 2015;

Rep 2019; 9:16973.

2020; 16(24):124.

December 2020.

2008; 4(6):767-776.

195(2):437-444.

18:1476-1487.

in the context of rheumatoid arthritis. Nat Rev Rheumatol 2016; 12(8):472-485.

[146] Schett G & Gravellese E. Bone erosion in rheumatoid arthritis: Mechanism, diagnosis, and treatment. Nat Rev Rheumatol 2012; 8(11):656-664.

[147] Brennan FM & McInnes IB. Evidence that cytokines paly a role in rheumatoid arthritis. J Clin Invest 2018;

[148] Zhang JM & An J. Cytokines, inflammation and pain. Int Anaesthesiol

[149] Alves CH, Farrell E, Vis M, Colin EM, Lubberts E. Animal models of bone loss in inflammatory arthritis: From cytokines in the bench to novel treatments for bone loss In the bedside – A comprehensive review. Clin Rev Allergy Immunol 2016; 51(1):27-47.

[150] Kukar M, Petryna O, Efthimiou P. Biological targets in the treatment of rheumatoid arthritis: A comprehensive review of current and in-development biological disease modifying antirheumatic drugs. Biologics 2009;

[151] Radhakrishnan A, Tudawe D,

Haleagrahara N. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats. Exp Ther Med 2014;

[152] Haleagrahara N, Swaminathan N, Chakravarthi S, Radhakrishnan AK. Therapeutic efficacy of vitamin E δ-tocotrienol in collagen-induced ratmodel of arthritis. J Biomed Biotechnol

Radhakrishnan AK, Chang SK, Khaza'ai H. Investigation of the curative effects of palm vitamin E tocotrienols on

Chakravarthi S, Chew GS,

118(11):3537-3545.

Clin 2007; 45(2):27-37.

3:443-457.

7(5):1408-1414.

2014; 2:539540.

[153] Zainal Z, Rahim AA,

**230**

[163] Gómez-Acebo I, Dierssen-Sotos T, de-Pedro M, Pèrez-Gómez B et al. Epidemiology of non-steroidal antiinflammatory drugs consumption in Spain. The MCC-Spain study. BMC Public Health 2018; 18:1134.

[164] Vaishnavi PRR, Gaikwad N, Dhaneria SP. Assessment of nonsteroidal anti-inflammatory drug use pattern using World Health Organization indicators: A crosssectional study in a tertiary care teaching hospital in Chhattisgargh. Indian J Pharmacol 2017; 49(6):445-450.

[165] Scarpignato C & Hunt RH. Nonsteroidal anti-inflammatory drugrelated injury to the gastrointestinal tract: Clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 2010; 39(3):433-464.

[166] Nafeeza MI, Fauzee AM, Kamsiah J, Gapor MT. Comparative effects of a tocotrienol-rich fraction in aspirin-induced gastric lesions in rats. Asia Pacific J Clin Nutr 2012; 11(4):309-313.

[167] Azlina MFN, Kamisah Y, Chua KH, Ibrahim IAA, Qadriyah HMS. Preventive effect of tocotrienol on stress-induced gastric mucosal lesions and its relation to oxidative and inflammatory biomarkers. PLoS One 2015; 10(10):e0139348.

[168] Singh PK & Krishnan S. Vitamin E analogues as radiation response modifiers. Evid Based Complement Alternat Med 2015; 2015:741301.

[169] Arrand JE & Michael BD. Recent advances in the study in ionizing radiation damage and repair. Int J Radiat Biol 1992; 61(6):712-720.

[170] Multoff G & Radons J. Radiation, inflammation, and immune responses in cancer. Front Oncol 2012; 2:58.

[171] Roos WP & Kaina B. DNA damageinduced cell death by apoptosis. Trends Mol Med 2006; 12(9):440-450.

[172] Nukala U, Thakkar S, Krager KJ, Breen PJ, Compadre CM, Aykin-Burns N. Antioxidant tocols as radiation countermeasures (Challenges to be addressed to use tocols as radiation countermeasures in human). Antioxidants (Basel) 2018; 7(2):33.

[173] Kobashigawa S, Kashino G, Suzuki K, Yamashita S, Mori H. Ionizing radiation-induced cell death is partly caused by increase in mitochondrial reactive oxygen species in normal human fibroblast cells. Radiat Res 2015; 183(4):455-464.

[174] Redza-Dutordoir M & Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016; 1863(12):2977-2992.

[175] Chen Q, Chai YC, Mazumder S, Jiang C, Macklis RM, Chisolm GM, Almasan A. The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome C release, capase activation, and mitochondrial dysfunction. Cell Death Differ 2003; 10(3):323-334.

[176] Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS. Gammatocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol 2009; 85(7):598-606.

[177] Compadre CM, Singh A, Thakkar S, Zheng G, Breen PJ, Ghosh SP, Kiaei M, Varughese KI, Hauer-Jensen M. Molecular dynamics guided design of tocoflexol: A new radioprotectant tocotrienol with enhanced bioavailability. Drug Dev Res 2014; 75(1):10-22.

[178] Felemovicius I, Bonsack ME, Baptista ML, Delanev JP. Intestinal radioprotection by vitamin E (alpha-tocopherol). Ann Surg 1995; 222(4):504-510.

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[180] Berbēe M, Fu Q, Boerma M, Wang J, Kumar KS, Hauer-Jensen M. γ-tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative-stress after total-body irradiation by an HMG-CoA reductasedependant mechanism. Radiat Res 2009; 171(5):596-605.

[181] Kulkarni S, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol 2012; 14(4):495-503.

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2008; 99(6):1247-1254.

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[204] Narimah AHH, Gapor MT, Khalid BAK, Wan-Ngah WZ. Antiproliferation effect of palm-oil γ-tocotrienol and α-tocopherol on cervical carcinoma and hepatoma cell apoptosis. Biomed Res India 2009;

[205] Wu SJ & NG IT. Tocotrienols inhibited growth and induced apoptosis in human HeLa cells through the cell cycle signalling pathway. Integr Cancer

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[208] Ye C, Zhao W, Li M, Zhuang J, Yan X, Lu Q, Chang C, Huang X, Zhou J, Xie B, Zhang Z, Yao X, Yan J, Guo H. δ-tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway. PLoS One 2015; 10(4):e0122712.

[209] Ng KL, Radhakrishnan AK, Selvaduray KR. Gamma-tocotrienol inhibits proliferation of human chronic leukemic cells via activation of extrinsic and intrinsic apoptotic pathways. J Bld

Dis Ther 2016; 1(1):102.

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[196] Edmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol

[197] Kashyap D & Tuli HS. Flavonoids in triple negative breast cancer:

Chemopreventive phytonutrients. Arch

[198] Kashyap D, Sharma A, Tuli HS, Sak K, Mukherjee T, Biashayee A. Molecular targets of celastrol in cancer: Recent trends and advancements. Crit Rev Oncol Hematol 2018; 128:70-81.

[199] Tuli HS, Sharma AK, Sandhu SS, Kashyap D. Cordycepin: A bioactive metabolite with therapeutic potential.

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[201] Ahn KS, G Sethi, Krishnan K, Aggarwal BB. Gamma-tocotrienol inhibits nuclear factor-κB signalling pathway through inhibition of receptorinteracting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 2007; 282(1):809-820.

[202] Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YI. Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 2008; 99(11):1832-1841.

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Translational potential for cancer immunotherapy. J Immunother 2012; 35:299-308.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[186] De Silva L, Chuah LH,

[187] Miyazawa T, Shibata A, Nakagawa K, Tsuzuki T. Anti-

[188] Sailo BL, Banik K,

2018; 130:259-272.

14(1):5-18.

20(2):372.

2014; 14:e157-e165.

22:1765-1781.

20(3):656.

[189] Fontana F, Raimondi M, Marzagalli M, Moretti RM,

42:149-162.

Meganathan P, Fu JY. Tocotrienol and cancer metastasis. Biofactors 2016;

angiogenic function of tocotrienol. Asia Oac J Clin Nutr 2008; 17:253-256.

Padmavathi G, Javadi M, Bordoloi D, Kunnumakkara AB. Tocotrienols: The promising analogues of vitamin E for cancer therapeutics. Pharmacol Res

Montagnani M, Limonta P. Tocotrienols and cancer: From the state if the art to promising novel patent. Recent Pat Anticancer Drug Discov 2019;

[190] Tham SY, Loh HS, Mai CW, Fu JY. Tocotrienols modulates a life or death decision in cancers. Int J Mol Sci 2019;

[191] Rizvi S, Raza ST, Ahmed F, Ahmad A, Abbas S, Mahdi F. The role of vitamin E in human health and some diseases. Sultan Qaboos Univ Med J

[192] Kanchi MM, Shanmugam MK,

[193] Aggarwal V, Kashyap D, Sak K, Tuli HS, Jain A, Chaudhary A, Garg VK, Sethi G, Yerer MB. Molecular mechanisms of action of tocotrienols in cancer: Recent trends and advancements. Int J Mol Sci 2019;

[194] Liu Y & Zeng G. Cancer and innate immune system interaction:

Tocotrienols: The unsaturated sidekick shifting new paradigms in vitamin E therapeutics. Drug Discov Today 2017;

Rane G, Sethi G, Kumar AP.

[178] Felemovicius I, Bonsack ME, Baptista ML, Delanev JP. Intestinal radioprotection by vitamin E (alpha-tocopherol). Ann Surg 1995;

222(4):504-510.

[179] Kulkarni S, Ghosh SP, Satyamirta M, Mog S, Hieber K, Romanyukha L, Gambles K, Toles R, Kao TC, Hauer-Jensen M, Kumar KS.

Gamma-tocotrienol protects

Radiat Res 2010; 173(6):738-747.

[180] Berbēe M, Fu Q, Boerma M, Wang J, Kumar KS, Hauer-Jensen M. γ-tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative-stress after total-body irradiation by an HMG-CoA reductasedependant mechanism. Radiat Res

[181] Kulkarni S, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol 2012;

[182] World Health Organization. *Cancer*. Available at: https://www.who. int/news-room/fact-sheets/detail/ cancer. Accessed 2 December 2020.

[183] Mai CW, Chung FFL, Leong CO.

[184] Mai CW, Kang WB, Pichika MR. Should a toll-like receptor 4 (TLR-4) agonist or antagonist be designed to treat cancer? TLR-4: Its expression and effects in the ten most common cancers. Onco Targets Ther 2013; 6:1573-1587.

[185] Chung FFL, Mai CW, Ng YP, Leong CO. Cytochrome P450 2W1 (CYP2W1) in colorectal cancers. Curr Cancer Drug Targets 2016; 16(1):71-78.

Targeting legumain as a novel therapeutics in cancer. Curr Drugs Target 2017; 18(11):1259-1268.

2009; 171(5):596-605.

14(4):495-503.

haematopoietic stem and progenitor cells in mice after total-body irradiation.

**232**

[195] Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, Wang I, Shifrin N, Raulet DH. Recognition of tumours by innate immune system and natural killer cells. Adv Immunol 2014; 122:91-128.

[196] Edmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol 2007; 35:485-516.

[197] Kashyap D & Tuli HS. Flavonoids in triple negative breast cancer: Chemopreventive phytonutrients. Arch Cancer Res 2018; 6:2017-2018.

[198] Kashyap D, Sharma A, Tuli HS, Sak K, Mukherjee T, Biashayee A. Molecular targets of celastrol in cancer: Recent trends and advancements. Crit Rev Oncol Hematol 2018; 128:70-81.

[199] Tuli HS, Sharma AK, Sandhu SS, Kashyap D. Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci 2013; 93:863-869.

[200] Yu W, Simmons-Menchaca M, Gapor A, Sanders BG, Kline K. Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer 1999; 33(1):26-32.

[201] Ahn KS, G Sethi, Krishnan K, Aggarwal BB. Gamma-tocotrienol inhibits nuclear factor-κB signalling pathway through inhibition of receptorinteracting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 2007; 282(1):809-820.

[202] Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YI. Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 2008; 99(11):1832-1841.

[203] Sun W, Wang Q, Chen B, Liu H, Xu W. Gamma-tocotrienol-induced apoptosis in human gastric cance*r* SGC-7901 cells is associated with a suppression in nitrogen-activated protein kinase signalling. Br J Nutr 2008; 99(6):1247-1254.

[204] Narimah AHH, Gapor MT, Khalid BAK, Wan-Ngah WZ. Antiproliferation effect of palm-oil γ-tocotrienol and α-tocopherol on cervical carcinoma and hepatoma cell apoptosis. Biomed Res India 2009; 20(3):180.

[205] Wu SJ & NG IT. Tocotrienols inhibited growth and induced apoptosis in human HeLa cells through the cell cycle signalling pathway. Integr Cancer Ther 2010; 9(1):66-72.

[206] Park SK, Sanders BG, Kline K. Tocotrienols induced apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependant increase in extrinsic death receptor signalling. Breast Cancer Res Treat 2010; 124(2):361-375.

[207] Lim SW, Loh HS, Ting KN, Bradshaw TD, Zeenathul NA. Cytotoxicity and apoptotic activities of alpha-, gamma-, and deltatocotrienol isomers on human cancer cells. BMC Complement Altern Med 2014; 14:469.

[208] Ye C, Zhao W, Li M, Zhuang J, Yan X, Lu Q, Chang C, Huang X, Zhou J, Xie B, Zhang Z, Yao X, Yan J, Guo H. δ-tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway. PLoS One 2015; 10(4):e0122712.

[209] Ng KL, Radhakrishnan AK, Selvaduray KR. Gamma-tocotrienol inhibits proliferation of human chronic leukemic cells via activation of extrinsic and intrinsic apoptotic pathways. J Bld Dis Ther 2016; 1(1):102.

[210] Rajasinghe ID & Gupta SV. Tocotrienol-rich mixture inherits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells. Nutr Diet Suppl 2017; 9:103-114.

[211] Xu W, Mi Y, He P, He S, Niu L. γ-tocotrienol inhibits proliferation and induces apoptosis via the mitochondrial pathway in human cervical cancer HeLa cells. Molecules 2017; 22(8):1299.

[212] Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting cancer stem cells for chemoprevention of pancreatic cancer. Curr Med Chem 2018; 25(22):2585-2594.

[213] Schnerch D, Yalcintepe J, Schmidts A, Becker H, Follo M, Engelhardt M, Wäsch R. Cell cycle control in acute leukaemia. Am J Cancer Res 2021; 2(5):508-528.

[214] Ding Y, Peng Y, Deng I, Fan J, Huang B. Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin. J Steroid Biochem Biol 2017; 167:67-77.

[215] Abubakar IB, Lim KH, Kam TS, Loh HS. Enhancement of apoptotic activities on brain cells via the combination of γ-tocotrienol and jerantinine A. Phytomedicine 2017; 30:74-84.

[216] Sato C, Kaneko S, Sato A, Virgona N, Namiki K, Yano T. Combination effect of δ-tocotrienol and γ-tocopherol on prostate cancer cell growth. J Nutr Sci Vataminol 2017; 63(5):349-354.

[217] Yeganehjoo H, DeBose-Boyd R, McFarlin BK, Mo H. Synergistic impact of δ-tocotrienol and geranylgeraniol on the growth and HMG CoA reductase of human DU145 prostate carcinoma cells. Nutr Cancer 2017; 69(4):682-691.

[218] Fallah A, Sadeghinia A, Kahroba H, Samadi A, Heidari HR, Bradaran B, Zeinali S., Molavi O. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependant diseases. Biomed Pharmacother 2019; 110:775-785.

[219] Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2(3):213-219.

[220] Petrovic N. Targeting angiogenesis in cancer treatments: Where do we stand? J Pharm Pharm Sci 2016; 19(2):226-238.

[221] Prager GW & Poettler M. Angiogenesis in cancer: Basic mechanisms and therapeutic advances. Hamostaseologie 2012; 32(2):105-114.

[222] Abraham A, Kattoor AJ, Dakdeen T, Mehta JL. Vitamin E and its anticancer effects. Crit Rev Food Sci Nutr 2019; 59(17):2831-2838.

[223] Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T. Synergistic anticancer effect of tocotrienol combined with chemotherapeutic a, gents or dietary components: A Review. Int J Mol Sci 2016; 17(10):1605.

[224] Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Miyazawa T. Delta-tocotrienol suppresses VEGF induced angiogenesis whereas alpha-tocopherol does not. J Agric Food Chem 2009; 57(18):8696-8704.

[225] Bryan BA & D'Amore PA. What tangle webs they weave: Rho-GTPase control of angiogenesis. Cell Moll Life Sci 2007; 64(16):2053-2065.

[226] Burdeos GC, Ito J, Eitsuka T, Nakagawa K, Kimura F, Miyazawa T. Delta and gamma-tocotrienols suppress human hepatocellular carcinoma cells proliferation: Vi-MEK-ERK

**235**

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[234] Steuber N, Vo K, Wadhwa R, Birch J, Jacoban P, Chavez P, Elbavoumi TA. Tocotrienol nanoemulsion platform of cucurmin elicit elevated apoptosis and augmentation of anticancer efficacy against breast and ovarian carcinomas.

Int J Mol Sci 2016; 17:1792.

Biomolecules 2018; 8:97.

5574-5576.

147:992-1009.

112:2773-2783.

21(3):206-213.

[235] Sánchez-Rodriguez C, Palao-Suay R, Rodrigáñez L, Aguilar M, Martin-Saldaña S, Román J, Sanz-Fernández R. Alpha-tocopheryl succinate-based polymeric

nanoparticles for the treatment of head and neck squamous cell carcinoma.

[236] Dillekàs H, Rogers MS, Straume O. Are 90% of death from cancer caused by metastases? Cancer Med 2019; 8(12):

[237] Guan X. Cancer metastases: Challenges and opportunities. Acta Pharm Sin B 2015; 5(5):402-418.

[238] Saxena M & Christofori G. Rebuilding cancer metastasis in the mouse. Mol Oncol 2013; 7(2): 283-296.

[239] Sajid I, Majumder T, Arif MH, Alam Z. Potential anticancer activity of tocotrienols. Vitam Miner 2017; 6:2.

[240] Friedl P & Alexander S. Cancer invasion and the microenvironment: Plasticity and reciprocity. Cell 2011;

[241] Ji X, Wang Z, Geamanu A, Sarkar FH, Gupta SV. Inhibition of cell growth and induction of apoptosis in non-small cell lung cancer cells by δ-tocotrienol is associated with notch-1 down regulation. J Cell Biochem 2011;

[242] Liu HK, Wang Q, Li Y, Sun WG, Liu JR, Yang YM, Xu WL, Sun XR, Chen BQ. Inhibitory effects of gammatocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 2010;

*DOI: http://dx.doi.org/10.5772/intechopen.96451*

pathway-associated upstream signalling.

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Food Funct 2016; 7:4170-4174.

Trevino J, Sebti SM, Malafa MP. Gamma-tocotrienol a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer cell metastasis. Oncotarget 2017;

[228] Marelli MM, Marzagalli M, Moretti RM, Baretta G, Casati L, Comitato R, Gravina GL, Festuccia C, Limonta P. Vitamin E δ-tocotrienol triggers endoplasmic reticulum stressmediated apoptosis in human melanoma

cells. Sci Rep 2016; 6:30502.

[229] Marzagalli M, Moretti RM, Messi E, Marelli MM, Fontana F, Anastasia A, Bani MR, Baretta G, Limonta P. Targerting melanoma stem cells with the vitamin E derivative δ-tocotrienol. Sci Rep 2018; 8:587.

[230] Kaneko S, Sato C, Shiozawa N, Sato A, Virgona N, Yano T. Suppressive effect of δ-tocotrienol on hypoxia adaptation of prostate cancer stemlike cells. Anticancer Res 2018;

[231] Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Gamma-tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by downregulating multiple molecules. Br J

Cancer 2016; 115:814-824.

Treat 2016; 2:38-42.

[232] Sato A, Virgona N, Sekine Y, Yano T. The evidence to date: A redoxinactive analogue of tocotrienol as a new anti-mesothelioma agent. J Rare Dis Res

[233] Gagic Z, Nikolic K, Ivkovic B, Filipic S, Agbaba D. QSAR studies and design of new analogues of vitamin E with enhanced antiproliferative activity on MCF-breast cancer cells. J Taiwan Inst Chem Eng 2016; 59:33-44.

1399:1391-1399.

8(19):31554-31567.

*Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases DOI: http://dx.doi.org/10.5772/intechopen.96451*

pathway-associated upstream signalling. Food Funct 2016; 7:4170-4174.

*Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects*

[218] Fallah A, Sadeghinia A, Kahroba H, Samadi A, Heidari HR, Bradaran B, Zeinali S., Molavi O. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependant diseases. Biomed Pharmacother 2019;

[219] Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006;

[220] Petrovic N. Targeting angiogenesis in cancer treatments: Where do we stand? J Pharm Pharm Sci 2016;

mechanisms and therapeutic advances. Hamostaseologie 2012; 32(2):105-114.

Dakdeen T, Mehta JL. Vitamin E and its anticancer effects. Crit Rev Food Sci

[223] Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T. Synergistic anticancer effect of tocotrienol combined with chemotherapeutic a, gents or dietary components: A Review.

suppresses VEGF induced angiogenesis

[225] Bryan BA & D'Amore PA. What tangle webs they weave: Rho-GTPase control of angiogenesis. Cell Moll Life

[221] Prager GW & Poettler M. Angiogenesis in cancer: Basic

[222] Abraham A, Kattoor AJ,

Nutr 2019; 59(17):2831-2838.

Int J Mol Sci 2016; 17(10):1605.

[224] Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Miyazawa T. Delta-tocotrienol

whereas alpha-tocopherol does not. J Agric Food Chem 2009;

Sci 2007; 64(16):2053-2065.

[226] Burdeos GC, Ito J, Eitsuka T, Nakagawa K, Kimura F, Miyazawa T. Delta and gamma-tocotrienols suppress human hepatocellular carcinoma cells proliferation: Vi-MEK-ERK

57(18):8696-8704.

110:775-785.

2(3):213-219.

19(2):226-238.

[210] Rajasinghe ID & Gupta SV. Tocotrienol-rich mixture inherits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells. Nutr Diet

[211] Xu W, Mi Y, He P, He S, Niu L. γ-tocotrienol inhibits proliferation and induces apoptosis via the mitochondrial pathway in human cervical cancer HeLa

cells. Molecules 2017; 22(8):1299.

[212] Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting cancer stem cells for chemoprevention of pancreatic cancer. Curr Med Chem

2018; 25(22):2585-2594.

Res 2021; 2(5):508-528.

Biol 2017; 167:67-77.

30:74-84.

63(5):349-354.

69(4):682-691.

[213] Schnerch D, Yalcintepe J, Schmidts A, Becker H, Follo M, Engelhardt M, Wäsch R. Cell cycle control in acute leukaemia. Am J Cancer

[214] Ding Y, Peng Y, Deng I, Fan J, Huang B. Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin. J Steroid Biochem

[215] Abubakar IB, Lim KH, Kam TS, Loh HS. Enhancement of apoptotic activities on brain cells via the combination of γ-tocotrienol and jerantinine A. Phytomedicine 2017;

[216] Sato C, Kaneko S, Sato A, Virgona N, Namiki K, Yano T. Combination effect of δ-tocotrienol and γ-tocopherol on prostate cancer cell growth. J Nutr Sci Vataminol 2017;

[217] Yeganehjoo H, DeBose-Boyd R, McFarlin BK, Mo H. Synergistic impact of δ-tocotrienol and geranylgeraniol on the growth and HMG CoA reductase of human DU145 prostate carcinoma cells. Nutr Cancer 2017;

Suppl 2017; 9:103-114.

**234**

[227] Husain K, Centeno BA, Coppola D, Trevino J, Sebti SM, Malafa MP. Gamma-tocotrienol a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer cell metastasis. Oncotarget 2017; 8(19):31554-31567.

[228] Marelli MM, Marzagalli M, Moretti RM, Baretta G, Casati L, Comitato R, Gravina GL, Festuccia C, Limonta P. Vitamin E δ-tocotrienol triggers endoplasmic reticulum stressmediated apoptosis in human melanoma cells. Sci Rep 2016; 6:30502.

[229] Marzagalli M, Moretti RM, Messi E, Marelli MM, Fontana F, Anastasia A, Bani MR, Baretta G, Limonta P. Targerting melanoma stem cells with the vitamin E derivative δ-tocotrienol. Sci Rep 2018; 8:587.

[230] Kaneko S, Sato C, Shiozawa N, Sato A, Virgona N, Yano T. Suppressive effect of δ-tocotrienol on hypoxia adaptation of prostate cancer stemlike cells. Anticancer Res 2018; 1399:1391-1399.

[231] Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Gamma-tocotrienol suppresses growth and sensitises human colorectal tumours to capecitabine in a nude mouse xenograft model by downregulating multiple molecules. Br J Cancer 2016; 115:814-824.

[232] Sato A, Virgona N, Sekine Y, Yano T. The evidence to date: A redoxinactive analogue of tocotrienol as a new anti-mesothelioma agent. J Rare Dis Res Treat 2016; 2:38-42.

[233] Gagic Z, Nikolic K, Ivkovic B, Filipic S, Agbaba D. QSAR studies and design of new analogues of vitamin E with enhanced antiproliferative activity on MCF-breast cancer cells. J Taiwan Inst Chem Eng 2016; 59:33-44.

[234] Steuber N, Vo K, Wadhwa R, Birch J, Jacoban P, Chavez P, Elbavoumi TA. Tocotrienol nanoemulsion platform of cucurmin elicit elevated apoptosis and augmentation of anticancer efficacy against breast and ovarian carcinomas. Int J Mol Sci 2016; 17:1792.

[235] Sánchez-Rodriguez C, Palao-Suay R, Rodrigáñez L, Aguilar M, Martin-Saldaña S, Román J, Sanz-Fernández R. Alpha-tocopheryl succinate-based polymeric nanoparticles for the treatment of head and neck squamous cell carcinoma. Biomolecules 2018; 8:97.

[236] Dillekàs H, Rogers MS, Straume O. Are 90% of death from cancer caused by metastases? Cancer Med 2019; 8(12): 5574-5576.

[237] Guan X. Cancer metastases: Challenges and opportunities. Acta Pharm Sin B 2015; 5(5):402-418.

[238] Saxena M & Christofori G. Rebuilding cancer metastasis in the mouse. Mol Oncol 2013; 7(2): 283-296.

[239] Sajid I, Majumder T, Arif MH, Alam Z. Potential anticancer activity of tocotrienols. Vitam Miner 2017; 6:2.

[240] Friedl P & Alexander S. Cancer invasion and the microenvironment: Plasticity and reciprocity. Cell 2011; 147:992-1009.

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Section 3

Vitamin E and Oxidative

Stress

## Section 3
