Vitamin E Applications in Pathological Conditions

**3**

( 1

**Chapter 1**

**Abstract**

**1. Introduction**

peroxidation [1, 2].

Products

*and André Rolim Baby*

Vitamin E in Human Skin:

Functionality and Topical

*Claudineia Aparecida Sales de Oliveira Pinto,* 

the development, safe use and evaluation of effectiveness.

to its ability to react mainly with the peroxyl radical (HOH•

**Keywords:** vitamin E, skin, protection, antioxidant, cosmetology

Vitamin E is the most well-known fat-soluble non-enzymatic antioxidant, mainly for its ability to inhibit the activity of pro-oxidant agents generated by reactive oxygen species (ROS). Vitamin E can eliminate free radicals induced by endogenous and/or exogenous agents such as ultraviolet radiation, drugs and pollution agents, avoiding their deleterious effects. The antioxidant activity of vitamin E is directly linked to its ability to inhibit the lipid peroxidation in unsaturated fatty acids, incorporating itself into cell membranes, which effectively inhibits lipid

The antioxidant activity of vitamin E (alpha-tocopherol) has its property due

O2), which favors lipid peroxidation. The free radical scavenging reaction occurs through the formation of a stable, low-energy radical, tocopheroxyl, which does not have the capacity to react with the free radical-forming agent [3]. Alpha-tocopherol

) and singlet oxygen

*Tércio Elyan Azevedo Martins, Renata Miliani Martinez,* 

Vitamins are part of the antioxidant system of human skin, and are detectable in different layers, so the topical application can be an alternative to maintain the functionality of the system. The capacity of the antioxidant gradient of keratinocytes is associated with attenuation of the action of related free radicals in both esthetics and health. These problems arise from extrinsic aging and are related to the risk of cancer. Vitamin E has been proven to have antioxidant and moisturizing properties in the skin and can protect against the damage of UVB radiation, with emphasis on the reduction of acute erythema and photoaging. The choice for the use of topical vitamin E, compared to the oral is given by the safety as mild irritation and it has potential for multifunctional topical formulations. The purpose of the chapter is to review the topical use of formulations with vitamin E, addressing

*Thamires Batello Freire, Maria Valéria Robles Velasco* 

#### **Chapter 1**

## Vitamin E in Human Skin: Functionality and Topical Products

*Claudineia Aparecida Sales de Oliveira Pinto, Tércio Elyan Azevedo Martins, Renata Miliani Martinez, Thamires Batello Freire, Maria Valéria Robles Velasco and André Rolim Baby*

#### **Abstract**

Vitamins are part of the antioxidant system of human skin, and are detectable in different layers, so the topical application can be an alternative to maintain the functionality of the system. The capacity of the antioxidant gradient of keratinocytes is associated with attenuation of the action of related free radicals in both esthetics and health. These problems arise from extrinsic aging and are related to the risk of cancer. Vitamin E has been proven to have antioxidant and moisturizing properties in the skin and can protect against the damage of UVB radiation, with emphasis on the reduction of acute erythema and photoaging. The choice for the use of topical vitamin E, compared to the oral is given by the safety as mild irritation and it has potential for multifunctional topical formulations. The purpose of the chapter is to review the topical use of formulations with vitamin E, addressing the development, safe use and evaluation of effectiveness.

**Keywords:** vitamin E, skin, protection, antioxidant, cosmetology

#### **1. Introduction**

Vitamin E is the most well-known fat-soluble non-enzymatic antioxidant, mainly for its ability to inhibit the activity of pro-oxidant agents generated by reactive oxygen species (ROS). Vitamin E can eliminate free radicals induced by endogenous and/or exogenous agents such as ultraviolet radiation, drugs and pollution agents, avoiding their deleterious effects. The antioxidant activity of vitamin E is directly linked to its ability to inhibit the lipid peroxidation in unsaturated fatty acids, incorporating itself into cell membranes, which effectively inhibits lipid peroxidation [1, 2].

The antioxidant activity of vitamin E (alpha-tocopherol) has its property due to its ability to react mainly with the peroxyl radical (HOH• ) and singlet oxygen ( 1 O2), which favors lipid peroxidation. The free radical scavenging reaction occurs through the formation of a stable, low-energy radical, tocopheroxyl, which does not have the capacity to react with the free radical-forming agent [3]. Alpha-tocopherol

is the main agent capable of removing peroxyl radicals from lipid membranes, such as membranes or low-density lipoproteins (LDL) [4].

It is a classic dermatological ingredient used alone in its purified form, alphatocopherol or by its derivatives. However, the conversion to the purified (isolated) form is required in skin to obtain the desired effects. Topical applications are designed for treating melasma, protecting against ultraviolet radiation (UVR) and improving aging damages [5, 6], The association of vitamin E with other antioxidants increase the effects in skin [7].

Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in many skins' therapies, such as: yellow nail syndrome, epidermolysis bullosa, cutaneous ulcers, pressure ulcers and burns, sub corneal pustular dermatosis, scleroderma, morphea, calcinosis cutis, Raynaud's phenomenon, and inflammatory diseases. The oral supplementation of vitamin E could reduce the pigmentation in melasma and contact dermatitis lesions, too demonstrated remission of atopic dermatitis, prevention of sunburn reaction as well as the subsequent chronic skin damage [5]. Vitamin E combined with other antioxidants has shown positive results topically in the photoprotection, as well as delay the growth of the melanoma by promoting the apoptosis of tumor cells and inhibiting VEGF-mediated angiogenesis. Other results with alpha-tocopherol: improvement in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, collagen production and overall appearance by clinical evaluations of skin. Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB [8]. It is difficult to determine the *in vivo* antioxidative activity of vitamin E because it is naturally present in the skin, but future studies with the isolated form and its derivatives can be explored in topical products [9].

#### **2. Topical products (cosmetics x medicines)**

Skin products can be classified as medicines, cosmetics and cosmeceuticals, however, the teaching line between the categories is tenuous, being widely discussed by dermatologists, pharmacists and beauticians. Medicines and cosmetics are already widely discussed and accepted by world regulatory agencies; however, the term cosmeceutical is used as a marketing appeal and is not recognized as an official legal category. Skin products considered to be cosmetics are generally defined as products to clean, beautify, promote attractiveness, or change appearance, while medicines are intended for the diagnosis, cure, mitigation, treatment or prevention of diseases, which can affect the structure or any function of the skin. Regulatory agencies in different countries seek to organize the offer of products to ensure the safety for users.

Topical products that contain vitamin E can be classified as medicines or cosmetics, depending on their purpose. If the product is intended to lubricate the skin, it will be considered cosmetic and if it has therapeutic use as a healing agent, it will be a medicine. There are legal limits on the daily consumption of vitamin E as a supplement, however, for most international regulatory agencies, such as the NHS, FDA, Health Canada the limits for topical use are not described [10].

#### **3. Types of vitamin E for topical applications**

The antioxidant alpha-tocopherol acetate is the most common form of vitamin E in skin care products. In 2001, the Scientific Committee on Cosmetic and Non-Food

**5**

**4. Vitamin E in skin damage**

*Vitamin E in Human Skin: Functionality and Topical Products*

Products for Consumers (SCCNFP) presented its opinion during the 18th Plenary Meeting. At the time, SCCNFP believed that alpha-tocopherol acetate did not pose a threat to consumer health and therefore did not propose any restrictions or use

The Cosmetic Ingredients Review Panel (CIR) in 2002 has assessed the safety of 14 tocopherols and tocotrienols and concluded that these ingredients are safe when used in cosmetics. The Panel further reviewed data from clinical and animal studies to determine the safety of tocopherols and tocotrienol ingredients and considered it appropriate to extrapolate existing information to conclude on the safety of all

Since vitamin E can absorb ultraviolet light to produce free radicals, there is a possibility that strong exposure to sunlight after topical application may cause skin reactions. However, vitamin E concentrations between 0.1–1.0% are generally considered to be safe and effective for increasing vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects [8]. Vitamin E as alpha-tocopherol or tocopherol acetate is used in over-the-counter products in

Vitamin E is the main fat-soluble antioxidant in the body with biological activity and it is the collective name for the eight mains naturally occurring substances such four tocopherols and four tocotrienols. The eight analogues of vitamin E share similar chemical antioxidant activity, however, they are distinguished by their individual physico-chemical and biological effects at the molecular level in humans and higher animals. Alpha tocopherol is the most active, being considered an important asset in protecting cell membranes from lipid peroxidation promoted by

Alpha-tocopherol is practically insoluble in water and this characteristic can difficult the development of topical products with high water content. In addition, this molecule is easily oxidized by atmospheric oxygen. Vitamin E acid acetate and succinate esters are applicable for clinical use due to their high oxidation stability but require the use of surfactants to improve the water solubility. Alpha-tocopherol is solubilized by large amounts of surfactants, but the hydrolysis of acetate is the

limiting step in terms of its concentration during bioavailability [15].

The antioxidant properties of vitamin E are attributed to its free aromatic hydroxyl group; thus, the esters of vitamin E need to be hydrolyzed during absorption by the skin to exhibit this activity. In the biologically inactive esterified form, vitamin E acetate is more used because of its greater stability, acting as a prodrug, being hydrolyzed in active free vitamin E (alpha-tocopherol) after penetration into the skin. The bioconversion of vitamin E into the active form can be influenced by the technology involved in the development of formulations, by the target layer of the skin and exposure to ultraviolet rays. The stratum corneum seems to have less efficiency in the bioconversion of esters of vitamin E when compared to the nucleated epidermal layers. Thus, alpha-tocopherol should provide more efficient antioxidant protection for skin surface lipids and skin barrier constituents than vitamin E esters. However, in the nucleated epidermis the bioconversion of vitamin E acetate to active free form occurs at a much higher rate. In this sense, the choice of which vitamin E molecule to be used must consider the target layer of the skin and include product development strategies so that the activity of vitamin E is fully utilized [15, 16].

Vitamin E, more specifically alpha tocopherol, is considered one of the main fat-soluble and non-enzymatic antioxidant agents of natural origin, due to its

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

tocopherols and tocotrienols [12].

concentrations ranging from 1.0 to 5.0% [13–15].

conditions [11].

free radicals [13–15].

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

as membranes or low-density lipoproteins (LDL) [4].

and its derivatives can be explored in topical products [9].

**2. Topical products (cosmetics x medicines)**

ensure the safety for users.

increase the effects in skin [7].

is the main agent capable of removing peroxyl radicals from lipid membranes, such

It is a classic dermatological ingredient used alone in its purified form, alphatocopherol or by its derivatives. However, the conversion to the purified (isolated) form is required in skin to obtain the desired effects. Topical applications are designed for treating melasma, protecting against ultraviolet radiation (UVR) and improving aging damages [5, 6], The association of vitamin E with other antioxidants

Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in many skins' therapies, such as: yellow nail syndrome, epidermolysis bullosa, cutaneous ulcers, pressure ulcers and burns, sub corneal pustular dermatosis, scleroderma, morphea, calcinosis cutis, Raynaud's phenomenon, and inflammatory diseases. The oral supplementation of vitamin E could reduce the pigmentation in melasma and contact dermatitis lesions, too demonstrated remission of atopic dermatitis, prevention of sunburn reaction as well as the subsequent chronic skin damage [5]. Vitamin E combined with other antioxidants has shown positive results topically in the photoprotection, as well as delay the growth of the melanoma by promoting the apoptosis of tumor cells and inhibiting VEGF-mediated angiogenesis. Other results with alpha-tocopherol: improvement in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, collagen production and overall appearance by clinical evaluations of skin. Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB [8]. It is difficult to determine the *in vivo* antioxidative activity of vitamin E because it is naturally present in the skin, but future studies with the isolated form

Skin products can be classified as medicines, cosmetics and cosmeceuticals, however, the teaching line between the categories is tenuous, being widely discussed by dermatologists, pharmacists and beauticians. Medicines and cosmetics are already widely discussed and accepted by world regulatory agencies; however, the term cosmeceutical is used as a marketing appeal and is not recognized as an official legal category. Skin products considered to be cosmetics are generally defined as products to clean, beautify, promote attractiveness, or change appearance, while medicines are intended for the diagnosis, cure, mitigation, treatment or prevention of diseases, which can affect the structure or any function of the skin. Regulatory agencies in different countries seek to organize the offer of products to

Topical products that contain vitamin E can be classified as medicines or cosmetics, depending on their purpose. If the product is intended to lubricate the skin, it will be considered cosmetic and if it has therapeutic use as a healing agent, it will be a medicine. There are legal limits on the daily consumption of vitamin E as a supplement, however, for most international regulatory agencies, such as the NHS,

The antioxidant alpha-tocopherol acetate is the most common form of vitamin E in skin care products. In 2001, the Scientific Committee on Cosmetic and Non-Food

FDA, Health Canada the limits for topical use are not described [10].

**3. Types of vitamin E for topical applications**

**4**

Products for Consumers (SCCNFP) presented its opinion during the 18th Plenary Meeting. At the time, SCCNFP believed that alpha-tocopherol acetate did not pose a threat to consumer health and therefore did not propose any restrictions or use conditions [11].

The Cosmetic Ingredients Review Panel (CIR) in 2002 has assessed the safety of 14 tocopherols and tocotrienols and concluded that these ingredients are safe when used in cosmetics. The Panel further reviewed data from clinical and animal studies to determine the safety of tocopherols and tocotrienol ingredients and considered it appropriate to extrapolate existing information to conclude on the safety of all tocopherols and tocotrienols [12].

Since vitamin E can absorb ultraviolet light to produce free radicals, there is a possibility that strong exposure to sunlight after topical application may cause skin reactions. However, vitamin E concentrations between 0.1–1.0% are generally considered to be safe and effective for increasing vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects [8]. Vitamin E as alpha-tocopherol or tocopherol acetate is used in over-the-counter products in concentrations ranging from 1.0 to 5.0% [13–15].

Vitamin E is the main fat-soluble antioxidant in the body with biological activity and it is the collective name for the eight mains naturally occurring substances such four tocopherols and four tocotrienols. The eight analogues of vitamin E share similar chemical antioxidant activity, however, they are distinguished by their individual physico-chemical and biological effects at the molecular level in humans and higher animals. Alpha tocopherol is the most active, being considered an important asset in protecting cell membranes from lipid peroxidation promoted by free radicals [13–15].

Alpha-tocopherol is practically insoluble in water and this characteristic can difficult the development of topical products with high water content. In addition, this molecule is easily oxidized by atmospheric oxygen. Vitamin E acid acetate and succinate esters are applicable for clinical use due to their high oxidation stability but require the use of surfactants to improve the water solubility. Alpha-tocopherol is solubilized by large amounts of surfactants, but the hydrolysis of acetate is the limiting step in terms of its concentration during bioavailability [15].

The antioxidant properties of vitamin E are attributed to its free aromatic hydroxyl group; thus, the esters of vitamin E need to be hydrolyzed during absorption by the skin to exhibit this activity. In the biologically inactive esterified form, vitamin E acetate is more used because of its greater stability, acting as a prodrug, being hydrolyzed in active free vitamin E (alpha-tocopherol) after penetration into the skin. The bioconversion of vitamin E into the active form can be influenced by the technology involved in the development of formulations, by the target layer of the skin and exposure to ultraviolet rays. The stratum corneum seems to have less efficiency in the bioconversion of esters of vitamin E when compared to the nucleated epidermal layers. Thus, alpha-tocopherol should provide more efficient antioxidant protection for skin surface lipids and skin barrier constituents than vitamin E esters. However, in the nucleated epidermis the bioconversion of vitamin E acetate to active free form occurs at a much higher rate. In this sense, the choice of which vitamin E molecule to be used must consider the target layer of the skin and include product development strategies so that the activity of vitamin E is fully utilized [15, 16].

#### **4. Vitamin E in skin damage**

Vitamin E, more specifically alpha tocopherol, is considered one of the main fat-soluble and non-enzymatic antioxidant agents of natural origin, due to its

advantages in terms of the protective activity against physical and chemical damage promoted by free radicals (FR). Vitamin E is an antioxidant capable of binding to the membrane in various tissues [17, 18]. Therefore, it is involved in several oxidative mechanisms in epidermis and dermis, catalyzed by ultraviolet radiation (UVR) and pollutants (**Figure 1**).

#### **4.1 Oxidative stress: lipid peroxidation and free radicals' formation**

The first studies related to the damage caused by the formation of FR on the skin, promoting lipid peroxidation, date from the 1950s and 1960s. To avoid the damages, the use of natural and synthetic substances was suggested in order to prevent the formation of FR [19, 20].

Reactive oxygen species (ROS) such as superoxide (O2 −•), hydroxyl radicals (OH• ), peroxyl (HOH• ) and singlet oxygen (1 O2), can be formed by endogenous (physiological) processes such as inflammation, physical activity in excess, nutritional disorder, hereditary issues, neoplasms, and even, by processes related to exogenous sources such as UVR and pollution agents. In the skin, the main damage related to lipid peroxidation generated by FR from exogenous sources is the activation of melanogenesis and damage to collagen fibers [19, 21, 22].

The lipid peroxidation of the epidermis cells occurs through the action of the ROS, which has the ability to bind to the unsaturated bonds present in the polyunsaturated fatty acids of the cell membrane phospholipids [22, 23]. The process starts between polyunsaturated fatty acids (PUFA) and the oxygen radical, obtaining a lipid radical, which causes a rearrangement process in the presence of molecular oxygen, becoming a peroxy lipid radical. The lipid peroxyl radical is also capable of attacking unsaturated lipids, generating new radicals, such as the lipid radical as in the first stage of the reaction and the lipid hydro peroxide radical, thus promoting a cyclic reaction. Thus, it is necessary to use substances capable of interacting with cell membranes and to extinguish the free radicals formed, such as vitamin E [24, 25].

In a more detailed way, the mechanism involved in the lipid peroxidation process occurs through a chain reaction of the polyunsaturated fatty acids (PUFA) of biological membranes, which due to the large amount of unsaturation, become extremely susceptible to attack by free radicals. The process begins with the activity

#### **Figure 1.**

*Oxidative mechanisms involving vitamin E in human skin exposed to ultraviolet radiation and pollution. ROS, reactive oxygen species.*

**7**

pathologies [33, 34].

the release of O2−

*Vitamin E in Human Skin: Functionality and Topical Products*

as atopic dermatitis, related to lipid peroxidation [27–29].

stress, such as the oxidation of purine and guanine [31, 32].

**4.2 Free radicals and the activation of melanogenesis**

reactions and generation of superoxide anion (O2

enzyme tyrosinase, releasing O2<sup>−</sup>

of the free radical like OH\*, which extracts H from PUFA resulting in the radical PUFA\*. After the molecular rearrangement of a conjugated diene, the molecule is susceptible to attack by O2, resulting in a peroxyl radical (PUFAOO\*). PUFAOO\* can extract H from the adjacent PUFA, thus propagating a chain reaction. Selfoxidation occurs continuously, which can seriously affect the functionality of the

The action of pollutants and UV radiation (UVR) on the skin has already been studied, but the mechanisms involved are still uncertain, knowing that the damage is initially related to the composition of the skin's sebum and the quality of the stratum corneum, which may lead to the formation of wrinkles, hyperchromies (spots), wrinkles and accelerated extrinsic aging and dermatological diseases such

The chronic and acute damage to the skin caused by UVR (UVB and UVA) are related to the direct absorption of rays and indirectly through photosensitization reactions. Mostly (> 95%), UVA radiation, more specifically UVAI (340–400 nm), has the major ability to penetrate the skin and it causes deeper damage. The aggression of UVA radiation targets collagen and supporting fibers, in addition to cellular DNA. The DNA damage is related to the mutagenic power of UVA radiation, which

Studies prove the mutagenic power of UVA through direct oxidation reactions of DNA nucleic acids with ROS, which can lead to simple disruptions of the DNA strands or to disruptions in symmetrical positions in the two strands. Several studies (*in vivo* and *in vitro*) have evaluated the damage to DNA bases caused by oxidative

As the UVR, polluting agents have harmful effects on the skin by increasing the oxidative stress and decreasing the physiological enzymatic and non-enzymatic antioxidant capacity. With the formation of FR and ROS, an interaction occurs with the lipid layer membrane, initiating the cascade reactions of lipid peroxidation and the release of pro-inflammatory mediators, which result in the accumulation of neutrophils and phagocytic cells, that also generate radicals free, thus promoting a cyclical reaction. Oxidative stress initiates a series of quite complex biological processes that result in DNA damage, activation of transcription factors such as activating protein 1 (AP1) and the nuclear factor Kappa-B (NF-KB) and even some pathways of signaling involved in cell growth and differentiation and degradation of dermal connective tissue. Pollutants are also capable of inducing functional changes in lipids, DNA, skin proteins, favoring the acceleration of skin aging, inflammatory processes and dermatological

Melanogenesis can be considered as the first skin defense, being directly influenced by the skin phototype and, consequently, by the amount and type of melanin present. Melanocytes are particularly vulnerable to excessive oxidative stress from ROS due to their pro-oxidant state and the melanin synthesis involves oxidation

promoting oxidative stress. The initiation of melanin synthesis occurs by a single route, with the conversion of tyrosine to dopa by the catalytic activity of the

capable of reacting with nucleophilic compounds, the synthesis follows two distinct pathways, eumelanogenesis and pheomelanogenesis, which respectively produce

the darkest and lightest melanin monomers (red-yellow) [35, 36].

−

. From the obtaining of dopaquinin, a specific orthoquinone,

, which also oxidizes dopa to dopaquinone with

) and hydrogen peroxide (H2O2),

can act directly or indirectly through photosensitization reactions [30].

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

tissue [26].

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

**4.1 Oxidative stress: lipid peroxidation and free radicals' formation**

Reactive oxygen species (ROS) such as superoxide (O2

) and singlet oxygen (1

tion of melanogenesis and damage to collagen fibers [19, 21, 22].

and pollutants (**Figure 1**).

(OH•

prevent the formation of FR [19, 20].

), peroxyl (HOH•

vitamin E [24, 25].

advantages in terms of the protective activity against physical and chemical damage promoted by free radicals (FR). Vitamin E is an antioxidant capable of binding to the membrane in various tissues [17, 18]. Therefore, it is involved in several oxidative mechanisms in epidermis and dermis, catalyzed by ultraviolet radiation (UVR)

The first studies related to the damage caused by the formation of FR on the skin, promoting lipid peroxidation, date from the 1950s and 1960s. To avoid the damages, the use of natural and synthetic substances was suggested in order to

(physiological) processes such as inflammation, physical activity in excess, nutritional disorder, hereditary issues, neoplasms, and even, by processes related to exogenous sources such as UVR and pollution agents. In the skin, the main damage related to lipid peroxidation generated by FR from exogenous sources is the activa-

The lipid peroxidation of the epidermis cells occurs through the action of the ROS, which has the ability to bind to the unsaturated bonds present in the polyunsaturated fatty acids of the cell membrane phospholipids [22, 23]. The process starts between polyunsaturated fatty acids (PUFA) and the oxygen radical, obtaining a lipid radical, which causes a rearrangement process in the presence of molecular oxygen, becoming a peroxy lipid radical. The lipid peroxyl radical is also capable of attacking unsaturated lipids, generating new radicals, such as the lipid radical as in the first stage of the reaction and the lipid hydro peroxide radical, thus promoting a cyclic reaction. Thus, it is necessary to use substances capable of interacting with cell membranes and to extinguish the free radicals formed, such as

In a more detailed way, the mechanism involved in the lipid peroxidation process occurs through a chain reaction of the polyunsaturated fatty acids (PUFA) of biological membranes, which due to the large amount of unsaturation, become extremely susceptible to attack by free radicals. The process begins with the activity

*Oxidative mechanisms involving vitamin E in human skin exposed to ultraviolet radiation and pollution. ROS,* 

−•), hydroxyl radicals

O2), can be formed by endogenous

**6**

**Figure 1.**

*reactive oxygen species.*

of the free radical like OH\*, which extracts H from PUFA resulting in the radical PUFA\*. After the molecular rearrangement of a conjugated diene, the molecule is susceptible to attack by O2, resulting in a peroxyl radical (PUFAOO\*). PUFAOO\* can extract H from the adjacent PUFA, thus propagating a chain reaction. Selfoxidation occurs continuously, which can seriously affect the functionality of the tissue [26].

The action of pollutants and UV radiation (UVR) on the skin has already been studied, but the mechanisms involved are still uncertain, knowing that the damage is initially related to the composition of the skin's sebum and the quality of the stratum corneum, which may lead to the formation of wrinkles, hyperchromies (spots), wrinkles and accelerated extrinsic aging and dermatological diseases such as atopic dermatitis, related to lipid peroxidation [27–29].

The chronic and acute damage to the skin caused by UVR (UVB and UVA) are related to the direct absorption of rays and indirectly through photosensitization reactions. Mostly (> 95%), UVA radiation, more specifically UVAI (340–400 nm), has the major ability to penetrate the skin and it causes deeper damage. The aggression of UVA radiation targets collagen and supporting fibers, in addition to cellular DNA. The DNA damage is related to the mutagenic power of UVA radiation, which can act directly or indirectly through photosensitization reactions [30].

Studies prove the mutagenic power of UVA through direct oxidation reactions of DNA nucleic acids with ROS, which can lead to simple disruptions of the DNA strands or to disruptions in symmetrical positions in the two strands. Several studies (*in vivo* and *in vitro*) have evaluated the damage to DNA bases caused by oxidative stress, such as the oxidation of purine and guanine [31, 32].

As the UVR, polluting agents have harmful effects on the skin by increasing the oxidative stress and decreasing the physiological enzymatic and non-enzymatic antioxidant capacity. With the formation of FR and ROS, an interaction occurs with the lipid layer membrane, initiating the cascade reactions of lipid peroxidation and the release of pro-inflammatory mediators, which result in the accumulation of neutrophils and phagocytic cells, that also generate radicals free, thus promoting a cyclical reaction. Oxidative stress initiates a series of quite complex biological processes that result in DNA damage, activation of transcription factors such as activating protein 1 (AP1) and the nuclear factor Kappa-B (NF-KB) and even some pathways of signaling involved in cell growth and differentiation and degradation of dermal connective tissue. Pollutants are also capable of inducing functional changes in lipids, DNA, skin proteins, favoring the acceleration of skin aging, inflammatory processes and dermatological pathologies [33, 34].

#### **4.2 Free radicals and the activation of melanogenesis**

Melanogenesis can be considered as the first skin defense, being directly influenced by the skin phototype and, consequently, by the amount and type of melanin present. Melanocytes are particularly vulnerable to excessive oxidative stress from ROS due to their pro-oxidant state and the melanin synthesis involves oxidation reactions and generation of superoxide anion (O2 − ) and hydrogen peroxide (H2O2), promoting oxidative stress. The initiation of melanin synthesis occurs by a single route, with the conversion of tyrosine to dopa by the catalytic activity of the enzyme tyrosinase, releasing O2<sup>−</sup> , which also oxidizes dopa to dopaquinone with the release of O2− . From the obtaining of dopaquinin, a specific orthoquinone, capable of reacting with nucleophilic compounds, the synthesis follows two distinct pathways, eumelanogenesis and pheomelanogenesis, which respectively produce the darkest and lightest melanin monomers (red-yellow) [35, 36].

The homeostasis of human melanocytes in the epidermis is maintained mainly through a complex paracrine network, involving growth factors and cytokines synthesized by epidermal keratinocytes and dermal fibroblasts and modulated by UV radiation. Keratinocyte-derived endothelin-1 is a potent mitogen and a melanogenic factor capable of reducing H2O2 generation and apoptosis in human UV-irradiated melanocytes [37]. The α-MSH melanocortin and adrenocorticotropic hormone (ACTH) are synthesized by keratinocytes and melanocytes and stimulate the synthesis of eumelanin, as well as the survival and proliferation of melanocytes by binding and activating the melanocortin 1 receptor (MC1R). The MC1R is a receptor located on the surface of melanocytes with the ability to bind to protein G. Studies show that the treatment of human melanocytes in culture with α-MSH, results in a decrease in the generation of H2O2, due to exposure to UV rays [35].

With the production of ROS, oxidative stress formed can interrupt melanocyte homeostasis, compromising their survival or even leading to malignant pathogens. Thus, the balance between the pro and antioxidant properties of melanin in the skin is mainly determined by the proportions of eumelanin and pheomelanin, the levels of melanin intermediates and the concentrations of reactive metals in the melanosome microenvironment. The generation of H2O2 in response to the action of UV radiation is inversely proportional to the constitutive pigmentation, suggesting a natural antioxidant effect of melanin [35, 38]. The inhibition of melanogenesis occurs in several stages, such as the inhibition of the enzyme tyrosinase that acts in several phases of the melanin production cascade, and also influences the posttranscriptional concentration of tyrosinase and other enzymes related to melanogenesis, such as tyrosinase-related protein 1 (TRP1) and DOPA chrome tautomerase (TRP2) [39].

#### **4.3 Role of vitamin E in skin's oxidative stress**

The mechanism of action of vitamin E (**Figure 2**) regarding the antioxidant activity in the skin is directly related to the chemical mediation of the phenolic hydroxyl (OH) of its structure, capable of donating H to the peroxyl radical (PUFAOO\*), resulting in the formation of a stable lipid species (PUFAOOH). Thus, when donating the hydroxyl H, vitamin E becomes a relatively non-reactive free

#### **Figure 2.**

*Mechanism of lipid peroxidation and vitamin E in cells. PUFA, polyunsaturated fatty acids; PUFA\*, lipid radical; PUFAOO\*, Peroxy lipid radical; OH\*, oxygen radical - hydroxyl; O2, oxygen; VE-OH, Vitamin E, alpha-tocopherol; VE-O\*, radical tocopheroxyl.*

**9**

*Vitamin E in Human Skin: Functionality and Topical Products*

on the radical's singlet oxygen and superoxide anion [19].

ase-2 (COX-2) and NADPH oxidase [43–45].

the body and skin [8, 49, 50].

(CPD) induced by UVB [46].

**5. Topical treatments with vitamin E**

radical, as the unpaired electron moves to the aromatic ring. Thus, with electronic displacement, incorporation occurs in biological membranes, being located awfully close to the polyunsaturated fatty acids of the cell membrane phospholipids, interrupting the chain reaction. Vitamin E stops the reaction by the ability to donate hydrogen from the OH group to the unsaturated lipid or to the lipid peroxyl radical (PUFOO \*), forming the low-energy tocopheroxyl stable radical (VE-O \*), which in turn does not present the ability to act as a free radical forming agent [40, 41]. Vitamin E also has antioxidant activity involving other lipid radicals, acting directly

Studies have shown the activity of vitamin E in the modulation of damage caused by FR mediated by the action of UVR on the skin, such as lipid peroxidation, photoaging, immunosuppression and photocarcinogenesis [42]. Vitamin E is able to reduce the inflammatory reactions of the skin, attenuating the production of prostaglandin involved in the process, pro-inflammatory cytokines, cyclooxygen-

In addition to its anti-inflammatory capacity, vitamin E is also able to modulate the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways and to reduce the increase in collagenase expression. PKC modulation may be representative in terms of cell growth control, however, the interaction between vitamin E (alpha-tocopherol) and PKC protein does not occur directly, assuming that it occurs preventively to its action at the cellular level [45, 46].

Vitamin E has the ability to significantly suppress collagen degradation by inhibiting metalloprotein 1 (MMP-1), involved in the initial process of collagen hydrolysis [44]. It can be identified in deeper layers of the skin, supposing its activity to minimize the photocarcinogenesis process, being considered as one of the main antioxidants of the human epidermis. Another characteristic of vitamin E is its use as an early and very sensitive marker for oxidative damage promoted by the environment [47, 48]. Thus, vitamin E prevents the lipoperoxidation of cell membranes and the degradation of fatty acids that are essential for the proper functioning of

Vitamin E can eliminate FR induced by UVA radiation, protect endogenous antioxidants from degrading processes, prevent lipid peroxidation and reduce immunosuppression caused by UVR. To increase protection against erythema and sunburn, the association of vitamins E and C is indicated, presenting potential against skin aging and skin cancer. Another activity of vitamin E on the skin is its application before sun exposure, avoiding the formation of the cyclobutane pyrimidine dimer

In general, exposure excessive to pollution and ultraviolet radiation promotes a greater production of free radicals, thus requiring an oral and/or topical supplementation of antioxidant substances, such as vitamin E, thus, the endogenous

After vitamin E depletion, oral intake is the best way to replenish the stock of this antioxidant in skin. In fact, oral supplementation brings cosmetic effects after 8–12 weeks. For alpha-tocopherol alone, a photoprotection effect by reduction of human skin malondialdehyde concentration was observed [52]. The combination of vitamin E with other antioxidants is very beneficial for skin treatments. Alphatocopherol in combination with ascorbic acid increased UVB photoprotection in the human epidermis [53, 54]. The same combination showed a reduction in UV-induced inflammation [55]. Good outcomes for treating chloasma were seen

mechanism is not sufficient to prevent deleterious skin damage [51].

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

#### *Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

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

The homeostasis of human melanocytes in the epidermis is maintained mainly through a complex paracrine network, involving growth factors and cytokines synthesized by epidermal keratinocytes and dermal fibroblasts and modulated by UV radiation. Keratinocyte-derived endothelin-1 is a potent mitogen and a melanogenic factor capable of reducing H2O2 generation and apoptosis in human UV-irradiated melanocytes [37]. The α-MSH melanocortin and adrenocorticotropic hormone (ACTH) are synthesized by keratinocytes and melanocytes and stimulate the synthesis of eumelanin, as well as the survival and proliferation of melanocytes by binding and activating the melanocortin 1 receptor (MC1R). The MC1R is a receptor located on the surface of melanocytes with the ability to bind to protein G. Studies show that the treatment of human melanocytes in culture with α-MSH, results in a decrease in the generation of H2O2, due to exposure to UV rays [35]. With the production of ROS, oxidative stress formed can interrupt melanocyte homeostasis, compromising their survival or even leading to malignant pathogens. Thus, the balance between the pro and antioxidant properties of melanin in the skin is mainly determined by the proportions of eumelanin and pheomelanin, the levels of melanin intermediates and the concentrations of reactive metals in the melanosome microenvironment. The generation of H2O2 in response to the action of UV radiation is inversely proportional to the constitutive pigmentation, suggesting a natural antioxidant effect of melanin [35, 38]. The inhibition of melanogenesis occurs in several stages, such as the inhibition of the enzyme tyrosinase that acts in several phases of the melanin production cascade, and also influences the posttranscriptional concentration of tyrosinase and other enzymes related to melanogenesis, such as tyrosinase-related protein 1 (TRP1) and DOPA chrome tautomerase

The mechanism of action of vitamin E (**Figure 2**) regarding the antioxidant activity in the skin is directly related to the chemical mediation of the phenolic hydroxyl (OH) of its structure, capable of donating H to the peroxyl radical

(PUFAOO\*), resulting in the formation of a stable lipid species (PUFAOOH). Thus, when donating the hydroxyl H, vitamin E becomes a relatively non-reactive free

*Mechanism of lipid peroxidation and vitamin E in cells. PUFA, polyunsaturated fatty acids; PUFA\*, lipid radical; PUFAOO\*, Peroxy lipid radical; OH\*, oxygen radical - hydroxyl; O2, oxygen; VE-OH, Vitamin E,* 

**8**

**Figure 2.**

*alpha-tocopherol; VE-O\*, radical tocopheroxyl.*

(TRP2) [39].

**4.3 Role of vitamin E in skin's oxidative stress**

radical, as the unpaired electron moves to the aromatic ring. Thus, with electronic displacement, incorporation occurs in biological membranes, being located awfully close to the polyunsaturated fatty acids of the cell membrane phospholipids, interrupting the chain reaction. Vitamin E stops the reaction by the ability to donate hydrogen from the OH group to the unsaturated lipid or to the lipid peroxyl radical (PUFOO \*), forming the low-energy tocopheroxyl stable radical (VE-O \*), which in turn does not present the ability to act as a free radical forming agent [40, 41]. Vitamin E also has antioxidant activity involving other lipid radicals, acting directly on the radical's singlet oxygen and superoxide anion [19].

Studies have shown the activity of vitamin E in the modulation of damage caused by FR mediated by the action of UVR on the skin, such as lipid peroxidation, photoaging, immunosuppression and photocarcinogenesis [42]. Vitamin E is able to reduce the inflammatory reactions of the skin, attenuating the production of prostaglandin involved in the process, pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) and NADPH oxidase [43–45].

In addition to its anti-inflammatory capacity, vitamin E is also able to modulate the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways and to reduce the increase in collagenase expression. PKC modulation may be representative in terms of cell growth control, however, the interaction between vitamin E (alpha-tocopherol) and PKC protein does not occur directly, assuming that it occurs preventively to its action at the cellular level [45, 46].

Vitamin E has the ability to significantly suppress collagen degradation by inhibiting metalloprotein 1 (MMP-1), involved in the initial process of collagen hydrolysis [44]. It can be identified in deeper layers of the skin, supposing its activity to minimize the photocarcinogenesis process, being considered as one of the main antioxidants of the human epidermis. Another characteristic of vitamin E is its use as an early and very sensitive marker for oxidative damage promoted by the environment [47, 48]. Thus, vitamin E prevents the lipoperoxidation of cell membranes and the degradation of fatty acids that are essential for the proper functioning of the body and skin [8, 49, 50].

Vitamin E can eliminate FR induced by UVA radiation, protect endogenous antioxidants from degrading processes, prevent lipid peroxidation and reduce immunosuppression caused by UVR. To increase protection against erythema and sunburn, the association of vitamins E and C is indicated, presenting potential against skin aging and skin cancer. Another activity of vitamin E on the skin is its application before sun exposure, avoiding the formation of the cyclobutane pyrimidine dimer (CPD) induced by UVB [46].

In general, exposure excessive to pollution and ultraviolet radiation promotes a greater production of free radicals, thus requiring an oral and/or topical supplementation of antioxidant substances, such as vitamin E, thus, the endogenous mechanism is not sufficient to prevent deleterious skin damage [51].

#### **5. Topical treatments with vitamin E**

After vitamin E depletion, oral intake is the best way to replenish the stock of this antioxidant in skin. In fact, oral supplementation brings cosmetic effects after 8–12 weeks. For alpha-tocopherol alone, a photoprotection effect by reduction of human skin malondialdehyde concentration was observed [52]. The combination of vitamin E with other antioxidants is very beneficial for skin treatments. Alphatocopherol in combination with ascorbic acid increased UVB photoprotection in the human epidermis [53, 54]. The same combination showed a reduction in UV-induced inflammation [55]. Good outcomes for treating chloasma were seen

with the same mixture during double blinded clinical trials [56]. When more antioxidants act together, strong outcomes are seen, such as reduction of UVB-induced wrinkle and increased collagen synthesis [57] and treatments of melasma [58, 59]. Despite the benefits to skin appearance, oral intake is not considered cosmetic treatment for its systemic effects.

Topical delivery also plays an important role in restock vitamin E. It is widely used in its purified forms or indirectly using vegetable seed oils [60]. It is a classical ingredient in dermatology and still used in cosmetics worldwide in a recent growth tendency. Cosmetics containing vitamin E are most valuable in the USA, UK and France. The top cosmetic claims used in labels and the categories are in **Figure 3** [61].

The lipophilic nature of vitamin E requires an oily or alcoholic phase at the topical formulation. In cosmetics, the main drivers capable of delivering this type of molecule are serums, tonics, oils and especially emulsions. For vitamin E alone, hydro-alcoholic solution of alpha-tocopherol showed a reduction of UV-induced erythema in the epidermis [62] and the reduction on the number of epidermal sunburn cells. While O/W and W/O emulsions containing alpha-tocopherol acetate increased skin hydration and water-binding capacity in the stratum corneum [63]. Vitamin E is also used as coadjutant in other topical products to improve physical–chemical characteristics or to donate different effects. One of the most studied associations is with vitamin C, due its primary replenisher of vitamin E mechanism in skin. Vitamin C regenerates the oxidized form of vitamin E to its reduced form [64, 65]. A similar mechanism is expected using other antioxidants. **Table 1** shows examples of associations of vitamin E and other molecules. The type of molecule and/or type of formulation is chosen depending on the target to address.

The metabolization of derivatives into the active form of vitamin E (alphatocopherol) occurs at a far extend in the nucleated epidermis [6]. Therefore, the conversion is highly dependent on the delivery system of cosmetic preparations into controlling skin permeation [14]. To address this issue, several innovations on cosmetic formulations have appeared during the last decade.

The use of chemical permeation enhancers (e.g. alcohol, surfactants, terpenoids) is a good strategy to change stratum corneum polarity and fluidity. Likewise, the use of devices that create micron-scale pores in skin (e.g. iontophoresis, microneedles) is also available in clinics [78]. The benefits of using those techniques is to maintain the original formulation. However, adaptations may be needed to maintain stability in the case of adding chemical agents. Another strategy is to change the formulation completely by using new delivery systems to encapsulate vitamin E.

**11**

*Vitamin E in Human Skin: Functionality and Topical Products*

**Vitamin E Combined molecule Effect Model Reference**

Improved the appearance of aging skin (Skin color, elasticity, radiance, smoothness, scaliness and wrinkles)

Protected the skin from UV damage by reduction on the number of sunburn cells

activity against *S. aureus* and *P. aeruginosa* with a sustained release of probiotic cells over 24 h

Reduction of age spots and melasma

periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance

The formulation with filters showed better stability comparing with the vitamins alone

Decreased the diameter

inflammation due lipid peroxidation caused by *Propionibacterium acnes* leakage through follicles and sebaceous glands in

of lesions

skin cancer

*acne vulgaris*

against erythema and sunburn cell formation Aqueous solution applied to pig skin

Commercial serum applied *in vivo*

Emulsion containing 5% of the mixture *in vivo*

*In vivo* application of the multivitamin by iontophoresis

*In vivo* In mouse skin

In chronic leprosy

Topically solution in the skin of white Yorkshire pigs

*In vivo* [5]

Dressing [69]

*In vivo* [71]

[66]

[67]

[68]

[70]

[72]

[73]

[74]

L-ascorbic acid (15%) Synergic protection

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

L-ascorbic acid (20%) + *Rubus idaeus* leaf cell culture (0.0005%)

Bioflavanoids from *Gingko biloba* + ascorbyl tetraisopalmitate + retinyl palmitate

vitamin A (10 000 IU) + vitamin D (1000 IU) + vitamin B1 (50 mg) + vitamin B2 (12.7 mg) + vitamin B6 (15 mg) + vitamin C (500 mg) + nicotinamide (100 mg) + dexpanthenol (vitamin B5) (25 mg)

Vitamin E Photostable filters (octyl

Vitamin E Amniotic membrane

methoxycinnamate, avobenzone and 4-methylbenzilidene camphor) + vitamins A (1,700,000 UI/g) and C [2% (w/w) ascorbyl tetraisopalmitate]

mesenchymal stem cell

Vitamin E Ferulic acid + Vitamin C Suggests preventing

Vitamin E Vitamin C Prevention of

Vitamin E *L. plantarum* A good antibacterial

Vitamin E Resveratrol + Baicalin Improvement on the

Alphatocopherol (1%)

Tocopheryl acetate (1%)

Tocopheryl acetate

Vitamin E 5 IU

#### **Figure 3.**

*Evolution of the most explored categories using tocopherol in cosmetics' labels between 2016 and 2020 (A). Claims used in cosmetics' labels containing tocopherol between 2016 and 2020(B).*


*Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

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

ment for its systemic effects.

**Figure 3** [61].

with the same mixture during double blinded clinical trials [56]. When more antioxidants act together, strong outcomes are seen, such as reduction of UVB-induced wrinkle and increased collagen synthesis [57] and treatments of melasma [58, 59]. Despite the benefits to skin appearance, oral intake is not considered cosmetic treat-

Topical delivery also plays an important role in restock vitamin E. It is widely used in its purified forms or indirectly using vegetable seed oils [60]. It is a classical ingredient in dermatology and still used in cosmetics worldwide in a recent growth tendency. Cosmetics containing vitamin E are most valuable in the USA, UK and France. The top cosmetic claims used in labels and the categories are in

The lipophilic nature of vitamin E requires an oily or alcoholic phase at the topical formulation. In cosmetics, the main drivers capable of delivering this type of molecule are serums, tonics, oils and especially emulsions. For vitamin E alone, hydro-alcoholic solution of alpha-tocopherol showed a reduction of UV-induced erythema in the epidermis [62] and the reduction on the number of epidermal sunburn cells. While O/W and W/O emulsions containing alpha-tocopherol acetate increased skin hydration and water-binding capacity in the stratum corneum [63]. Vitamin E is also used as coadjutant in other topical products to improve physical–chemical characteristics or to donate different effects. One of the most studied associations is with vitamin C, due its primary replenisher of vitamin E mechanism in skin. Vitamin C regenerates the oxidized form of vitamin E to its reduced form [64, 65]. A similar mechanism is expected using other antioxidants. **Table 1** shows examples of associations of vitamin E and other molecules. The type of molecule

and/or type of formulation is chosen depending on the target to address.

cosmetic formulations have appeared during the last decade.

The metabolization of derivatives into the active form of vitamin E (alphatocopherol) occurs at a far extend in the nucleated epidermis [6]. Therefore, the conversion is highly dependent on the delivery system of cosmetic preparations into controlling skin permeation [14]. To address this issue, several innovations on

The use of chemical permeation enhancers (e.g. alcohol, surfactants, terpenoids) is a good strategy to change stratum corneum polarity and fluidity. Likewise,

microneedles) is also available in clinics [78]. The benefits of using those techniques is to maintain the original formulation. However, adaptations may be needed to maintain stability in the case of adding chemical agents. Another strategy is to change the formulation completely by using new delivery systems to encapsulate

the use of devices that create micron-scale pores in skin (e.g. iontophoresis,

*Evolution of the most explored categories using tocopherol in cosmetics' labels between 2016 and 2020* 

*(A). Claims used in cosmetics' labels containing tocopherol between 2016 and 2020(B).*

**10**

**Figure 3.**

vitamin E.


#### **Table 1.**

*Examples of association between vitamin E and other active molecules.*

Micro and nanoemulsions are strong candidates for its permeation capacity. Nevertheless, reduced sizes may have systemic effects, which is not allowed for cosmetics. Regulatory issues must be address in controlling the particle size. Vitamin E microemulsions (256 nm) reach dermis, however with the aid of surfactants [79]. More recently, bigels are a viable cosmetic formulation. These biphasic systems formed by hydrogels and organogels show good spreadability and emollient and moisturizing effect, besides its transdermal capacity [80]. However, bigels containing alpha-tocopherol showed no difference against regular emulsions for hyperpigmentation and inflammatory markers in in vivo tests [81]. More tests are required to evaluate the benefits and safety of new cosmetic formulations.

#### **6. Safety and efficacy of topical products with vitamin E**

Many products in the cosmetic market have vitamin E in its composition. The definition of optimal dosage of vitamin E in cosmetics products depends on the derivative molecule and the type of formulation.

#### **6.1 Safety of Vitamin E**

Studies with animals to evaluate safety is common in many countries, especially in oral products. In animal experiments, 200 mg/kg was administered orally to frogs, rabbits, cats, dogs, and monkeys, with repeated application to mice over a period of 10–61 days. In food of rats, 4.000 mg/kg of Vitamin E was added and, in these experiments, was not mutagenic, teratogenic nor carcinogenic properties [82].

The toxicity of vitamin E is very low, because in clinical studies, a daily dosage of 100–300 mg of vitamin E was considered harmless, even when their use extends over a long period of time. Double-blind studies demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. They mentioned that the optimal human plasma concentration of vitamin E is between 1.0 and 1.5 mg/dl [82].

Numerous genotoxicity studies were conducted with tocopherol, tocopheryl acetate, tocopheryl phosphate (MTP), and tocopheryl succinate. The only remarkable result was tocopheryl succinate with only a weak positive in a sister chromatid exchange assay in the presence of metabolic activation [12].

**13**

observed [12].

female rabbits [88].

days 7 and 14 [12].

**6.2 Efficacy of Vitamin E for topical formulations**

*Vitamin E in Human Skin: Functionality and Topical Products*

contact dermatitis, erythema multiforme, and xanthoma [5].

Tocopherol and tocopheryl acetate are generally recognized as safe food ingredients [12]. According to Brigelius-Flohe et al. [83], vitamin E supplements for pregnancy usually contain only small doses of vitamin E, although adverse effects have not been observed at higher doses. The original report on tocopherols indicated that tocopheryl succinate, up to 75 mg/d in the diet did not have reproductive or developmental effects in rats. In relation to tocopheryl acetate, 1.6 g/kg/d, generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice [84]. There is no published report documenting adverse fetal effects due to use of topical vitamin products. Topical application of vitamin E can rarely cause

Vitamin E and its derivatives are widely used in many cosmetic and dermatologic products, in general, papers with side effects such as allergic or irritant skin reactions are rare. In clinical studies, tocopherol and tocopherol acetate were found to be safe for use in topical skin formulation since irritant or sensitizing reactions were found only in very small percentages [85]. Tocopheryl acetate was not irritating to rabbit eyes in one study, but it produced weak-to-moderate conjunctival irritation in another study [86]. Positive patch test results of alfa-tocopherol are rare and need to be critically reviewed. However, the derivative (alpha-tocopheryl linoleate), demonstrated allergic popular and follicular contact dermatitis in 1000 cases, reported in Switzerland by a line cosmetic in 1992. This compound was easily oxidized under the storage condition [8]. According to Baumann and Spencer [87], 33% of the patients studied developed a contact dermatitis to the vitamin E. The ingredients considered safe to use in cosmetics were Ascorbyl tocopheryl acetate, Ascorbyl tocopheryl maleate, Dioleyl tocopheryl methylsilanol, Potassium ascorbyl tocopheryl phosphate, Sodium tocopheryl phosphate, Tocopherol, Tocophersolan, Tocopheryl acetate, Tocopheryl linoleate, Tocopheryl linoleate/oleate, Tocopheryl nicotinate, Tocopheryl phosphate, Tocopheryl succinate and Tocotrienols. remembering that the concentrations and conditions of use in the safety tests must be

Tocopheryl acetate, 0.2 mL applied under an occlusive patch for 24 hours prior to irradiation, was not phototoxic in a study in 11 participants [84]. According to ECHA [86], animal and clinical testing concluded that tocopheryl acetate was not photoallergenic or phototoxic. The dermal LD50 of tocopheryl acetate is >3 g/kg bw in albino rats. Five animals per group were dosed with 1 or 3 g/kg bw undiluted tocopheryl acetate in vegetable oil under an occlusive patch for 24 hours. Slight erythema was observed 24 to 48 hours after exposure. Slight abrasion was observed in one low dose female, two high-dose females, and two high-dose males [86]. The acute dermal toxicity of mixed tocopheryl phosphates (MTPs) was determined in New Zeal and rabbits; the dermal LD50 was greater than 1,130 mg/kg bw MTP in

An aqueous gel containing 1,130 mg/kg bw MTP (918 mg/kg bw a-tocopherol equivalents) was applied to the clipped dorsal skin of 5 male and 5 female rabbits for 24 hours using surgical gauze. At 24 hours, slight-to-well-defined erythema was observed in 4 of 5 males and all females, and slight-to-moderate edema was observed in 2 of 5 males and all females. Signs of irritation were not observed at

According to Costa [89], vitamin E has a wetting action and in an *in vitro* study, it was found that if it was applied on living skin equivalent cultures also reduced the Transepidermal Water Loss (TEWL), so improving barrier function [72]. Lin *et al* [66], reported that a stable aqueous solution of 15% vitamin C (L-ascorbic

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

#### *Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

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

Ferulic acid Inhibition of

Retinaldehyde (0.05%) + glycylglycine oleamide (0.1%)

*Examples of association between vitamin E and other active molecules.*

Micro and nanoemulsions are strong candidates for its permeation capacity. Nevertheless, reduced sizes may have systemic effects, which is not allowed for cosmetics. Regulatory issues must be address in controlling the particle size. Vitamin E microemulsions (256 nm) reach dermis, however with the aid of surfactants [79]. More recently, bigels are a viable cosmetic formulation. These biphasic systems formed by hydrogels and organogels show good spreadability and emollient and moisturizing effect, besides its transdermal capacity [80]. However, bigels containing alpha-tocopherol showed no difference against regular emulsions for hyperpigmentation and inflammatory markers in in vivo tests [81]. More tests are required to evaluate the benefits and safety of new cosmetic

**Vitamin E Combined molecule Effect Model Reference**

melanization

Improvement on the elastin fiber production and a protection effect of the elastin and fibrillin fiber network against UV-induced alterations

*In vitro* application of alphatocopheryl ferulate

*In vitro* and *ex vivo*

[75, 76]

[77]

Many products in the cosmetic market have vitamin E in its composition. The definition of optimal dosage of vitamin E in cosmetics products depends on the

Studies with animals to evaluate safety is common in many countries, especially in oral products. In animal experiments, 200 mg/kg was administered orally to frogs, rabbits, cats, dogs, and monkeys, with repeated application to mice over a period of 10–61 days. In food of rats, 4.000 mg/kg of Vitamin E was added and, in these experiments, was not mutagenic, teratogenic nor carcino-

The toxicity of vitamin E is very low, because in clinical studies, a daily dosage of 100–300 mg of vitamin E was considered harmless, even when their use extends over a long period of time. Double-blind studies demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. They mentioned that the optimal human plasma concentration of vitamin E is between 1.0 and

Numerous genotoxicity studies were conducted with tocopherol, tocopheryl acetate, tocopheryl phosphate (MTP), and tocopheryl succinate. The only remarkable result was tocopheryl succinate with only a weak positive in a sister chromatid

exchange assay in the presence of metabolic activation [12].

**6. Safety and efficacy of topical products with vitamin E**

derivative molecule and the type of formulation.

**12**

formulations.

Alphatocopherol

Deltatocopherol glucoside (0.05%)

**Table 1.**

**6.1 Safety of Vitamin E**

genic properties [82].

1.5 mg/dl [82].

Tocopherol and tocopheryl acetate are generally recognized as safe food ingredients [12]. According to Brigelius-Flohe et al. [83], vitamin E supplements for pregnancy usually contain only small doses of vitamin E, although adverse effects have not been observed at higher doses. The original report on tocopherols indicated that tocopheryl succinate, up to 75 mg/d in the diet did not have reproductive or developmental effects in rats. In relation to tocopheryl acetate, 1.6 g/kg/d, generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice [84]. There is no published report documenting adverse fetal effects due to use of topical vitamin products. Topical application of vitamin E can rarely cause contact dermatitis, erythema multiforme, and xanthoma [5].

Vitamin E and its derivatives are widely used in many cosmetic and dermatologic products, in general, papers with side effects such as allergic or irritant skin reactions are rare. In clinical studies, tocopherol and tocopherol acetate were found to be safe for use in topical skin formulation since irritant or sensitizing reactions were found only in very small percentages [85]. Tocopheryl acetate was not irritating to rabbit eyes in one study, but it produced weak-to-moderate conjunctival irritation in another study [86]. Positive patch test results of alfa-tocopherol are rare and need to be critically reviewed. However, the derivative (alpha-tocopheryl linoleate), demonstrated allergic popular and follicular contact dermatitis in 1000 cases, reported in Switzerland by a line cosmetic in 1992. This compound was easily oxidized under the storage condition [8]. According to Baumann and Spencer [87], 33% of the patients studied developed a contact dermatitis to the vitamin E. The ingredients considered safe to use in cosmetics were Ascorbyl tocopheryl acetate, Ascorbyl tocopheryl maleate, Dioleyl tocopheryl methylsilanol, Potassium ascorbyl tocopheryl phosphate, Sodium tocopheryl phosphate, Tocopherol, Tocophersolan, Tocopheryl acetate, Tocopheryl linoleate, Tocopheryl linoleate/oleate, Tocopheryl nicotinate, Tocopheryl phosphate, Tocopheryl succinate and Tocotrienols. remembering that the concentrations and conditions of use in the safety tests must be observed [12].

Tocopheryl acetate, 0.2 mL applied under an occlusive patch for 24 hours prior to irradiation, was not phototoxic in a study in 11 participants [84]. According to ECHA [86], animal and clinical testing concluded that tocopheryl acetate was not photoallergenic or phototoxic. The dermal LD50 of tocopheryl acetate is >3 g/kg bw in albino rats. Five animals per group were dosed with 1 or 3 g/kg bw undiluted tocopheryl acetate in vegetable oil under an occlusive patch for 24 hours. Slight erythema was observed 24 to 48 hours after exposure. Slight abrasion was observed in one low dose female, two high-dose females, and two high-dose males [86]. The acute dermal toxicity of mixed tocopheryl phosphates (MTPs) was determined in New Zeal and rabbits; the dermal LD50 was greater than 1,130 mg/kg bw MTP in female rabbits [88].

An aqueous gel containing 1,130 mg/kg bw MTP (918 mg/kg bw a-tocopherol equivalents) was applied to the clipped dorsal skin of 5 male and 5 female rabbits for 24 hours using surgical gauze. At 24 hours, slight-to-well-defined erythema was observed in 4 of 5 males and all females, and slight-to-moderate edema was observed in 2 of 5 males and all females. Signs of irritation were not observed at days 7 and 14 [12].

#### **6.2 Efficacy of Vitamin E for topical formulations**

According to Costa [89], vitamin E has a wetting action and in an *in vitro* study, it was found that if it was applied on living skin equivalent cultures also reduced the Transepidermal Water Loss (TEWL), so improving barrier function [72]. Lin *et al* [66], reported that a stable aqueous solution of 15% vitamin C (L-ascorbic

acid) and 1% vitamin E (alpha-tocopherol) when applied topically to pig skin, daily for 4 days, could provide quadruples photoprotection for skin. This was observed by skin biopsy specimens processed for routine histology. The entire 8 mm center section of the histologic ribbon was analyzed, and the results expressed as sunburn cells/mm.

An *in vivo* study with resveratrol, baicalin and Vitamin E topic formulation demonstrated activation of endogenous antioxidants with ROS scavenging, simultaneously. This was observed by percutaneous absorption, biopsies, and biomarkers. A significant improvement was observed in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance by clinical evaluations that were performed by an expert clinical grader at baseline and for 8–12 weeks. In addition to the increase in collagen production (18.9%) in dermal thickness detected by ultrasound measurements [71].

Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB. Magnetic resonance images showed that there was no increase in skin thickness associated with edema. However, the cytotoxic effects of UV exposure as measured in Chinese hamster embryo cells can also be reversed by the presence of other antioxidants as well as a-tocopherol, ascorbic acid, butylated hydroxytoluene (BHT) and GSH. However, before exposure UV these components do not protect against cytotoxicity. In this study, it was observed that high dietary levels of vitamin E can restore the level of incorporation of thymidine dimers into DNA, in UV-exposed epidermal cells in relation to control non irradiated cells. The DNA was isolated and determined by the method of Gendominico Record et al. 1991 [90].

Gaspar and Campos [72], evaluated photoprotective formulations with a combination of photostable (octyl methoxycinnamate, benzophenone-3 and octocrylene or photoinstable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor), both in addition to A, C and E. vitamins The combination of photostable filters showed a better response compared to the others. The filter components and vitamins were quantified by HPLC analysis and spectrophotometry. The formulation containing only vitamins, showed irritation and hairless in mouse skin, this was observed by histopathology.

Ferulic acid, by protecting vitamins C and E, can prevent UV-induced thymine dimer formation when applied topically to skin evaluated by fluorescence microscope coupled with a camera. Studies mentioned a presence of mutations in thymine dimer in keratoses and squamous cell carcinomas of skin, so this result requires that this combination can prevent skin cancer [74]. The photoprotective actions demonstrated by the topical application of alpha-tocopherol in mice may not be restricted to the action of itself [91]. It is likely that the dimers formed from UVB photo-oxidation of alpha-tocopherol, and perhaps the trimers as well, may themselves confer photoprotection, this was observed by similarities in the UV absorbance spectrum. Vitamin E slowed melanoma growth by promoting tumor cell apoptosis and inhibiting VEGF-mediated angiogenesis. The mechanism of the *in vivo* antitumor effect of VES was determined by immunohistochemical detection of proliferation and apoptosis [8].

#### **6.3 Skin disorders**

Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in therapy of yellow nail syndrome in a dosage of 1000 IU once a day for a period of 6 months; epidermolysis bullosa (300–600 IU/day); in cutaneous ulcers with treatment of pressure sores in doses of 800 IU/L gradually increasing to 1600 IU/L; in wound healing with zinc and

**15**

*Vitamin E in Human Skin: Functionality and Topical Products*

vitamin C for pressure ulcers and burns; in subcorneal pustular dermatosis (d-alphatocopheryl acetate) 100 IU/day, gradually increasing to 400 IU/day for 4 weeks; in scleroderma, morphea, calcinosis cutis, and Raynaud's phenomenon respond to vitamin E in a range from 200 to 1200 IU per day; in Hailey–Hailey disease with derivative of vitamin E *d-* alpha-tocopheryl acetate in doses of 800–1200 IU/L by

Vitamin E has been reported to be effective in inflammatory diseases with attenuation of pro-inflammatory cytokine TNF, evaluated by a section of skin mice by quantitative ELISA kit [64]. In a combination of oral vitamins, A, C, and E with or not proanthocyanidin there was a significant reduction of pigmentation in melasma and pigmented contact dermatitis lesions in two randomized clinical double-bind study [5, 92]. Oral vitamin E (400 IE/day) for 8 months, improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels [93]. In oral combination with carotenoids (ß-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins there was decreases the UV-induced expression of Metalloproteinases 1 and 9, that means prevention of sunburn reaction as well as subsequent chronic skin damage,

In chronic leprosy a topical combination of vitamin E and with an amniotic membrane mesenchymal stem cell decreased the diameter of these lesions, evaluated by randomized controlled trial and monitored weekly [73]. In a dressing based on the association of Vitamin E and *L. plantarum* showed a good antibacterial activity against *S. aureus* and *P. aeruginosa* and guaranteed a sustained release of probiotic cells over 24 h, suggesting a successful and ecologically sustainable alternative

Chung *et al*. [85], demonstrated that a topical occlusive pretreatment with 5% vitamin E for 24 h protected against UV-induced upregulation of human macrophage metalloelastase in human skin *in vivo*. There was improving photoprotection of sunscreens against free radical formation in viable epidermal layers in the cultured human dermal fibroblasts. In a topical tocoretinate, hybrid compound of retinoic acid and tocopherol was reduced the clinical symptoms of lichen and

Studies show that there was an improvement in the healing of wounds in diabetic rats by topical vitamin E [95]. According to Kuriyama et al. [9], some animal's studies even suggest that topical vitamin E at a concentration of 20% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to 0.5% prednisone ointment. Those skin conditions are generally self-reported as dry skin [96]. With the onset of xerosis, several inappropriate situations can arise, such as the release of inflammatory mediators, hyperproliferation of keratinocytes and interruption of epidermal differentiation, in addition to changes in lipid structure and enzymatic activity [97]. Skin aging, specifically after age 65, presents several constitutional and functional changes in all layers of the skin, such as cellular senescence, decreased proliferative capacity, decreased ability to repair cellular DNA, abnormalities related to chromosomes, loss of telomeres, DNA extranuclear related mutations, oxidative stress and genetic mutations, promoting the formation of wrinkles, loss of elasticity and dryness of the skin [98, 99]. According to Rhie et al., 2001, the alpha-tocopherol concentration in the epidermis is negatively affected with aging and especially with photoaging, in this case the levels found are even

Over the years, the main histological changes occur with the basal cells, which suffer from dyscrasia, presenting an increase in volume and size, which can be accentuated by the action of UV radiation. As for the functionality of the basal cells, there is a decrease in mitotic activity and an increase in the cell cycle time and

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

clinically evaluation [5].

evaluated by clinical trials [94].

to the cotton in wound care [69].

lower when compared to young skin [100].

macular amyloidosis [5].

#### *Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

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

mined by the method of Gendominico Record et al. 1991 [90].

mouse skin, this was observed by histopathology.

of proliferation and apoptosis [8].

**6.3 Skin disorders**

detected by ultrasound measurements [71].

cells/mm.

acid) and 1% vitamin E (alpha-tocopherol) when applied topically to pig skin, daily for 4 days, could provide quadruples photoprotection for skin. This was observed by skin biopsy specimens processed for routine histology. The entire 8 mm center section of the histologic ribbon was analyzed, and the results expressed as sunburn

An *in vivo* study with resveratrol, baicalin and Vitamin E topic formulation demonstrated activation of endogenous antioxidants with ROS scavenging, simultaneously. This was observed by percutaneous absorption, biopsies, and biomarkers. A significant improvement was observed in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance by clinical evaluations that were performed by an expert clinical grader at baseline and for 8–12 weeks. In addition to the increase in collagen production (18.9%) in dermal thickness

Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB. Magnetic resonance images showed that there was no increase in skin thickness associated with edema. However, the cytotoxic effects of UV exposure as measured in Chinese hamster embryo cells can also be reversed by the presence of other antioxidants as well as a-tocopherol, ascorbic acid, butylated hydroxytoluene (BHT) and GSH. However, before exposure UV these components do not protect against cytotoxicity. In this study, it was observed that high dietary levels of vitamin E can restore the level of incorporation of thymidine dimers into DNA, in UV-exposed epidermal cells in relation to control non irradiated cells. The DNA was isolated and deter-

Gaspar and Campos [72], evaluated photoprotective formulations with a combination of photostable (octyl methoxycinnamate, benzophenone-3 and octocrylene or photoinstable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor), both in addition to A, C and E. vitamins The combination of photostable filters showed a better response compared to the others. The filter components and vitamins were quantified by HPLC analysis and spectrophotometry. The formulation containing only vitamins, showed irritation and hairless in

Ferulic acid, by protecting vitamins C and E, can prevent UV-induced thymine dimer formation when applied topically to skin evaluated by fluorescence microscope coupled with a camera. Studies mentioned a presence of mutations in thymine dimer in keratoses and squamous cell carcinomas of skin, so this result requires that this combination can prevent skin cancer [74]. The photoprotective actions demonstrated by the topical application of alpha-tocopherol in mice may not be restricted to the action of itself [91]. It is likely that the dimers formed from UVB photo-oxidation of alpha-tocopherol, and perhaps the trimers as well, may themselves confer photoprotection, this was observed by similarities in the UV absorbance spectrum. Vitamin E slowed melanoma growth by promoting tumor cell apoptosis and inhibiting VEGF-mediated angiogenesis. The mechanism of the *in vivo* antitumor effect of VES was determined by immunohistochemical detection

Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in therapy of yellow nail syndrome in a dosage of 1000 IU once a day for a period of 6 months; epidermolysis bullosa (300–600 IU/day); in cutaneous ulcers with treatment of pressure sores in doses of 800 IU/L gradually increasing to 1600 IU/L; in wound healing with zinc and

**14**

vitamin C for pressure ulcers and burns; in subcorneal pustular dermatosis (d-alphatocopheryl acetate) 100 IU/day, gradually increasing to 400 IU/day for 4 weeks; in scleroderma, morphea, calcinosis cutis, and Raynaud's phenomenon respond to vitamin E in a range from 200 to 1200 IU per day; in Hailey–Hailey disease with derivative of vitamin E *d-* alpha-tocopheryl acetate in doses of 800–1200 IU/L by clinically evaluation [5].

Vitamin E has been reported to be effective in inflammatory diseases with attenuation of pro-inflammatory cytokine TNF, evaluated by a section of skin mice by quantitative ELISA kit [64]. In a combination of oral vitamins, A, C, and E with or not proanthocyanidin there was a significant reduction of pigmentation in melasma and pigmented contact dermatitis lesions in two randomized clinical double-bind study [5, 92]. Oral vitamin E (400 IE/day) for 8 months, improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels [93]. In oral combination with carotenoids (ß-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins there was decreases the UV-induced expression of Metalloproteinases 1 and 9, that means prevention of sunburn reaction as well as subsequent chronic skin damage, evaluated by clinical trials [94].

In chronic leprosy a topical combination of vitamin E and with an amniotic membrane mesenchymal stem cell decreased the diameter of these lesions, evaluated by randomized controlled trial and monitored weekly [73]. In a dressing based on the association of Vitamin E and *L. plantarum* showed a good antibacterial activity against *S. aureus* and *P. aeruginosa* and guaranteed a sustained release of probiotic cells over 24 h, suggesting a successful and ecologically sustainable alternative to the cotton in wound care [69].

Chung *et al*. [85], demonstrated that a topical occlusive pretreatment with 5% vitamin E for 24 h protected against UV-induced upregulation of human macrophage metalloelastase in human skin *in vivo*. There was improving photoprotection of sunscreens against free radical formation in viable epidermal layers in the cultured human dermal fibroblasts. In a topical tocoretinate, hybrid compound of retinoic acid and tocopherol was reduced the clinical symptoms of lichen and macular amyloidosis [5].

Studies show that there was an improvement in the healing of wounds in diabetic rats by topical vitamin E [95]. According to Kuriyama et al. [9], some animal's studies even suggest that topical vitamin E at a concentration of 20% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to 0.5% prednisone ointment. Those skin conditions are generally self-reported as dry skin [96].

With the onset of xerosis, several inappropriate situations can arise, such as the release of inflammatory mediators, hyperproliferation of keratinocytes and interruption of epidermal differentiation, in addition to changes in lipid structure and enzymatic activity [97]. Skin aging, specifically after age 65, presents several constitutional and functional changes in all layers of the skin, such as cellular senescence, decreased proliferative capacity, decreased ability to repair cellular DNA, abnormalities related to chromosomes, loss of telomeres, DNA extranuclear related mutations, oxidative stress and genetic mutations, promoting the formation of wrinkles, loss of elasticity and dryness of the skin [98, 99]. According to Rhie et al., 2001, the alpha-tocopherol concentration in the epidermis is negatively affected with aging and especially with photoaging, in this case the levels found are even lower when compared to young skin [100].

Over the years, the main histological changes occur with the basal cells, which suffer from dyscrasia, presenting an increase in volume and size, which can be accentuated by the action of UV radiation. As for the functionality of the basal cells, there is a decrease in mitotic activity and an increase in the cell cycle time and the cell migration time, which can promote changes in the outermost layer of the skin. The horny extract does not change its thickness, however, the replacement of lipids happens slowly, which significantly affects the function of barrier, protection and maintenance of natural hydration [101, 102].

Thus, the topical use of vitamin E is adequate for its recognized antioxidant and protective activities, favoring the improvement of the skin barrier due to its lipophilic character and also, effectively avoiding lipid peroxidation by protecting cell membranes from the action of free radicals [103]. Gehring et al. [63] evaluated the hydration capacity of the stratum corneum by the use of vitamin E (5%) in water/ oil and oil/water emulsions, demonstrating moisturizing activity in the stratum corneum, in addition to providing indications that indicate retention of water in the stratum corneum. Gonullu and collaborators [104] also report that the topical use of vitamin E for a period of two to four weeks can improve the ability of water to retain in the skin, favoring hydration.

While aging decreases keratinocyte proliferation, the abnormal hyperproliferation those cells are seen in psoriasis. Psoriasis is a chronic inflammatory process of the skin which affects 1–2% of the population and can affect the quality of life. It is most characterized by the presence of erythematous plaques with silvery scale on various regions of the body including the scalp, extensor regions of the extremities, and intertriginous areas of the skin [19, 105, 106]. Studies on the influence of vitamin E on psoriasis include oral and topical treatment evaluation of the vitamins combination, minerals, among others (vitamins A, C, D, E, B1, B2, B3, B5, B6, B12, magnesium, zinc, selenium, folic acid, copper, lysine and proline), that act on oxidative stress, energy metabolism, the immune system and optimized collagen formation. The consumption of olive oil, a vitamin E source, is also associated with improvement in psoriasis symptoms, acting positively in the suppression of serum levels of metalloproteinase-3 (MMP-3), protein of the cartilage olimeric matrix (COMP) as well as the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) [107]. Topical treatments include the application of products added with plant extracts containing vitamin E and other derivatives, the results are representative in relieving the symptoms of psoriasis induced in the mouse model, suppressing the levels of Interleukin-22 involved in extensive proliferation of keratinocytes and pathogenesis of psoriasis. The critical importance of the interleukin axis for the pathogenesis of psoriatic disease has resulted in new biological treatments targeting these cytokines, indicating that vitamin E is a component of interest in the treatment of psoriasis [106–109].

#### **7. Discussion**

Antioxidants consumed orally or topically may impact several organs in the body and among them, the skin. Systemic or centralized effects of these molecules can be modulated by the administration pathway and cellular machinery involved in their metabolization. When compared with other natural bioactive compounds, vitamin E has a specific mechanism of activation in skin due its lipophilicity. Alpha-tocopherol is the active molecule, but several derivatives are available in the market to address solubility, cost and pharmacotechnical necessities. The acetate and succinate esters exhibit better oxidation stability and are often associated with surfactants to improve water-solubility. The hydrolyzation of those molecules is mandatory to achieve biological effects and is mainly driven by enzymatic complexes in skin. The application of derivatives is an interesting alternative for slow delivery of this vitamin since the necessity of activation may lead to accumulation and a reservoir effect [110].

**17**

*Vitamin E in Human Skin: Functionality and Topical Products*

The natural lipophilicity of vitamin E impacts also its biological effects in skin. Vitamin E structure forms complexes with lipids in the cellular membrane and therefore acts promptly against the ROS formation due UV or pollution exposure [111]. The reduction/blockage of oxidative stress' cascade protects skin against several damages visible as wrinkles, melasma and cancer. Besides the lipid peroxidation, vitamin E has an important role in DNA integrity and epigenetic gene modulation [112]. As a natural component of the healthy tissue, vitamin E is associated with impaired skin treatments, such as psoriasis, dry skin, atopic dermatitis and

The presence of vitamin E is expected in skin, which makes permeation experiments, bioavailability studies and quantification analysis more challenging. Raman confocal spectroscopy showed good sensibility to evaluate the health benefits and safety of vitamin E in human skin *in vivo* [113]. This technique can elucidate the extend of vitamin E overcoming skin barrier and achieving the nucleated epidermis for bioconversion. The complex mechanism of action of vitamin E depends on other bioactive molecules, especially vitamin C. As the primary replenisher of vitamin E in skin, the benefits of using those vitamins cannot be investigated separately and a wider look of the literature is required to make a fair comparison [114]. Further investigation using Raman could bring more data about the mechanisms and contribution of each ingredient. Nevertheless, it is very common that topical products present a combination of molecules acting synergistically to achieve better results. The cosmetic market is always releasing innovative products despite vitamin E is considered a very classic dermatological active. New delivery systems focused on better absorption, deeper permeation or simpler hydrolysis are the R&D main targets. Since vitamin E is generally recognized as safe (GRASA) food ingredient and used in over-the-counter products with broader concentration range (1.0 to 5.0%), there is little regulatory concern about the exploration of this molecule in cosmetics and supplements. The focus of this chapter is topical applications and therefore, the oral toxicity data was not extensively covered. Safety assessment of alpha-tocopherol and its most used esters showed no phototoxicity, no genotoxicity and no ocular and dermal sensibilization [12]. The use of vitamin E in topical applications is a safe, effective and well accepted worldwide, especially in associa-

Vitamin E, more specifically alpha-tocopherol, can be considered a substance with antioxidant activity with the ability to protect long-chain unsaturated fatty acids. It is also capable of playing an important role in a wide variety of physiological and biochemical functions, mediated by the antioxidant function or by its stabilizing effect on cell membranes, breaking down the peroxyl chain propagation reactions and eliminating the efficient lipid peroxyl radicals. Is has been used for decades and is still a very good a widespread ingredient for dermatological products and formulations, especially when associated with other antioxidants such as vitamin C. However, it is important to emphasize the need for more in-depth studies on the use of its derivatives and associations, regarding the conversion speed and the converted amount of vitamin E in skin. There are few studies related to the topical safety and efficacy of vitamin E in the literature, although it is widely used in cosmetics and dermatologic products. A low incidence of contact dermatitis has been reported. However, more studies would be needed for a conclusive answer regarding its topical safety. The definition of optimal dosage in cosmetics depends

on the derivative molecule and the type of cosmetic formulation.

other skin disorders related to oxidative stress and inflammation [5].

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

tion with other antioxidants.

**8. Conclusions**

#### *Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

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

and maintenance of natural hydration [101, 102].

retain in the skin, favoring hydration.

ment of psoriasis [106–109].

and a reservoir effect [110].

**7. Discussion**

the cell migration time, which can promote changes in the outermost layer of the skin. The horny extract does not change its thickness, however, the replacement of lipids happens slowly, which significantly affects the function of barrier, protection

Thus, the topical use of vitamin E is adequate for its recognized antioxidant and protective activities, favoring the improvement of the skin barrier due to its lipophilic character and also, effectively avoiding lipid peroxidation by protecting cell membranes from the action of free radicals [103]. Gehring et al. [63] evaluated the hydration capacity of the stratum corneum by the use of vitamin E (5%) in water/ oil and oil/water emulsions, demonstrating moisturizing activity in the stratum corneum, in addition to providing indications that indicate retention of water in the stratum corneum. Gonullu and collaborators [104] also report that the topical use of vitamin E for a period of two to four weeks can improve the ability of water to

While aging decreases keratinocyte proliferation, the abnormal hyperproliferation those cells are seen in psoriasis. Psoriasis is a chronic inflammatory process of the skin which affects 1–2% of the population and can affect the quality of life. It is most characterized by the presence of erythematous plaques with silvery scale on various regions of the body including the scalp, extensor regions of the extremities, and intertriginous areas of the skin [19, 105, 106]. Studies on the influence of vitamin E on psoriasis include oral and topical treatment evaluation of the vitamins combination, minerals, among others (vitamins A, C, D, E, B1, B2, B3, B5, B6, B12, magnesium, zinc, selenium, folic acid, copper, lysine and proline), that act on oxidative stress, energy metabolism, the immune system and optimized collagen formation. The consumption of olive oil, a vitamin E source, is also associated with improvement in psoriasis symptoms, acting positively in the suppression of serum levels of metalloproteinase-3 (MMP-3), protein of the cartilage olimeric matrix (COMP) as well as the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) [107]. Topical treatments include the application of products added with plant extracts containing vitamin E and other derivatives, the results are representative in relieving the symptoms of psoriasis induced in the mouse model, suppressing the levels of Interleukin-22 involved in extensive proliferation of keratinocytes and pathogenesis of psoriasis. The critical importance of the interleukin axis for the pathogenesis of psoriatic disease has resulted in new biological treatments targeting these cytokines, indicating that vitamin E is a component of interest in the treat-

Antioxidants consumed orally or topically may impact several organs in the body and among them, the skin. Systemic or centralized effects of these molecules can be modulated by the administration pathway and cellular machinery involved in their metabolization. When compared with other natural bioactive compounds, vitamin E has a specific mechanism of activation in skin due its lipophilicity. Alpha-tocopherol is the active molecule, but several derivatives are available in the market to address solubility, cost and pharmacotechnical necessities. The acetate and succinate esters exhibit better oxidation stability and are often associated with surfactants to improve water-solubility. The hydrolyzation of those molecules is mandatory to achieve biological effects and is mainly driven by enzymatic complexes in skin. The application of derivatives is an interesting alternative for slow delivery of this vitamin since the necessity of activation may lead to accumulation

**16**

The natural lipophilicity of vitamin E impacts also its biological effects in skin. Vitamin E structure forms complexes with lipids in the cellular membrane and therefore acts promptly against the ROS formation due UV or pollution exposure [111]. The reduction/blockage of oxidative stress' cascade protects skin against several damages visible as wrinkles, melasma and cancer. Besides the lipid peroxidation, vitamin E has an important role in DNA integrity and epigenetic gene modulation [112]. As a natural component of the healthy tissue, vitamin E is associated with impaired skin treatments, such as psoriasis, dry skin, atopic dermatitis and other skin disorders related to oxidative stress and inflammation [5].

The presence of vitamin E is expected in skin, which makes permeation experiments, bioavailability studies and quantification analysis more challenging. Raman confocal spectroscopy showed good sensibility to evaluate the health benefits and safety of vitamin E in human skin *in vivo* [113]. This technique can elucidate the extend of vitamin E overcoming skin barrier and achieving the nucleated epidermis for bioconversion. The complex mechanism of action of vitamin E depends on other bioactive molecules, especially vitamin C. As the primary replenisher of vitamin E in skin, the benefits of using those vitamins cannot be investigated separately and a wider look of the literature is required to make a fair comparison [114]. Further investigation using Raman could bring more data about the mechanisms and contribution of each ingredient. Nevertheless, it is very common that topical products present a combination of molecules acting synergistically to achieve better results.

The cosmetic market is always releasing innovative products despite vitamin E is considered a very classic dermatological active. New delivery systems focused on better absorption, deeper permeation or simpler hydrolysis are the R&D main targets. Since vitamin E is generally recognized as safe (GRASA) food ingredient and used in over-the-counter products with broader concentration range (1.0 to 5.0%), there is little regulatory concern about the exploration of this molecule in cosmetics and supplements. The focus of this chapter is topical applications and therefore, the oral toxicity data was not extensively covered. Safety assessment of alpha-tocopherol and its most used esters showed no phototoxicity, no genotoxicity and no ocular and dermal sensibilization [12]. The use of vitamin E in topical applications is a safe, effective and well accepted worldwide, especially in association with other antioxidants.

#### **8. Conclusions**

Vitamin E, more specifically alpha-tocopherol, can be considered a substance with antioxidant activity with the ability to protect long-chain unsaturated fatty acids. It is also capable of playing an important role in a wide variety of physiological and biochemical functions, mediated by the antioxidant function or by its stabilizing effect on cell membranes, breaking down the peroxyl chain propagation reactions and eliminating the efficient lipid peroxyl radicals. Is has been used for decades and is still a very good a widespread ingredient for dermatological products and formulations, especially when associated with other antioxidants such as vitamin C. However, it is important to emphasize the need for more in-depth studies on the use of its derivatives and associations, regarding the conversion speed and the converted amount of vitamin E in skin. There are few studies related to the topical safety and efficacy of vitamin E in the literature, although it is widely used in cosmetics and dermatologic products. A low incidence of contact dermatitis has been reported. However, more studies would be needed for a conclusive answer regarding its topical safety. The definition of optimal dosage in cosmetics depends on the derivative molecule and the type of cosmetic formulation.

#### **Author details**

Claudineia Aparecida Sales de Oliveira Pinto1 \*, Tércio Elyan Azevedo Martins1,2, Renata Miliani Martinez1 , Thamires Batello Freire1 , Maria Valéria Robles Velasco1 and André Rolim Baby1

1 Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

2 Aesthetics and Cosmetics Course, Paulista University, São Paulo, Brazil

\*Address all correspondence to: clausal@usp.br

© 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.

**19**

*Vitamin E in Human Skin: Functionality and Topical Products*

[10] National Institutes of Healthy. Vitamin E Fact Sheet for Health Professionals [Internet]. 2021 [cited 2021 Apr 14]. p. 1-1. Available from: https://ods.od.nih.gov/factsheets/ VitaminE-HealthProfessional/

[11] SCCNFP. Opinion of the scientific committee on cosmetic products and non-food products intended for consumers concerning the use of alphatocopherol acetate in cosmetic products [Internet]. 2001 [cited 2021 Apr 19]. Available from: https://ec.europa.eu/ health/archive/ph\_risk/committees/sccp/

[12] Fiume MM, Bergfeld WF, Belsito D V., Hill RA, Klaassen CD, Liebler DC, et al. Safety Assessment of Tocopherols and Tocotrienols as Used in Cosmetics.

[13] Traber MG, Rallis M, Podda M, Weber C, Maibach HI, Packer L. Penetration and distribution of α-tocopherol, α- or γ-tocotrienols applied individually onto murine skin.

[14] Manela-Azulay M, Bagatin E. Cosmeceuticals vitamins. Clin Dermatol. 2009 Sep;27(5):469-474.

[15] Zingg JM. Water-Soluble Vitamin E—Tocopheryl Phosphate. In: Advances

in Food and Nutrition Research. Academic Press Inc.; 2018. p. 311-363.

[16] Thiele JJ, Hsieh SN, Ekanayake-Mudiyanselage S. Vitamin E: critical review of its current use in cosmetic and

[17] Burke K. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther. 2007;20(5):314-321.

clinical dermatology. Vol. 31, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2005.

documents/out148\_en.pdf

Int J Toxicol. 2018 Sep 1;37(2\_suppl):61S-94S.

Lipids. 1998;33(1):87-91.

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

[1] Poljšak B, Fink R. The protective role of antioxidants in the defence against ROS/RNS-mediated environmental pollution. Oxid Med Cell Longev.

Mechanism of Its Antioxidant Activity.

Chandra N. Free radicals, antioxidants and functional foods: Impact on human

[5] Keen MA, Hassan I. Vitamin E in dermatology. Indian Dermatol Online J.

[6] Thiele JJ, Hsieh SN, Ekanayake-Mudiyanselage S. Vitamin E: critical review of its current use in cosmetic and clinical dermatology. Dermatologic

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

Cook-Mills JM, Eggersdorfer M, Frank J, et al. Vitamin E: Emerging aspects and new directions. Vol. 102, Free Radical Biology and Medicine. Elsevier Inc.;

Mudiyanselage S. Vitamin E in human skin: Organ-specific physiology and

dermatology. Vol. 28, Molecular Aspects

[9] Kuriyama K, Shimizu T, Horiguchi T, Watabe M, Abe Y. Vitamin E ointment at high dose levels suppresses contact dermatitis in rats by stabilizing keratinocytes. Inflamm Res. 2002;51(10):483-489.

[2] Pekiner BD. Vitamin E as an antioxidant. J Fac Pharm, Ankara.

[3] Yamaguchi R. Vitamin E:

Food Sci Technol Int Tokyo.

[4] Lobo V, Patil A, Phatak A,

health. Pharmacogn Rev. 2010;4(8):118-126.

**References**

2014;2014:1-22.

2003;32(4):243-267.

1997;3(4):301-309.

2016;7(4):311-315.

Surg. 2005;31:805-813.

[8] Thiele JJ, Ekanayake-

considerations for its use in

of Medicine. 2007. p. 646-667.

2017. p. 16-36.

*Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

#### **References**

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

**18**

**Author details**

Renata Miliani Martinez1

and André Rolim Baby1

Paulo, São Paulo, Brazil

Claudineia Aparecida Sales de Oliveira Pinto1

\*Address all correspondence to: clausal@usp.br

provided the original work is properly cited.

, Thamires Batello Freire1

2 Aesthetics and Cosmetics Course, Paulista University, São Paulo, Brazil

1 Department of Pharmacy, School of Pharmaceutical Sciences, University of São

© 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,

\*, Tércio Elyan Azevedo Martins1,2,

, Maria Valéria Robles Velasco1

[1] Poljšak B, Fink R. The protective role of antioxidants in the defence against ROS/RNS-mediated environmental pollution. Oxid Med Cell Longev. 2014;2014:1-22.

[2] Pekiner BD. Vitamin E as an antioxidant. J Fac Pharm, Ankara. 2003;32(4):243-267.

[3] Yamaguchi R. Vitamin E: Mechanism of Its Antioxidant Activity. Food Sci Technol Int Tokyo. 1997;3(4):301-309.

[4] Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010;4(8):118-126.

[5] Keen MA, Hassan I. Vitamin E in dermatology. Indian Dermatol Online J. 2016;7(4):311-315.

[6] Thiele JJ, Hsieh SN, Ekanayake-Mudiyanselage S. Vitamin E: critical review of its current use in cosmetic and clinical dermatology. Dermatologic Surg. 2005;31:805-813.

[7] Galli F, Azzi A, Birringer M, Cook-Mills JM, Eggersdorfer M, Frank J, et al. Vitamin E: Emerging aspects and new directions. Vol. 102, Free Radical Biology and Medicine. Elsevier Inc.; 2017. p. 16-36.

[8] Thiele JJ, Ekanayake-Mudiyanselage S. Vitamin E in human skin: Organ-specific physiology and considerations for its use in dermatology. Vol. 28, Molecular Aspects of Medicine. 2007. p. 646-667.

[9] Kuriyama K, Shimizu T, Horiguchi T, Watabe M, Abe Y. Vitamin E ointment at high dose levels suppresses contact dermatitis in rats by stabilizing keratinocytes. Inflamm Res. 2002;51(10):483-489.

[10] National Institutes of Healthy. Vitamin E Fact Sheet for Health Professionals [Internet]. 2021 [cited 2021 Apr 14]. p. 1-1. Available from: https://ods.od.nih.gov/factsheets/ VitaminE-HealthProfessional/

[11] SCCNFP. Opinion of the scientific committee on cosmetic products and non-food products intended for consumers concerning the use of alphatocopherol acetate in cosmetic products [Internet]. 2001 [cited 2021 Apr 19]. Available from: https://ec.europa.eu/ health/archive/ph\_risk/committees/sccp/ documents/out148\_en.pdf

[12] Fiume MM, Bergfeld WF, Belsito D V., Hill RA, Klaassen CD, Liebler DC, et al. Safety Assessment of Tocopherols and Tocotrienols as Used in Cosmetics. Int J Toxicol. 2018 Sep 1;37(2\_suppl):61S-94S.

[13] Traber MG, Rallis M, Podda M, Weber C, Maibach HI, Packer L. Penetration and distribution of α-tocopherol, α- or γ-tocotrienols applied individually onto murine skin. Lipids. 1998;33(1):87-91.

[14] Manela-Azulay M, Bagatin E. Cosmeceuticals vitamins. Clin Dermatol. 2009 Sep;27(5):469-474.

[15] Zingg JM. Water-Soluble Vitamin E—Tocopheryl Phosphate. In: Advances in Food and Nutrition Research. Academic Press Inc.; 2018. p. 311-363.

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[17] Burke K. Interaction of vitamins C and E as better cosmeceuticals. Dermatol Ther. 2007;20(5):314-321.

[18] Varma SD, Kovtun S, Hegde KR. Role of ultraviolet irradiation and oxidative stress in cataract formationmedical prevention by nutritional antioxidants and metabolic agonists. Eye Contact Lens. 2011;37(4):233-245.

[19] Nachbar F, Korting H. The role of vitamin E in normal and damaged skin. J Mol Med. 1995;73(1):7-17.

[20] Nada A, Krishnaiah YSR, Zaghloul AA, Khattab I. In vitro and in vivo permeation of vitamin e and vitamin e acetate from cosmetic formulations. Med Princ Pract. 2011;20(6):509-513.

[21] Boussouira B, Pham D. Squalene and Skin Barrier Function: From Molecular Target to Biomarker of Environmental Exposure. In: Skin Stress Response Pathways. 2016. p. 29-48.

[22] Martins TEA, Pinto CAS de O, de Oliveira AC, Velasco MVR, Guitiérrez ARG, Rafael MFC, et al. Contribution of topical antioxidants to maintain healthy skin—A review. Sci Pharm. 2020;88(2):1-17.

[23] Silva SAM, Michniak-Kohn B, Leonardi GR. An overview about oxidation in clinical practice of skin aging. An Bras Dermatol. 2017;92(3):367-374.

[24] Mayer P. The effects of vitamin E on the skin. Cosmet Toilet. 1993;108(99-109).

[25] Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2 nonenal. Oxid Med Cell Longev. 2014;2014:1-31.

[26] Rimbach G, Minihane A, Majewicz J, Fischer A, Pallauf J, Virgli F, et al. Regulation of cell signalling by vitamin E. Proc Nutr Soc. 2002;61(4):415-425.

[27] Valacchi G, Sticozzi C, Pecorelli A, Cervellati F, Cervellati C, Maioli E. Cutaneous responses to environmental stressors. Ann N Y Acad Sci. 2012;1271(1):75-81.

[28] Portugal-Cohen M, Oron M, Cohen D, Ma'or Z. Antipollution skin protection – A new paradigm and its demonstration on two active compounds. Clin Cosmet Investig Dermatol. 2017;10:185-193.

[29] Velasco MVR, Sauce R, de Oliveira CA, Pinto CAS d. O, Martinez RM, Baah S, et al. Active ingredients, mechanisms of action and efficacy tests antipollution cosmetic and personal care products. Brazilian J Pharm Sci. 2018;54(Special Issue):1-8.

[30] Delinasios GJ, Karbaschi M, Cooke MS, Young AR. Vitamin E inhibits the UVAI induction of "light" and "dark" cyclobutane pyrimidine dimers, and oxidatively generated DNA damage, in keratinocytes. Sci Rep [Internet]. 2018;8(1):1-12. Available from: http://dx.doi.org/10.1038/ s41598-017-18924-4

[31] Drouin R, Therrien JP. UVB-induced Cyclobutane Pyrimidine Dimer Frequency Correlates with Skin Cancer Mutational Hotspots in p53. Photochem Photobiol. 1997;66(5):719-726.

[32] Iwamatsu Y, Aoki C, Takahashi M, Teranishi M, Ding Y, Sun C, et al. UVB sensitivity and cyclobutane pyrimidine dimer (CPD) photolyase genotypes in cultivated and wild rice species. Photochem Photobiol Sci. 2008;7(3):311-320.

[33] Soeur J, Belaïdi JP, Chollet C, Denat L, Dimitrov A, Jones C, et al. Photo-pollution stress in skin: Traces of pollutants (PAH and particulate matter) impair redox homeostasis in keratinocytes exposed to UVA1. J Dermatol Sci. 2017;86(2):162-169.

**21**

*Vitamin E in Human Skin: Functionality and Topical Products*

Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. Nutr Cancer.

[43] Wu S, Gao J, Dinh QT, Chen C, Fimmel S. IL-8 production and AP-1 transactivation induced by UVA in human keratinocytes: Roles of d-αtocopherol. Mol Immunol. 2008;45(8):

[44] Park K. Role of micronutrients in skin health and function. Biomol Ther.

[45] Ricciarelli R, Maroni P, Özer N, Zingg JM, Azzi A. Age-dependent increase of collagenase expression can be reduced by α-tocopherol via protein kinase C inhibition. Free Radic Biol

Med. 1999;27(7-8):729-737.

Protective role of vitamin E preconditioning of human dermal fibroblasts against thermal stress in vitro. Life Sci [Internet]. 2017;184:1-9.

Available from: http://dx.doi. org/10.1016/j.lfs.2017.07.002

[47] Shindo Y, Witt E, Han D, Epstein W, Packer L. Enzymic and non-enzymic antioxidants in

Invest Dermatol [Internet].

ep12371744

1997;108(5):753-757.

[46] Butt H, Mehmood A, Ali M,

Tasneem S, Anjum MS, Tarar MN, et al.

epidermis and dermis of human skin. J

1994;102(1):122-124. Available from: http://dx.doi.org/10.1111/1523-1747.

[48] Thiele J, Schroeter C, Hsieh S, Podda M, Packer L. The antioxidant network of the stratum corneum. Curr Probl Dermatol. 2001;29(1):26-42.

[49] Thiele JJ, Traber MG, Polefka TG, Cross CE, Packer L. Ozone-exposure depletes vitamin E and induces lipid peroxidation in murine stratum corneum. J Invest Dermatol.

2000;38(1):87-97.

2288-2296.

2015;23(3):207-217.

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[34] Cooper S, Bowden G. Ultraviolet B Regulation of Transcription Factor Families: Roles of Nuclear Factor-kappa

B (NF-κB) and Activator Protein-1 (AP-1) in UVB-Induced Skin Carcinogenesis. Curr Cancer Drug

[35] Denat L, Kadekaro A, Marrot L,

Melanocytes as Instigators and Victims of Oxidative Stress. J Invest Dermatol.

[36] Herrling T, Jung K, Fuchs J. The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair. Spectrochim Acta - Part A Mol Biomol Spectrosc.

Targets. 2007;7(4):325-334.

Leachman S, Abdel-Male Z.

2014;134(6):1512-1518.

2008;69(5):1429-1435.

2005;65(10):4292-4299.

2009;31(4):200-208.

[37] Kadekaro AL, Kavanagh R, Kanto H, Terzieva S, Hauser J,

Kobayashi N, et al. α-melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res.

[38] Baldea I, Mocan T, Cosgarea R. The role of ultraviolet radiation and tyrosine

Comparison of the inhibitory effects of vitamin e analogues on melanogenesis

stimulated melanogenesis in the induction of oxidative stress alterations in fair skin melanocytes. Exp Oncol.

[39] Kamei Y, Otsuka Y, Abe K.

in mouse B16 melanoma cells. Cytotechnology. 2009;59(3):183-190.

[40] Kramer KA, Liebler DC. UVB induced photooxidation of vitamin E. Chem Res Toxicol. 1997;10(2):219-224.

Photooxidation of Tocopherols. Correlation between Singlet Oxygen Reactivity and Vitamin E Activity. Biochemistry. 1972;11(4):606-608.

[42] Burke K, Clive J, Combs Jr GF, Commisso J, Keen CL, Nakamura R.

[41] Grams G, Eskins K. Dye-Sensitized

*Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

[34] Cooper S, Bowden G. Ultraviolet B Regulation of Transcription Factor Families: Roles of Nuclear Factor-kappa B (NF-κB) and Activator Protein-1 (AP-1) in UVB-Induced Skin Carcinogenesis. Curr Cancer Drug Targets. 2007;7(4):325-334.

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

[27] Valacchi G, Sticozzi C, Pecorelli A, Cervellati F, Cervellati C, Maioli E. Cutaneous responses to environmental

stressors. Ann N Y Acad Sci.

demonstration on two active compounds. Clin Cosmet Investig Dermatol. 2017;10:185-193.

[29] Velasco MVR, Sauce R, de Oliveira CA, Pinto CAS d. O, Martinez RM, Baah S, et al. Active ingredients, mechanisms of action and efficacy tests antipollution cosmetic and personal care products. Brazilian J Pharm Sci. 2018;54(Special

[30] Delinasios GJ, Karbaschi M, Cooke MS, Young AR. Vitamin E inhibits the UVAI induction of "light" and "dark" cyclobutane pyrimidine dimers, and oxidatively generated DNA damage, in keratinocytes. Sci Rep [Internet]. 2018;8(1):1-12. Available from: http://dx.doi.org/10.1038/

[31] Drouin R, Therrien JP. UVB-induced

Frequency Correlates with Skin Cancer Mutational Hotspots in p53. Photochem

[32] Iwamatsu Y, Aoki C, Takahashi M, Teranishi M, Ding Y, Sun C, et al. UVB sensitivity and cyclobutane pyrimidine dimer (CPD) photolyase genotypes in cultivated and wild rice species. Photochem Photobiol Sci. 2008;7(3):311-320.

Cyclobutane Pyrimidine Dimer

Photobiol. 1997;66(5):719-726.

[33] Soeur J, Belaïdi JP, Chollet C, Denat L, Dimitrov A, Jones C, et al. Photo-pollution stress in skin: Traces of pollutants (PAH and particulate matter)

impair redox homeostasis in keratinocytes exposed to UVA1. J Dermatol Sci. 2017;86(2):162-169.

[28] Portugal-Cohen M, Oron M, Cohen D, Ma'or Z. Antipollution skin protection – A new paradigm and its

2012;1271(1):75-81.

Issue):1-8.

s41598-017-18924-4

[18] Varma SD, Kovtun S, Hegde KR. Role of ultraviolet irradiation and oxidative stress in cataract formationmedical prevention by nutritional antioxidants and metabolic agonists. Eye Contact Lens. 2011;37(4):233-245.

[19] Nachbar F, Korting H. The role of vitamin E in normal and damaged skin.

Zaghloul AA, Khattab I. In vitro and in vivo permeation of vitamin e and vitamin e acetate from cosmetic formulations. Med Princ Pract.

[21] Boussouira B, Pham D. Squalene and Skin Barrier Function: From Molecular Target to Biomarker of Environmental Exposure. In: Skin Stress Response Pathways. 2016. p. 29-48.

[22] Martins TEA, Pinto CAS de O, de

Guitiérrez ARG, Rafael MFC, et al. Contribution of topical antioxidants to maintain healthy skin—A review. Sci

[23] Silva SAM, Michniak-Kohn B, Leonardi GR. An overview about oxidation in clinical practice of skin

[24] Mayer P. The effects of vitamin E on

[25] Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: Production,

[26] Rimbach G, Minihane A,

vitamin E. Proc Nutr Soc. 2002;61(4):415-425.

metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2 nonenal. Oxid Med Cell Longev.

Majewicz J, Fischer A, Pallauf J, Virgli F, et al. Regulation of cell signalling by

Oliveira AC, Velasco MVR,

Pharm. 2020;88(2):1-17.

aging. An Bras Dermatol. 2017;92(3):367-374.

the skin. Cosmet Toilet. 1993;108(99-109).

2014;2014:1-31.

J Mol Med. 1995;73(1):7-17.

2011;20(6):509-513.

[20] Nada A, Krishnaiah YSR,

**20**

[35] Denat L, Kadekaro A, Marrot L, Leachman S, Abdel-Male Z. Melanocytes as Instigators and Victims of Oxidative Stress. J Invest Dermatol. 2014;134(6):1512-1518.

[36] Herrling T, Jung K, Fuchs J. The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair. Spectrochim Acta - Part A Mol Biomol Spectrosc. 2008;69(5):1429-1435.

[37] Kadekaro AL, Kavanagh R, Kanto H, Terzieva S, Hauser J, Kobayashi N, et al. α-melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res. 2005;65(10):4292-4299.

[38] Baldea I, Mocan T, Cosgarea R. The role of ultraviolet radiation and tyrosine stimulated melanogenesis in the induction of oxidative stress alterations in fair skin melanocytes. Exp Oncol. 2009;31(4):200-208.

[39] Kamei Y, Otsuka Y, Abe K. Comparison of the inhibitory effects of vitamin e analogues on melanogenesis in mouse B16 melanoma cells. Cytotechnology. 2009;59(3):183-190.

[40] Kramer KA, Liebler DC. UVB induced photooxidation of vitamin E. Chem Res Toxicol. 1997;10(2):219-224.

[41] Grams G, Eskins K. Dye-Sensitized Photooxidation of Tocopherols. Correlation between Singlet Oxygen Reactivity and Vitamin E Activity. Biochemistry. 1972;11(4):606-608.

[42] Burke K, Clive J, Combs Jr GF, Commisso J, Keen CL, Nakamura R. Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. Nutr Cancer. 2000;38(1):87-97.

[43] Wu S, Gao J, Dinh QT, Chen C, Fimmel S. IL-8 production and AP-1 transactivation induced by UVA in human keratinocytes: Roles of d-αtocopherol. Mol Immunol. 2008;45(8): 2288-2296.

[44] Park K. Role of micronutrients in skin health and function. Biomol Ther. 2015;23(3):207-217.

[45] Ricciarelli R, Maroni P, Özer N, Zingg JM, Azzi A. Age-dependent increase of collagenase expression can be reduced by α-tocopherol via protein kinase C inhibition. Free Radic Biol Med. 1999;27(7-8):729-737.

[46] Butt H, Mehmood A, Ali M, Tasneem S, Anjum MS, Tarar MN, et al. Protective role of vitamin E preconditioning of human dermal fibroblasts against thermal stress in vitro. Life Sci [Internet]. 2017;184:1-9. Available from: http://dx.doi. org/10.1016/j.lfs.2017.07.002

[47] Shindo Y, Witt E, Han D, Epstein W, Packer L. Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. J Invest Dermatol [Internet]. 1994;102(1):122-124. Available from: http://dx.doi.org/10.1111/1523-1747. ep12371744

[48] Thiele J, Schroeter C, Hsieh S, Podda M, Packer L. The antioxidant network of the stratum corneum. Curr Probl Dermatol. 2001;29(1):26-42.

[49] Thiele JJ, Traber MG, Polefka TG, Cross CE, Packer L. Ozone-exposure depletes vitamin E and induces lipid peroxidation in murine stratum corneum. J Invest Dermatol. 1997;108(5):753-757.

[50] Puri P, Nandar SK, Kathuria S, Ramesh V. Effects of air pollution on the skin: A review. Indian J Dermatol Venereol Leprol. 2017;83(4):415-423.

[51] Petruk G, Giudice R Del, Rigano MM, Monti DM. Antioxidants from plants protect against skin photoaging. Oxidative Medicine and Cellular Longevity. Hindawi Limited; 2018. p. 1-11.

[52] Mcardle F, Rhodes LE, Parslew RAG, Close GL, Jack CIA, Friedmann PS, et al. Effects of oral vitamin E and beta-carotene supplementation on ultraviolet radiation – induced oxidative stress in human skin. Am J Clin Nutr. 2004;80(1): 1270-1275.

[53] Placzek M, Gaube S, Kerkmann U, Gilbertz KP, Herzinger T, Haen E, et al. Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-αtocopherol. J Invest Dermatol [Internet]. 2005;124(2):304-307. Available from: http://dx.doi.org/10.1111/j.0022-202X. 2004.23560.x

[54] Eberlein-könig B, Placzek M, Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d- α -tocopherol (vitamin E). J Am Acad Dermatol. 1998;45-48.

[55] Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med. 1998;25(9):1006-1012.

[56] Hayakawa R, Ueda H, Nozaki T, Izawa Y, Yokotake J, Yazaki K, et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzym. 1981;3(1): 31-38.

[57] Cho H, Lee M, Lee JW, No K, Park S, Lee H, et al. by chronic ultraviolet B irradiation. Photodermatol Photoimmunol Photomed. 2007;23(5):155-162.

[58] Aladrén S, Garre A, Valderas-mart P, Piquero-casals J. Efficacy and Safety of an Oral Nutritional (Dietary) Supplement Containing Pinus pinaster Bark Extract and Grape Seed Extract in Combination with a High SPF Sunscreen in the Treatment of Mild-to-Moderate Melasma : A Prospective Clinical Study. Cosmetics. 2019;6(15):1-13.

[59] Handog EB, Amor D, Galang VF, Leon-godinez MA De, Chan GP. Pharmacology and therapeutics A randomized , double-blind , placebocontrolled trial of oral procyanidin with vitamins A , C , E for melasma among Filipino women. Int J Dermatol. 2009;48:896-901.

[60] Chen B, McClements DJ, Decker EA. Minor components in food oils: a critical review of their roles on lipid oxidation chemistry in bulk oils and emulsions. Crit Rev Food Sci Nutr. 2011;51(10):901-916.

[61] Mintel [Internet]. [cited 2021 Mar 12]. Available from: https://www. mintel.com/global-new-productsdatabase

[62] Dreher F, Denig N, Gabard B, Schwindt DA, Maibach HI. Effect of topical antioxidants on UV-induced erythema formation when administered after exposure. Dermatology. 1999;198(1):52-55.

[63] Gehring W, Fluhr J, Gloor M. Influence of vitamin E acetate on stratum corneum hydration. Arzneimittelforschung. 1998;48:772-775.

[64] Al-Niami F, Yi Zhen Chiang N. Topical Vitamin C and the Skin : J Clin

**23**

*Vitamin E in Human Skin: Functionality and Topical Products*

and Tolerance of a Nighttime Topical Antioxidant Containing Resveratrol, Baicalin, and Vitamin E for Treatment of Mild to Moderately Photodamaged Skin Christian Oresajo L'Oréal

Evaluation of Efficacy and Tolerance of a Nighttime Top [Internet]. Vol. 13, Article in Journal of drugs in dermatology. 2014. Available from: https://www.researchgate.net/

[72] Gaspar LR, Campos PMBGM. Photostability and efficacy studies of topical formulations containing

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Tournas JA, Burch JA, Selim MA, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol [Internet]. 2005;125(4):826- 832. Available from: http://dx.doi. org/10.1111/j.0022-202X.2005.23768.x

17;29(8):835-840.

Oktaviyanti RN, Pratiwi KD, et al. The efficacy of topical human amniotic membrane-mesenchymal stem cellconditioned medium (hAMMSC-CM) and a mixture of topical hAMMSC-CM + vitamin C and hAMMSC-CM + vitamin E on chronic plantar ulcers in leprosy: a randomized control trial. J

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mechanistic perspective. Free Radic Biol

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Wanitphakdeedecha R, Bumrungpert A,

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[68] Maia Campos PMBG, Gianeti MD, Kanashiro A, Lucisano-Valim YM, Gaspar LR. In Vitro Antioxidant and In Vivo Photoprotective Effects of an Association of Bioflavonoids with Liposoluble Vitamins. Photochem

Aesthethetic Dermatology.

and E: Beneficial effects from a

[66] Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, et al. UV

Am Acad Dermatol. 2003;48(6):

[67] Rattanawiwatpong P,

Maiprasert M. Anti-aging and brightening effects of a topical treatment containing vitamin C, vitamin E, and raspberry leaf cell culture extract: A split-face,

Dermatol. 2020;19(3):671-676.

Photobiol. 2006;82(3):683.

[69] Cerchiara T, Giordani B, Melgoza LM, Prata C, Parolin C, Dalena F, et al. New Spanish Broom dressings based on Vitamin E and *Lactobacillus plantarum* for superficial skin wounds. J Drug Deliv Sci Technol

[Internet]. 2020;56(December 2019):101499. Available from: https:// doi.org/10.1016/j.jddst.2020.101499

[70] Choi YK, Rho YK, Yoo KH, Lim YY, Li K, Kim BJ, et al. Effects of vitamin C vs. multivitamin on melanogenesis: Comparative study in vitro and in vivo. Int J Dermatol. 2010;49(2):218-226.

[71] Farris P, Yatskayer M, Chen N, Krol Bs Y, Oresajo C. Evaluation of Efficacy

Med. 2011;51(5):1000-1013.

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866-874.

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Aesthethetic Dermatology. 2017;10(7):14-17.

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

[57] Cho H, Lee M, Lee JW, No K, Park S, Lee H, et al. by chronic ultraviolet B

[58] Aladrén S, Garre A, Valderas-mart P, Piquero-casals J. Efficacy and Safety of an Oral Nutritional (Dietary) Supplement Containing Pinus pinaster Bark Extract and Grape Seed Extract in

Sunscreen in the Treatment of Mild-to-Moderate Melasma : A Prospective

[59] Handog EB, Amor D, Galang VF, Leon-godinez MA De, Chan GP. Pharmacology and therapeutics A randomized , double-blind , placebocontrolled trial of oral procyanidin with vitamins A , C , E for melasma among Filipino women. Int J Dermatol.

irradiation. Photodermatol Photoimmunol Photomed.

Combination with a High SPF

Clinical Study. Cosmetics.

2019;6(15):1-13.

2009;48:896-901.

2011;51(10):901-916.

database

[60] Chen B, McClements DJ,

Decker EA. Minor components in food oils: a critical review of their roles on lipid oxidation chemistry in bulk oils and emulsions. Crit Rev Food Sci Nutr.

[61] Mintel [Internet]. [cited 2021 Mar 12]. Available from: https://www. mintel.com/global-new-products-

[62] Dreher F, Denig N, Gabard B, Schwindt DA, Maibach HI. Effect of topical antioxidants on UV-induced erythema formation when administered

after exposure. Dermatology.

[63] Gehring W, Fluhr J, Gloor M. Influence of vitamin E acetate on stratum corneum hydration. Arzneimittelforschung. 1998;48:772-775.

[64] Al-Niami F, Yi Zhen Chiang N. Topical Vitamin C and the Skin : J Clin

1999;198(1):52-55.

2007;23(5):155-162.

[50] Puri P, Nandar SK, Kathuria S, Ramesh V. Effects of air pollution on the skin: A review. Indian J Dermatol Venereol Leprol. 2017;83(4):415-423.

Rigano MM, Monti DM. Antioxidants from plants protect against skin photoaging. Oxidative Medicine and Cellular Longevity. Hindawi Limited;

[51] Petruk G, Giudice R Del,

[52] Mcardle F, Rhodes LE,

Parslew RAG, Close GL, Jack CIA, Friedmann PS, et al. Effects of oral vitamin E and beta-carotene

supplementation on ultraviolet radiation – induced oxidative stress in human skin. Am J Clin Nutr. 2004;80(1):

[53] Placzek M, Gaube S, Kerkmann U, Gilbertz KP, Herzinger T, Haen E, et al. Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-αtocopherol. J Invest Dermatol [Internet]. 2005;124(2):304-307. Available from: http://dx.doi.org/10.1111/j.0022-202X.

[54] Eberlein-könig B, Placzek M, Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d- α -tocopherol (vitamin E). J Am Acad Dermatol.

[55] Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med.

[56] Hayakawa R, Ueda H, Nozaki T, Izawa Y, Yokotake J, Yazaki K, et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzym. 1981;3(1):

2018. p. 1-11.

1270-1275.

2004.23560.x

1998;45-48.

1998;25(9):1006-1012.

**22**

31-38.

[65] Traber MG, Stevens JF. Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;51(5):1000-1013.

[66] Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, et al. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol. 2003;48(6): 866-874.

[67] Rattanawiwatpong P, Wanitphakdeedecha R, Bumrungpert A, Maiprasert M. Anti-aging and brightening effects of a topical treatment containing vitamin C, vitamin E, and raspberry leaf cell culture extract: A split-face, randomized controlled trial. J Cosmet Dermatol. 2020;19(3):671-676.

[68] Maia Campos PMBG, Gianeti MD, Kanashiro A, Lucisano-Valim YM, Gaspar LR. In Vitro Antioxidant and In Vivo Photoprotective Effects of an Association of Bioflavonoids with Liposoluble Vitamins. Photochem Photobiol. 2006;82(3):683.

[69] Cerchiara T, Giordani B, Melgoza LM, Prata C, Parolin C, Dalena F, et al. New Spanish Broom dressings based on Vitamin E and *Lactobacillus plantarum* for superficial skin wounds. J Drug Deliv Sci Technol [Internet]. 2020;56(December 2019):101499. Available from: https:// doi.org/10.1016/j.jddst.2020.101499

[70] Choi YK, Rho YK, Yoo KH, Lim YY, Li K, Kim BJ, et al. Effects of vitamin C vs. multivitamin on melanogenesis: Comparative study in vitro and in vivo. Int J Dermatol. 2010;49(2):218-226.

[71] Farris P, Yatskayer M, Chen N, Krol Bs Y, Oresajo C. Evaluation of Efficacy

and Tolerance of a Nighttime Topical Antioxidant Containing Resveratrol, Baicalin, and Vitamin E for Treatment of Mild to Moderately Photodamaged Skin Christian Oresajo L'Oréal Evaluation of Efficacy and Tolerance of a Nighttime Top [Internet]. Vol. 13, Article in Journal of drugs in dermatology. 2014. Available from: https://www.researchgate.net/ publication/271538214

[72] Gaspar LR, Campos PMBGM. Photostability and efficacy studies of topical formulations containing UV-filters combination and vitamins A, C and E. Int J Pharm. 2007;343(1-2): 181-189.

[73] Prakoeswa CRS, Natallya FR, Harnindya D, Thohiroh A, Oktaviyanti RN, Pratiwi KD, et al. The efficacy of topical human amniotic membrane-mesenchymal stem cellconditioned medium (hAMMSC-CM) and a mixture of topical hAMMSC-CM + vitamin C and hAMMSC-CM + vitamin E on chronic plantar ulcers in leprosy: a randomized control trial. J Dermatolog Treat. 2018 Nov 17;29(8):835-840.

[74] Lin FH, Lin JY, Gupta RD, Tournas JA, Burch JA, Selim MA, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol [Internet]. 2005;125(4):826- 832. Available from: http://dx.doi. org/10.1111/j.0022-202X.2005.23768.x

[75] Funasaka Y, Komoto M, Ichihashi M. Depigmenting effect of α-tocopheryl ferulate on normal human melanocytes. Pigment Cell Res. 2000;13(SUPPL. 8):170-174.

[76] Ichihashi M, Funasaka Y, Ohashi A, Chacraborty A, Ahmed NU, Ueda M, et al. The inhibitory effect of DL-alphatocopheryl ferulate in lecithin on melanogenesis. Anticancer Res. 1999;19(5A):3769-3774.

[77] Rouvrais C, Bacqueville D, Bogdanowicz P, Haure MJ, Duprat L, Coutanceau C, et al. A new dermocosmetic containing retinaldehyde, delta-tocopherol glucoside and glycylglycine oleamide for managing naturally aged skin: Results from in vitro to clinical studies. Clin Cosmet Investig Dermatol. 2017;10:35-42.

[78] Kim B, Cho H, Moon SH, Ahn H, Bae S, Cho H. Transdermal delivery systems in cosmetics. Biomed Dermatology. 2020;4(10):1-12.

[79] Praça FG, Viegas JSR, Peh YH, Garbin TN, Medina WSG, Bentley MVLB. Microemulsion co-delivering vitamin A and vitamin E as a new platform for topical treatment of acute skin inflammation. Mater Sci Eng C [Internet]. 2020;110(August 2019):110639. Available from: https:// doi.org/10.1016/j.msec.2020.110639

[80] Shakeel A, Farooq U, Iqbal T, Yasin S, Lupi FR, Gabriele D. Key characteristics and modelling of bigels systems: A review. Mater Sci Eng C. 2019;97(December 2018):932-953.

[81] Martinez RM, Magalhães WV, Sufi BS, Padovani G, Nazato LIS, Robles MV, et al. Vitamin E-loaded bigels and emulsions : Physicochemical characterization and potential biological application. Colloids Surfaces B Biointerfaces. 2021;201(111651).

[82] Kappus H, Diplock AT. Tolerance and safety of vitamin e: a toxicological position report [Internet]. Vol. 13, Free Radical Biology & Medicine. 1992 [cited 2021 Apr 19]. Available from: https:// www.sciencedirect.com/science/article/ abs/pii/089158499290166E

[83] Brigelius-Flohé R, Kelly FJ, Salonen JT, Neuzil J, Zingg J-M, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr. 2002;76(4):703-716.

[84] Fiume MZ. Final report on the safety assessment of tocopherol, tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate/oleate, tocopheryl nicotinate, tocopheryl succinate, dioleyl tocopheryl methylsilanol, potassium ascorbyl tocopheryl phosphate, and tocophe. Vol. 21, International Journal of Toxicology. 2002. 51-116 p.

[85] Chung HJ, Young Seo J, Kyoung Lee M, Chul Eun H, Heung Lee J, Kang S, et al. Ultraviolet Modulation of Human Macrophage Metalloelastase in Human Skin In Vivo. 2002.

[86] European Chemicals Agency. 3,4-Dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyldecyl)-2Hbenzopyran-6-yl acetate. 2013.

[87] Baumann LS, Spencer J. The Effects of Topical Vitamin E on the Cosmetic Appearance of Scars. Vol. 25, Dermatol Surg. 1999.

[88] Libinaki R, Ogru E, Gianello R, Bolton L, Geytenbeek S. Evaluation of the safety of mixed tocopheryl phosphates (MTP)-A formulation of α-tocopheryl phosphate plus α-ditocopheryl phosphate. Food Chem Toxicol. 2006;44(7):916-932.

[89] Costa A. Tratado Internacional de Cosmecêuticos. 1st ed. Koogan G, editor. Rio de Janeiro; 2012. 744 p.

[90] Fryer MJ. Evidence for the photoprotective effects of vitamin e. Vol. 58. 1993.

[91] Krol ES, Kramer-Stickland KA, Liebler DC. Photoprotective actions of topically applied vitamin E [Internet]. Vol. 32, Drug Metabolism Reviews. 2000. Available from: www. dekker.com

[92] Sarkar R, Arora P, Garg Kv. Cosmeceuticals for hyperpigmentation: What is available? J Cutan Aesthet Surg. 2013;6(1):4.

**25**

*Vitamin E in Human Skin: Functionality and Topical Products*

chronological skin aging. Arch Dermatol. 2002;138(11):1462-1470.

of endogenously aged skin.

skin in vivo. J Invest Dermatol [Internet]. 2001;117(5):1212-1217. Available from: http://dx.doi. org/10.1046/j.0022-202x.2001.

Dermatology. 1979. p. 59-66.

Postulated mechanisms and

function. Clin Geriatr Med.

2001;17(4):617-630.

2012;4(03):1-8.

2006;57(6):465-473.

2017;08(05):1-6.

01469.x

[99] Makrantonaki E, Zouboulis CC. Characteristics and pathomechanisms

Dermatology. 2007;214(4):352-360.

[100] Rhie GE, Mi HS, Jin YS, Won WC, Kwang HC, Kyu HK, et al. Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human

[101] Lavker RM. Structural alterations in exposed and unexposed aged skin. Vol. 73, The Journal of Investigative

[102] Yaar M, Gilchrest BA. Skin aging:

consequent changes in structure and

[103] Nada A, Zaghloul A, Hedaya M, Khattab I. Stability of vitamin E and vitamin E acetate containing cosmetic preparations. J Glob Pharma Technol.

[104] Gönüllü Ü, Sensoy D, Üner M, Yener G, Altinkurt T. Comparing the moisturizing effects of ascorbic acid and

calcium ascorbate against that of tocopherol in emulsions. J Cosmet Sci.

[105] Vaule H, Leonard SW, Traber MG. Vitamin E delivery to human skin: Studies using deuterated α-tocopherol measured by apci LC-MC. Free Radic Biol Med. 2004 Feb 15;36(4):456-463.

[106] Usedom E, Neidig L, Allen HB. Psoriasis and Fat-soluble Vitamins: A Review. J Clin Exp Dermatol Res.

*DOI: http://dx.doi.org/10.5772/intechopen.98336*

[93] Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int

J Dermatol. 2002;41(3):146-150.

[94] Greul A-K, Grundmann J-U, Heinrich F, Pfitzner I, Bernhardt J,

Pharmacology andApplied Physiology Skin Pharmacology andApplied Skin Physiology Photoprotection of UV-Irradiated Human Skin: An

Antioxidative Combination of Vitamins E and C, Carotenoids, Selenium and Proanthocyanidins [Internet]. Vol. 15, Skin Pharmacol Appl Skin Physiol. 2002. Available from: www.karger.com/

[95] Ibrahim N 'Izzah, Wong SK, Mohamed IN, Mohamed N, Chin KY, Ima-Nirwana S, et al. Wound healing properties of selected natural products.

Vol. 15, International Journal of Environmental Research and Public Health. MDPI AG; 2018. p. 1-23.

[96] Thyssen JP, Johansen JD,

[97] Vaz S, Silva R, Amaral MH, Martins E, Sousa Lobo JM, Silva AC. Evaluation of the biocompatibility and skin hydration potential of vitamin

E-loaded lipid nanosystems

Biointerfaces [Internet].

colsurfb.2019.03.036

formulations: In vitro and human in vivo studies. Colloids Surfaces B

2019;179(November 2018):242-9. Available from: https://doi.org/10.1016/j.

[98] Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and

2013;93(4):406-410.

Zachariae C, Menné T, Linneberg A. Xerosis is associated with atopic dermatitis, hand eczema and contact sensitization independent of filaggrin gene mutations. Acta Derm Venereol.

Ambach A, et al. Skin Skin

journals/sph

*Vitamin E in Human Skin: Functionality and Topical Products DOI: http://dx.doi.org/10.5772/intechopen.98336*

[93] Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol. 2002;41(3):146-150.

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

[84] Fiume MZ. Final report on the safety assessment of tocopherol,

of Toxicology. 2002. 51-116 p.

Human Skin In Vivo. 2002.

Surg. 1999.

[85] Chung HJ, Young Seo J, Kyoung Lee M, Chul Eun H, Heung Lee J, Kang S, et al. Ultraviolet Modulation of Human Macrophage Metalloelastase in

[86] European Chemicals Agency. 3,4-Dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyldecyl)-2Hbenzopyran-6-yl acetate. 2013.

[87] Baumann LS, Spencer J. The Effects of Topical Vitamin E on the Cosmetic Appearance of Scars. Vol. 25, Dermatol

[88] Libinaki R, Ogru E, Gianello R, Bolton L, Geytenbeek S. Evaluation of

[89] Costa A. Tratado Internacional de Cosmecêuticos. 1st ed. Koogan G, editor.

[91] Krol ES, Kramer-Stickland KA, Liebler DC. Photoprotective actions of topically applied vitamin E [Internet]. Vol. 32, Drug Metabolism Reviews.

the safety of mixed tocopheryl phosphates (MTP)-A formulation of α-tocopheryl phosphate plus α-ditocopheryl phosphate. Food Chem Toxicol. 2006;44(7):916-932.

Rio de Janeiro; 2012. 744 p.

Vol. 58. 1993.

dekker.com

2013;6(1):4.

[90] Fryer MJ. Evidence for the photoprotective effects of vitamin e.

2000. Available from: www.

[92] Sarkar R, Arora P, Garg Kv.

Cosmeceuticals for hyperpigmentation: What is available? J Cutan Aesthet Surg.

tocopheryl acetate, tocopheryl linoleate, tocopheryl linoleate/oleate, tocopheryl nicotinate, tocopheryl succinate, dioleyl tocopheryl methylsilanol, potassium ascorbyl tocopheryl phosphate, and tocophe. Vol. 21, International Journal

[77] Rouvrais C, Bacqueville D, Bogdanowicz P, Haure MJ, Duprat L,

glucoside and glycylglycine oleamide for managing naturally aged skin: Results from in vitro to clinical studies. Clin

[78] Kim B, Cho H, Moon SH, Ahn H, Bae S, Cho H. Transdermal delivery systems in cosmetics. Biomed Dermatology. 2020;4(10):1-12.

[79] Praça FG, Viegas JSR, Peh YH,

[80] Shakeel A, Farooq U, Iqbal T, Yasin S, Lupi FR, Gabriele D. Key characteristics and modelling of bigels systems: A review. Mater Sci Eng C. 2019;97(December 2018):932-953.

[81] Martinez RM, Magalhães WV, Sufi BS, Padovani G, Nazato LIS, Robles MV, et al. Vitamin E-loaded bigels and emulsions : Physicochemical characterization and potential biological

application. Colloids Surfaces B Biointerfaces. 2021;201(111651).

abs/pii/089158499290166E

[83] Brigelius-Flohé R, Kelly FJ,

Salonen JT, Neuzil J, Zingg J-M, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr. 2002;76(4):703-716.

[82] Kappus H, Diplock AT. Tolerance and safety of vitamin e: a toxicological position report [Internet]. Vol. 13, Free Radical Biology & Medicine. 1992 [cited 2021 Apr 19]. Available from: https:// www.sciencedirect.com/science/article/

Garbin TN, Medina WSG, Bentley MVLB. Microemulsion co-delivering vitamin A and vitamin E as a new platform for topical treatment of acute skin inflammation. Mater Sci Eng C [Internet]. 2020;110(August 2019):110639. Available from: https:// doi.org/10.1016/j.msec.2020.110639

Coutanceau C, et al. A new dermocosmetic containing retinaldehyde, delta-tocopherol

Cosmet Investig Dermatol.

2017;10:35-42.

**24**

[94] Greul A-K, Grundmann J-U, Heinrich F, Pfitzner I, Bernhardt J, Ambach A, et al. Skin Skin Pharmacology andApplied Physiology Skin Pharmacology andApplied Skin Physiology Photoprotection of UV-Irradiated Human Skin: An Antioxidative Combination of Vitamins E and C, Carotenoids, Selenium and Proanthocyanidins [Internet]. Vol. 15, Skin Pharmacol Appl Skin Physiol. 2002. Available from: www.karger.com/ journals/sph

[95] Ibrahim N 'Izzah, Wong SK, Mohamed IN, Mohamed N, Chin KY, Ima-Nirwana S, et al. Wound healing properties of selected natural products. Vol. 15, International Journal of Environmental Research and Public Health. MDPI AG; 2018. p. 1-23.

[96] Thyssen JP, Johansen JD, Zachariae C, Menné T, Linneberg A. Xerosis is associated with atopic dermatitis, hand eczema and contact sensitization independent of filaggrin gene mutations. Acta Derm Venereol. 2013;93(4):406-410.

[97] Vaz S, Silva R, Amaral MH, Martins E, Sousa Lobo JM, Silva AC. Evaluation of the biocompatibility and skin hydration potential of vitamin E-loaded lipid nanosystems formulations: In vitro and human in vivo studies. Colloids Surfaces B Biointerfaces [Internet]. 2019;179(November 2018):242-9. Available from: https://doi.org/10.1016/j. colsurfb.2019.03.036

[98] Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and

chronological skin aging. Arch Dermatol. 2002;138(11):1462-1470.

[99] Makrantonaki E, Zouboulis CC. Characteristics and pathomechanisms of endogenously aged skin. Dermatology. 2007;214(4):352-360.

[100] Rhie GE, Mi HS, Jin YS, Won WC, Kwang HC, Kyu HK, et al. Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J Invest Dermatol [Internet]. 2001;117(5):1212-1217. Available from: http://dx.doi. org/10.1046/j.0022-202x.2001. 01469.x

[101] Lavker RM. Structural alterations in exposed and unexposed aged skin. Vol. 73, The Journal of Investigative Dermatology. 1979. p. 59-66.

[102] Yaar M, Gilchrest BA. Skin aging: Postulated mechanisms and consequent changes in structure and function. Clin Geriatr Med. 2001;17(4):617-630.

[103] Nada A, Zaghloul A, Hedaya M, Khattab I. Stability of vitamin E and vitamin E acetate containing cosmetic preparations. J Glob Pharma Technol. 2012;4(03):1-8.

[104] Gönüllü Ü, Sensoy D, Üner M, Yener G, Altinkurt T. Comparing the moisturizing effects of ascorbic acid and calcium ascorbate against that of tocopherol in emulsions. J Cosmet Sci. 2006;57(6):465-473.

[105] Vaule H, Leonard SW, Traber MG. Vitamin E delivery to human skin: Studies using deuterated α-tocopherol measured by apci LC-MC. Free Radic Biol Med. 2004 Feb 15;36(4):456-463.

[106] Usedom E, Neidig L, Allen HB. Psoriasis and Fat-soluble Vitamins: A Review. J Clin Exp Dermatol Res. 2017;08(05):1-6.

[107] Parlapally S, Cherukupalli N, Bhumireddy SR, Sripadi P, Anisetti R, Giri CC, et al. Chemical profiling and anti-psoriatic activity of methanolic extract of Andrographis nallamalayana J.L.Ellis. Nat Prod Res. 2016;30(11): 1256-1261.

[108] Aparicio-Soto M, Sánchez-Hidalgo M, Cárdeno A, Rosillo MÁ, Sánchez-Fidalgo S, Utrilla J, et al. Dietary extra virgin olive oil attenuates kidney injury in pristane-induced SLE model via activation of HO-1/Nrf-2 antioxidant pathway and suppression of JAK/STAT, NF-κB and MAPK activation. J Nutr Biochem. 2016;27:278-288.

[109] Sýs M, Švecová B, Švancara I, Metelka R. Determination of vitamin E in margarines and edible oils using square wave anodic stripping voltammetry with a glassy carbon paste electrode. Food Chem. 2017;229:621-627.

[110] Marra F, Ostacolo C, Laneri S, Bernardi A, Sacchi A, Padula C, et al. Synthesis, hydrolysis, and skin retention of amino acid esters of α-tocopherol. J Pharm Sci. 2009;98(7):2364-2376.

[111] Kamal MA, Raghunathan VA. Modulated phases of phospholipid bilayers induced by tocopherols. Biochim Biophys Acta - Biomembr [Internet]. 2012;1818(11):2486-2493. Available from: http://dx.doi. org/10.1016/j.bbamem.2012.06.016

[112] Zappe K, Pointner A, Switzeny OJ, Magnet U, Tomeva E, Heller J, et al. Counteraction of oxidative stress by Vitamin E affects epigenetic regulation by increasing global methylation and gene expression of MLH1 and DNMT1 dose dependently in Caco-2 cells. Oxid Med Cell Longev. 2018;2018.

[113] Mazurek S, Pichlak K, Szostak R. Quantitative determination of vitamins a and e in ointments using raman spectroscopy. Processes. 2021;9(1):1-9.

[114] Pullar JM, Carr AC, Vissers MCM. The roles of vitamin C in skin health. Nutrients. 2017;9(866):1-27.

**27**

**Chapter 2**

**Abstract**

**1. Introduction**

Vitamin E TPGS

Pharmaceutical Applications of

D-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) has been approved as a safe pharmaceutical adjuvant by FDA, and several drug delivery systems (DDS) based on TPGS have been developed. TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, vaccine system adjuvant, nutritional supplement, film plasticizer, anticancer reagent, and so on, are discussed in this review. Consequenly, TPGS can inhibit ATP-dependent P-glycoprotein activity and act as a potent excipient that promotes the efficiency of delivery and the therapeutic effect of drugs. Inhibition of P-gp occurs through mitochondria-dependent inhibition of the P-gp pump. Many of the latest studies address the use of TPGS for many poorly water-soluble or permeable drugs in the manufacture of nanodrugs or other formulations. In addition, it has been reported that TPGS shows a robust improvement in chylomicron secretion at low concentrations and improves intestinal lymphatic transport, which would also boost the potential of drug absorption. It also indicates that there are still many problems facing clinical translation of TPGS-based nanomedicines, requiring a more deep evaluation of TPGS properties and a future-based delivery method.

**Keywords:** TPGS, Bioavailability, Cancer cell, Prodrugs, Malaria and Osteoartharitis

An alternative to PEG, D-alpha-tocopheryl polyethylene glycol 1000 succinate

(TPGS), is an amphiphilic macromolecule, a water-soluble natural vitamin E derivative. It is a powerful nanotechnological emulsifier for biomedical applications. TPGS co-administration can enhance solubility, cellular internalization, inhibit the multi-drug efflux transport mechanism mediated by P-glycoprotein, which increase the oral bioavailability of different anticancer drugsVitamin E TPGS is a water-soluble derivative of natural vitamin E derived from vitamin E succinate esterification with polyethylene glycol (PEG) 1000 [1]. Because of its superior water solubility and biocompatibility, PEG is the most widely applied hydrophilic segment. In order for the molecular weight to be higher than the hydrophobic core, the micellar shell is usually chosen to shape the molecule. In micelles, these findings have critical micellar concentrations in the micromolar range, and are often smaller than 100 nm. Vitamin E TPGS is a nonionic surfactant with a molecular weight rate of 1513 g.mol-1 and a lipophilic alkyl tail and hydrophilic polar head amphiphilic frame that is fully soluble in water. It is constant, range of pH 4.6–7.6 less than 12 percent break down when kept for three months in neutral aqueous buffer. The

*Adnan Mansour Jasim and Mohammed Jasim Jawad*

#### **Chapter 2**

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

[114] Pullar JM, Carr AC, Vissers MCM. The roles of vitamin C in skin health.

Nutrients. 2017;9(866):1-27.

[107] Parlapally S, Cherukupalli N, Bhumireddy SR, Sripadi P, Anisetti R, Giri CC, et al. Chemical profiling and anti-psoriatic activity of methanolic extract of Andrographis nallamalayana J.L.Ellis. Nat Prod Res. 2016;30(11):

[108] Aparicio-Soto M, Sánchez-Hidalgo M, Cárdeno A, Rosillo MÁ, Sánchez-Fidalgo S, Utrilla J, et al. Dietary extra virgin olive oil attenuates kidney injury in pristane-induced SLE model via activation of HO-1/Nrf-2 antioxidant pathway and suppression of

JAK/STAT, NF-κB and MAPK activation. J Nutr Biochem.

[109] Sýs M, Švecová B, Švancara I, Metelka R. Determination of vitamin E in margarines and edible oils using square wave anodic stripping

voltammetry with a glassy carbon paste electrode. Food Chem. 2017;229:621-627.

[110] Marra F, Ostacolo C, Laneri S, Bernardi A, Sacchi A, Padula C, et al. Synthesis, hydrolysis, and skin retention of amino acid esters of α-tocopherol. J Pharm Sci. 2009;98(7):2364-2376.

[111] Kamal MA, Raghunathan VA. Modulated phases of phospholipid bilayers induced by tocopherols. Biochim Biophys Acta - Biomembr [Internet]. 2012;1818(11):2486-2493.

[112] Zappe K, Pointner A, Switzeny OJ, Magnet U, Tomeva E, Heller J, et al. Counteraction of oxidative stress by Vitamin E affects epigenetic regulation by increasing global methylation and gene expression of MLH1 and DNMT1 dose dependently in Caco-2 cells. Oxid

[113] Mazurek S, Pichlak K, Szostak R. Quantitative determination of vitamins a and e in ointments using raman spectroscopy. Processes. 2021;9(1):1-9.

Available from: http://dx.doi. org/10.1016/j.bbamem.2012.06.016

Med Cell Longev. 2018;2018.

2016;27:278-288.

1256-1261.

**26**

## Pharmaceutical Applications of Vitamin E TPGS

*Adnan Mansour Jasim and Mohammed Jasim Jawad*

#### **Abstract**

D-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) has been approved as a safe pharmaceutical adjuvant by FDA, and several drug delivery systems (DDS) based on TPGS have been developed. TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, vaccine system adjuvant, nutritional supplement, film plasticizer, anticancer reagent, and so on, are discussed in this review. Consequenly, TPGS can inhibit ATP-dependent P-glycoprotein activity and act as a potent excipient that promotes the efficiency of delivery and the therapeutic effect of drugs. Inhibition of P-gp occurs through mitochondria-dependent inhibition of the P-gp pump. Many of the latest studies address the use of TPGS for many poorly water-soluble or permeable drugs in the manufacture of nanodrugs or other formulations. In addition, it has been reported that TPGS shows a robust improvement in chylomicron secretion at low concentrations and improves intestinal lymphatic transport, which would also boost the potential of drug absorption. It also indicates that there are still many problems facing clinical translation of TPGS-based nanomedicines, requiring a more deep evaluation of TPGS properties and a future-based delivery method.

**Keywords:** TPGS, Bioavailability, Cancer cell, Prodrugs, Malaria and Osteoartharitis

#### **1. Introduction**

An alternative to PEG, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), is an amphiphilic macromolecule, a water-soluble natural vitamin E derivative. It is a powerful nanotechnological emulsifier for biomedical applications. TPGS co-administration can enhance solubility, cellular internalization, inhibit the multi-drug efflux transport mechanism mediated by P-glycoprotein, which increase the oral bioavailability of different anticancer drugsVitamin E TPGS is a water-soluble derivative of natural vitamin E derived from vitamin E succinate esterification with polyethylene glycol (PEG) 1000 [1]. Because of its superior water solubility and biocompatibility, PEG is the most widely applied hydrophilic segment. In order for the molecular weight to be higher than the hydrophobic core, the micellar shell is usually chosen to shape the molecule. In micelles, these findings have critical micellar concentrations in the micromolar range, and are often smaller than 100 nm. Vitamin E TPGS is a nonionic surfactant with a molecular weight rate of 1513 g.mol-1 and a lipophilic alkyl tail and hydrophilic polar head amphiphilic frame that is fully soluble in water. It is constant, range of pH 4.6–7.6 less than 12 percent break down when kept for three months in neutral aqueous buffer. The

Vitamin E TPGS safety has been notify at the oral LD50 is >7 000 mg/kg for adult male rats [2, 3]. In addition, a variety of compounds such as cyclosporines, taxans, hormones and antibiotics, both water-soluble and water-insoluble, can be solubilized by vitamin E TPGS [3]. Vitamin E TPGS could act as a P-gp inhibitor. It has the ability to inhibit the action of P-gp, stronger than other non-ionic surfactants such as Tween 80, Pluronics and Cremophor. It has been used in various formulations/ applications, such as producing nano suspensions [4], self-microemulsifying [3], nutrition supplement formulates nanoparticles, dependent prodrug, and strong dispersion/tablet, vaccine system adjuvant [5–8].

Vitamin E TPGS is widely used, with several functions, such as: hydrophobic drug vehicle, to amelorate ocular permeability and provide ocular retention. TPGS is used as a vitamin E accessory or to treat vitamin E insufficiency in people who are unable to consume lipids due to specific illness [9]. Tocofersolan oral solution has been confirmed by the European Medicines Agency in the treatment of vitamin E deficiency due to digestive malabsorption in pediatric patients, inborn misery or hereditary chronic cholestasis [10]. Tocofersolan is also used as an antioxidant and anti-inflammatory in cosmetics and pharmaceutical products. In different parts of health, especially in neuroprotection, dermal, cardiovascular, and bone health, these crucial benefits of vitamin E are valuable. In nanoformulations involving solid-lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, and polymeric nanoparticles, several TPGS formalizations have recently shown favorable results in improving the efficacy and bioavailability of many drugs [11]. Vitamin E has a prospective ban on metabolic syndrome and cardiovascular diseases (CVDs) [12]. These influences are mediated via inhibition of the HMG-CoA reductase enzyme thus antioxidant, anti-inflammatory activity, and block expression of adhesion molecules. Diabetic rat studies have confirmed that supplementation with TPGS decreases fasting blood glucose, oxidative stress and strengthens the integrity of vascular walls that help to resolve atherosclerotic lesions [13, 14]. Additionally, in dermatology, vitamin E is often used as a protective antioxidant and ultraviolet (UV) radiation that suits photoprotection and retards skin aging through its ability to improve collagen synthesis and avoid collagen dissolution [15, 16]. In addition to adding, TPGS has beneficial anti-cancer properties, such as preventing cancer cell proliferation, prohibiting angiogenesis, altering growth factors, encouraging cell cycle arrest, and inducing apoptosis [17]. The physicochemical and biological properties of TPGS relevant to drug delivery applications are generally described in **Figure 1** as well as, the role of TPGS in enhancing the bioavailability and targetability of anticancer drugs has been highlighted in this review.

**29**

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

**1.1 Vitamin E TPGS, an amphiphilic polymer**

*15. Micelles, 16. Liposomes, 17. Based prodrug [20].*

improvement, and selective antitumor activity [18].

**1.2 Structure and properties**

**Figure 2.**

to inhibit P-gp activity [21].

**2. Absorption/bioavailability enhancer**

E TPGS is a water-miscible form of vitamin E, which approved by the FDA and commonly used in drug delivery systems as a safe adjuvant. TPGS's biological and physicochemical properties provide several advantages for its drug delivery applications such as high biocompatibility, drug solubility enhancement, drug permeation

*Chemical structure of vitamin E TPGS. The lipophile to hydrophile equilibrium of the TPGS is an unique amphiphilic structure. Consequently, it is a waxy solid with an air-stable melting point of about 41° C, ranging from yellow to light brown in color. In nature, it is bulky and has a broader surface area, so it is considered the ideal emulsifier and strong solubilizer [19]. The chemical structure of TPGS used in many formulations/ applications shown in Figure 2, such as: 1. Improving drug bioavailability, 2. Properties of surfactants which improve the solubilization of drugs poorly water soluble, 3. Stabilizer of amorphous drug forms 4. Inhibiting the efflux of P-glycoprotein which improves drug permeability, 5. Emulsion vehicle, 6. The active ingredient in self-emulsifying formulations, 7. Minimize drug damage to dermal tissues, 8. Carrier for wound care and therapy, 9. Vitamin E water-soluble source, 10. Fabrication nanosuspensions, 11. Self-microemulsifying and solid tablet/dispersion 12. Vaccine device Adjuvant, 13. Boost of nutrition, 14. Nano-particles formulation,* 

Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate or TPGS) is a water-soluble derivative of natural vitamin E, formed together with polyethylene glycol 1000 by esterification of d-alpha-tocopheryl polyethylene glycol succinate. Furthermore, TPGS is a macromolecule consisting of a lipophilic alkyl tail and a hydrophilic polar head which has amphiphilic properties (see **Figure 2**). Vitamin E TPGS is an active solubilizer of various compounds that are watersoluble and insoluble in water, such as steroids, antibiotics, cyclosporins, taxanes, etc. [21]. TPGS vitamin E could function as a P-gp inhibitor with a higher capacity than other non-ionic surfactants, such as Tween 80, Pluronics and Cremophor EL,

Several studies indicated that the increased bioavailability was due to micelle formation improving solubility, while others showed that P-glycoprotein (P-gp) inhibition contributes to increased permeability support [22, 23]. Although several instances of TPGS use are poorly water-soluble drugs, there are also examples of the use of TPGS with water-soluble poorly permeable drugs. Many studies have been done to evaluate the mechanism by which TPGS improve bioavailability, many of these suggestions to micelle formation and through enhancing permeability across cell membranes by inhibition of multidrug efflux pump P-with regard to oral

**Figure 1.**

*Various pharmacological properties of vitamin E.*

#### **Figure 2.**

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

dispersion/tablet, vaccine system adjuvant [5–8].

Vitamin E TPGS safety has been notify at the oral LD50 is >7 000 mg/kg for adult male rats [2, 3]. In addition, a variety of compounds such as cyclosporines, taxans, hormones and antibiotics, both water-soluble and water-insoluble, can be solubilized by vitamin E TPGS [3]. Vitamin E TPGS could act as a P-gp inhibitor. It has the ability to inhibit the action of P-gp, stronger than other non-ionic surfactants such as Tween 80, Pluronics and Cremophor. It has been used in various formulations/ applications, such as producing nano suspensions [4], self-microemulsifying [3], nutrition supplement formulates nanoparticles, dependent prodrug, and strong

Vitamin E TPGS is widely used, with several functions, such as: hydrophobic drug vehicle, to amelorate ocular permeability and provide ocular retention. TPGS is used as a vitamin E accessory or to treat vitamin E insufficiency in people who are unable to consume lipids due to specific illness [9]. Tocofersolan oral solution has been confirmed by the European Medicines Agency in the treatment of vitamin E deficiency due to digestive malabsorption in pediatric patients, inborn misery or hereditary chronic cholestasis [10]. Tocofersolan is also used as an antioxidant and anti-inflammatory in cosmetics and pharmaceutical products. In different parts of health, especially in neuroprotection, dermal, cardiovascular, and bone health, these crucial benefits of vitamin E are valuable. In nanoformulations involving solid-lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, and polymeric nanoparticles, several TPGS formalizations have recently shown favorable results in improving the efficacy and bioavailability of many drugs [11]. Vitamin E has a prospective ban on metabolic syndrome and cardiovascular diseases (CVDs) [12]. These influences are mediated via inhibition of the HMG-CoA reductase enzyme thus antioxidant, anti-inflammatory activity, and block expression of adhesion molecules. Diabetic rat studies have confirmed that supplementation with TPGS decreases fasting blood glucose, oxidative stress and strengthens the integrity of vascular walls that help to resolve atherosclerotic lesions [13, 14]. Additionally, in dermatology, vitamin E is often used as a protective antioxidant and ultraviolet (UV) radiation that suits photoprotection and retards skin aging through its ability to improve collagen synthesis and avoid collagen dissolution [15, 16]. In addition to adding, TPGS has beneficial anti-cancer properties, such as preventing cancer cell proliferation, prohibiting angiogenesis, altering growth factors, encouraging cell cycle arrest, and inducing apoptosis [17]. The physicochemical and biological properties of TPGS relevant to drug delivery applications are generally described in **Figure 1** as well as, the role of TPGS in enhancing the bioavailability and targetability of anticancer drugs has been

**28**

**Figure 1.**

highlighted in this review.

*Various pharmacological properties of vitamin E.*

*Chemical structure of vitamin E TPGS. The lipophile to hydrophile equilibrium of the TPGS is an unique amphiphilic structure. Consequently, it is a waxy solid with an air-stable melting point of about 41° C, ranging from yellow to light brown in color. In nature, it is bulky and has a broader surface area, so it is considered the ideal emulsifier and strong solubilizer [19]. The chemical structure of TPGS used in many formulations/ applications shown in Figure 2, such as: 1. Improving drug bioavailability, 2. Properties of surfactants which improve the solubilization of drugs poorly water soluble, 3. Stabilizer of amorphous drug forms 4. Inhibiting the efflux of P-glycoprotein which improves drug permeability, 5. Emulsion vehicle, 6. The active ingredient in self-emulsifying formulations, 7. Minimize drug damage to dermal tissues, 8. Carrier for wound care and therapy, 9. Vitamin E water-soluble source, 10. Fabrication nanosuspensions, 11. Self-microemulsifying and solid tablet/dispersion 12. Vaccine device Adjuvant, 13. Boost of nutrition, 14. Nano-particles formulation, 15. Micelles, 16. Liposomes, 17. Based prodrug [20].*

#### **1.1 Vitamin E TPGS, an amphiphilic polymer**

E TPGS is a water-miscible form of vitamin E, which approved by the FDA and commonly used in drug delivery systems as a safe adjuvant. TPGS's biological and physicochemical properties provide several advantages for its drug delivery applications such as high biocompatibility, drug solubility enhancement, drug permeation improvement, and selective antitumor activity [18].

#### **1.2 Structure and properties**

Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate or TPGS) is a water-soluble derivative of natural vitamin E, formed together with polyethylene glycol 1000 by esterification of d-alpha-tocopheryl polyethylene glycol succinate. Furthermore, TPGS is a macromolecule consisting of a lipophilic alkyl tail and a hydrophilic polar head which has amphiphilic properties (see **Figure 2**).

Vitamin E TPGS is an active solubilizer of various compounds that are watersoluble and insoluble in water, such as steroids, antibiotics, cyclosporins, taxanes, etc. [21]. TPGS vitamin E could function as a P-gp inhibitor with a higher capacity than other non-ionic surfactants, such as Tween 80, Pluronics and Cremophor EL, to inhibit P-gp activity [21].

#### **2. Absorption/bioavailability enhancer**

Several studies indicated that the increased bioavailability was due to micelle formation improving solubility, while others showed that P-glycoprotein (P-gp) inhibition contributes to increased permeability support [22, 23]. Although several instances of TPGS use are poorly water-soluble drugs, there are also examples of the use of TPGS with water-soluble poorly permeable drugs. Many studies have been done to evaluate the mechanism by which TPGS improve bioavailability, many of these suggestions to micelle formation and through enhancing permeability across cell membranes by inhibition of multidrug efflux pump P-with regard to oral

deliveryBy beneficially emulsifying and solubilizing the medication in the finished dosage type and by considering a self-emulsifying drug delivery mechanism in the stomach that may be due to TPGS, TPGS increases the permeability of a drug across cell membranes by inhibiting P-glycoprotein and thus facilitates the absorption of a drug over the intestinal wall and into the cell membranes. Furthermore, TPGS is a more potent P-gp inhibitor than many associated excipients with surfactant properties, such as Pluronic P85 cremophor EL, Tween 80, and PEG 300, **Figure 3**. Yu *et al* [24] The solubility of amprenavir was amended in the existence of vitamin E-TPGS out of micelle solubilization. Vitamin E-TPGS prevent the efflux system and boost the permeability of amprenavir [24]. Chiefly, vitamin E-TPGS promotes the absorption flux of the drug by increasing its solubility and permeability.

#### **2.1 TPGS properties in drug delivery systems**

The water-miscible type of vitamin E, TPGS, consists of a hydrophilic chain of PEG connected to the hydrophobic portion of vitamin E. According to a particular amphiphilic structure, it shows wonderful drug delivery capability. Further research has shown that TPGS has great potential for P-gp inhibition and selective anticancer outcomes to resolve MDR tumors [25]. TPGS can be readily conjugated with polymers or therapeutic agents to form TPGS based polymers **Figure 4**. It is possible to further self-assemble the resulting composition into nanoparticles, in order to form nanoformulations, unmodified TPGS can also participate with other active compounds. After cell internalization, in response to the unique intracellular environment (e.g. pH, GSH and ROS), the nanoparticles can be degraded to release the therapeutic agents and TPGS [26]. The drugs can be easily pumped out into the extracellular environment without P-gp inhibition [27]. Dissociated TPGS can bind to mitochondrial respiratory complex II and cause mitochondrial dysfunction, resulting in decreased potential for mitochondrial membranes and increased generation of ROS cell apoptosis with decreased activation a level of P-gp ATP [18]. Besides, to further resolve MDR, TPGS can also inhibit the substrate-induced activity of ATPase. The intracellular concentration of therapeutic drugs can be greatly improved with P-gp inhibition. Meanwhile to enhance cell apoptosis, TPGS can inhibit Bcl-2 and Survivin (**Figure 1**) [28].

**31**

**Figure 4.**

*glycolic acid).*

**3. TPGS as a surfactant**

Poor water solubility and/or poor permeability remain the great snag for maximum activity of therapeutic drugs [3, 29, 30]. In drug delivery, TPGS can be used as a solubilizer, permeation enhancer, diffusion, and emulsifier as well as as

*Nanoprecipation methoed for preparing TPGS coated PLGA polymer nanoparticles. PLGA (Polylactic co* 

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

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

tion flux of the drug by increasing its solubility and permeability.

**2.1 TPGS properties in drug delivery systems**

deliveryBy beneficially emulsifying and solubilizing the medication in the finished dosage type and by considering a self-emulsifying drug delivery mechanism in the stomach that may be due to TPGS, TPGS increases the permeability of a drug across cell membranes by inhibiting P-glycoprotein and thus facilitates the absorption of a drug over the intestinal wall and into the cell membranes. Furthermore, TPGS is a more potent P-gp inhibitor than many associated excipients with surfactant properties, such as Pluronic P85 cremophor EL, Tween 80, and PEG 300, **Figure 3**. Yu *et al* [24] The solubility of amprenavir was amended in the existence of vitamin E-TPGS out of micelle solubilization. Vitamin E-TPGS prevent the efflux system and boost the permeability of amprenavir [24]. Chiefly, vitamin E-TPGS promotes the absorp-

The water-miscible type of vitamin E, TPGS, consists of a hydrophilic chain of PEG connected to the hydrophobic portion of vitamin E. According to a particular amphiphilic structure, it shows wonderful drug delivery capability. Further research has shown that TPGS has great potential for P-gp inhibition and selective anticancer outcomes to resolve MDR tumors [25]. TPGS can be readily conjugated with polymers or therapeutic agents to form TPGS based polymers **Figure 4**. It is possible to further self-assemble the resulting composition into nanoparticles, in order to form nanoformulations, unmodified TPGS can also participate with other active compounds. After cell internalization, in response to the unique intracellular environment (e.g. pH, GSH and ROS), the nanoparticles can be degraded to release the therapeutic agents and TPGS [26]. The drugs can be easily pumped out into the extracellular environment without P-gp inhibition [27]. Dissociated TPGS can bind to mitochondrial respiratory complex II and cause mitochondrial dysfunction, resulting in decreased potential for mitochondrial membranes and increased generation of ROS cell apoptosis with decreased activation a level of P-gp ATP [18]. Besides, to further resolve MDR, TPGS can also inhibit the substrate-induced activity of ATPase. The intracellular concentration of therapeutic drugs can be greatly improved with P-gp inhibition. Meanwhile to

enhance cell apoptosis, TPGS can inhibit Bcl-2 and Survivin (**Figure 1**) [28].

*The applications of vitamin E TPGS in drug delivery [20].Polyethyeleneglycol (PEG).*

**30**

**Figure 3.**

**Figure 4.**

*Nanoprecipation methoed for preparing TPGS coated PLGA polymer nanoparticles. PLGA (Polylactic co glycolic acid).*

#### **3. TPGS as a surfactant**

Poor water solubility and/or poor permeability remain the great snag for maximum activity of therapeutic drugs [3, 29, 30]. In drug delivery, TPGS can be used as a solubilizer, permeation enhancer, diffusion, and emulsifier as well as as

a surface stabilizer. It has been commonly used for many poorly water-soluble or permeable drugs in the manufacture of nanodrugs or other formulations, mainly for class II and IV Biopharmaceutical Classification System (BCS) drugs [31]. In addition, it has been clearly documented that TPGS shows a good boost in low concentration chylomicron secretion and promotes intestinal lymphatic transport [32], which would further improve the drug absorption potential. As a surfactant, TPGS shows a remarkable ability to surpass drug absorption through different biological barriers. For example, TPGS is used to generate repaglinide nanocrystals to increase the saturation solubility of the oral bioavailability reference drug from 15-to 25.7-fold [33]. In addition, TPGS can increase the penetration of drugs in colonic tissue [34]. Importantly, in the production of nanoparticles with small particle size, high drug encapsulation strength, and quick drug release, TPGS may also act as a pore-forming agent [35]. Furthermore, TPGS can be used as an emulsifier or surface stabilizer for drug formulations since the hydrophobic portion can trap hydrophobic drugs and the formulations can be stabilized by the hydrophilic portion.

#### **4. Role of TPGS to control cancer cell**

TPGS acts selectively as an anticancer TPGS by synergistic antitumor action, can induce apoptosis and demonstrate selective cytotoxic activity against in vitro cancer cells that can be combined or loaded with chemotherapeutic drugs to resolve adverse effects and potentiate therapeutic efficiency. The response of cancer cells and normal immortalized breast cells after TPGS therapy is of significant value. Via activating the apoptotic signaling pathways, TPGS can induce G1/S cell cycle arrest in breast cancer cell culture [28]. Jurkat clone E6–1 cells will induce apoptosis on T cell acute lymphocytic leukemia. Apoptosis has been demonstrated by encouraging cell cycle arrest, accelerating nuclear DNA fragmentation, and reducing the possible mitochondrial membrane after treatment with TPGS [36]. The selective processes for TPGS-mediated apoptosis cancer cells are sophisticated and can be described as follows:-

#### **4.1 α-Ractive oxygen species stimulation**

Alpha-tocopheryl succinate (alpha-TOS), through the eradication and suppression of mitochondrial respiratory complex II, would induce cancer cell apoptosis [37]. ROS formation can be activated by the subsidiary electron transfer chain defect. The increase of intracellular ROS, an apoptosis mediator, can induce protein, lipid, and enzyme oxidation and DNA damage that leads to cell destruction [38]. This mechanism is also associated with the selective activity of anticancer, as tumor cells may be more sensitive than healthy cells to ROS. Anti-apoptotic protein downregulation TPGS could inhibit the phosphorylation of protein kinase B and then downregulate Survivin, which represents anti-apoptotic proteins, and Bcl-2, which can induce caspase-3 and caspase-7 potential for programmed cell death dependent on caspase [39]. At the same time, caspase-independent programmed cell death and G1/S phase cell cycle arrest also happened. In general, TPGS also appears to be harmful to malignant cells, such as lung adenocarcinoma and breast cancer, through mitochondria-associated apoptosis and ROS [40], generation [41]. Recently reported that TPGS induces OS apoptosis in acute lymphoblastic leukemia involving a cell death signaling pathway. However, no information is ready to limit whether TPGS might eliminate Neuroblastoma tumor cells [42].

**33**

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

TPGS-DOX DOX Resistant

TPGS-DOX DOX Glioma, Breast

TPGS-PTX PTX Reluctant

TPGS-cisplatin Cisplatin,

TPGSmitoxantrone

TPGSgemcitabine

TPGScantharidin

**Table 1.**

DTX, Herceptn

TPGS can induce both caspase-dependent caspase and -independent DNA damage [43]. The ability of vitamin E to trigger caspase-independent programmed cell death could indeed be effective in prostate cancer chemotherapy as it can block tumor resistance usually associated with the use of classical chemotherapeutic

**Prodrug Payload Tumor oodel Application Dose References**

95-fold lower IC50 in MCF-7/ADR vs. free drug, MCF-7/ ADR, B16F10, H22 tumor growth/metastasis inhibition

High cellular uptake and cytotoxicity

PTX accumulation in A2780/T, cytotoxicity against A2780 and A2780/T, S180 tumor inhibition

and cytotoxicity, significant neuroprotective effects

cytotoxicity against SK-BR-3 cells with overexpression of

P-gp, β-tubulin, and p53 protein extracted from KB-8-5 cells, tumor growth inhibition in KB-3-1 and KB-8-5 tumor model

Cell cytotoxicity against MCF7 and MCF7/ADR cells

Improved cytotoxicity against pancreatic cancer BxPC-3

HER2

Dox-TPGS-LPs at concentrations equivalent to 5 μg/ml Dox

5.86 μg mL − 1 of DOX

Dox-TPGS-LPs at concentrations equivalent to 5 μg/ml Dox

At dose 25, 2.5, 0.25, 0.025 g/ mL of cisplatin

Dose at concentrations of 0.5, 0.05 and 0.005 μg/mL

PTX at dose 5 mg/kg)

25 mg/kg [49]

At

concentration 15.6 mg /ml

[47]

[48]

[47]

[49]

[50]

[51]

[52, 53]

drugs that trigger programmed cell death dependent on caspase [44].

breast cancer, hepatoma melanoma,

cancer

TPGS-cisplatin Cisplatin Hepatoma High cell uptake

5-FU, PTX Resistant

Mitoxantrone Resistant

Gemcitabine Pancreatic

epidermal carcinoma

breast cancer

*Doxorubicin (DOX), Paclitaxel (PTX), docetaxel (DTX), 5-fluorouracil (5-FU), lipopolysaccharide (LPS).*

*The P-gp inhibition effect of MDR in the drug delivery system is mainly discussed in this section.*

cancer

ovarian cancer, hepatoma

Breast cancer Enhanced

**4.2 DNA damage**

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

#### **4.2 DNA damage**

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

a surface stabilizer. It has been commonly used for many poorly water-soluble or permeable drugs in the manufacture of nanodrugs or other formulations, mainly for class II and IV Biopharmaceutical Classification System (BCS) drugs [31]. In addition, it has been clearly documented that TPGS shows a good boost in low concentration chylomicron secretion and promotes intestinal lymphatic transport [32], which would further improve the drug absorption potential. As a surfactant, TPGS shows a remarkable ability to surpass drug absorption through different biological barriers. For example, TPGS is used to generate repaglinide nanocrystals to increase the saturation solubility of the oral bioavailability reference drug from 15-to 25.7-fold [33]. In addition, TPGS can increase the penetration of drugs in colonic tissue [34]. Importantly, in the production of nanoparticles with small particle size, high drug encapsulation strength, and quick drug release, TPGS may also act as a pore-forming agent [35]. Furthermore, TPGS can be used as an emulsifier or surface stabilizer for drug formulations since the hydrophobic portion can trap hydrophobic drugs and the formulations can be stabilized by the hydrophilic

TPGS acts selectively as an anticancer TPGS by synergistic antitumor action, can induce apoptosis and demonstrate selective cytotoxic activity against in vitro cancer cells that can be combined or loaded with chemotherapeutic drugs to resolve adverse effects and potentiate therapeutic efficiency. The response of cancer cells and normal immortalized breast cells after TPGS therapy is of significant value. Via activating the apoptotic signaling pathways, TPGS can induce G1/S cell cycle arrest in breast cancer cell culture [28]. Jurkat clone E6–1 cells will induce apoptosis on T cell acute lymphocytic leukemia. Apoptosis has been demonstrated by encouraging cell cycle arrest, accelerating nuclear DNA fragmentation, and reducing the possible mitochondrial membrane after treatment with TPGS [36]. The selective processes for TPGS-mediated apoptosis cancer cells are sophisticated and can be

Alpha-tocopheryl succinate (alpha-TOS), through the eradication and suppression of mitochondrial respiratory complex II, would induce cancer cell apoptosis [37]. ROS formation can be activated by the subsidiary electron transfer chain defect. The increase of intracellular ROS, an apoptosis mediator, can induce protein, lipid, and enzyme oxidation and DNA damage that leads to cell destruction [38]. This mechanism is also associated with the selective activity of anticancer, as tumor cells may be more sensitive than healthy cells to ROS. Anti-apoptotic protein downregulation TPGS could inhibit the phosphorylation of protein kinase B and then downregulate Survivin, which represents anti-apoptotic proteins, and Bcl-2, which can induce caspase-3 and caspase-7 potential for programmed cell death dependent on caspase [39]. At the same time, caspase-independent programmed cell death and G1/S phase cell cycle arrest also happened. In general, TPGS also appears to be harmful to malignant cells, such as lung adenocarcinoma and breast cancer, through mitochondria-associated apoptosis and ROS [40], generation [41]. Recently reported that TPGS induces OS apoptosis in acute lymphoblastic leukemia involving a cell death signaling pathway. However, no information is ready to limit

whether TPGS might eliminate Neuroblastoma tumor cells [42].

**32**

portion.

described as follows:-

**4. Role of TPGS to control cancer cell**

**4.1 α-Ractive oxygen species stimulation**

TPGS can induce both caspase-dependent caspase and -independent DNA damage [43]. The ability of vitamin E to trigger caspase-independent programmed cell death could indeed be effective in prostate cancer chemotherapy as it can block tumor resistance usually associated with the use of classical chemotherapeutic drugs that trigger programmed cell death dependent on caspase [44].


#### **Table 1.**

*The P-gp inhibition effect of MDR in the drug delivery system is mainly discussed in this section.*

#### **4.3 TPGS based prodrugs**

A prodrug is a drug class with minimal to no therapeutic activity and can be submitted to a set of in vivo metabolism to generate parental drugs [45]. It is designed to improve the concentration of pharmacokinetic (PK), pharmaceutical and pharmacodynamic (PD) products, such as boosting drug solubility, safety, bioavailability, permeability, efficiency of treatment and reducing adverse effects. The prodrug can be classified purely into prodrug and precursor prodrug carrier-setup. The carrier-based prodrug, which is synthesized by a temporal connector merely conjugating polymer with the drug, can easily collect itself into nanoformulation as well as provide great potential for clinical recruitment [46]. The data summerized in **Table 1** explain the role of TPGS and prodrug payload on several types of tumor model with their application.

Over one natural system, stimulus-responsive prodrugs based on TPGS can be prepared to recognize optimum cancer therapy [54].

#### **5. Effect of TPGS on malaria**

Malaria is one of the main worldwide infectious diseases. In 2015 only, 212 million cases of malaria and 430,000 malaria deaths were reported [55]. *Plasmodium falciparum* and *P. vivax* respect the majority of the etiology of malaria and the vast majority of deaths are due to *P. falciparum* malaria [56]. *P. falciparum* infections are most likely to develop into severe symptoms such as intense anemia, difficult respiration and cerebral malaria (CM) among human-adapted Plasmodium spp. infections [57]. Several studies show that alpha-TOS inhibits the mitochondrial complex II in ROS generation, which induces selective apoptosis in several types of malignant cells, although it is mainly non-toxic to healthy cells [44, 58]. In addition, cells that lack the potency of the mitochondrial respiratory chain are resistant to alpha-TOS toxicity. Nevertheless the mechanism for alpha-TOS to remain obscure is selectively effective on cancer cells. The effect of plasmodium parasites that are highly susceptible to oxidative stress is doubtful for alpha-TOS. Alpha-Tocopheryl succinate-inhibits the development of cerebral malaria in mice [59].

TPGS is a suitable candidate for safe new anti-malarial drug, This research has shown that TPGS therapy of malaria, survival rates in mice infected with two parasites have been significantly elevated. Similarly, the severity of Evans blue staining on the brains taken from mice treated with TPGS was lower than the remedy not received by mice. This indicates that TPGS should prohibit the collapse of the BBB and the development of cerebral malaria. These data suggest that the potential candidate for malaria treatment drugs could be vitamin E-TPGS. Higher levels have been found after TPGS administration particularly in mitochondria, plasma membranes, and hepatocyte nuclei [60]. The majority of alpha-TOS in hepatocytes that can hydrolyze the esterified forms of vitamin E which may sooner or later hydrolyzed into alptocopherol [61]. In addition, the amount of alpha-tocopherol is comparatively lower in erythrocytes than in other organs such as the liver, kidney, or heart. Although the amount of TPGS is 10 times greater in well-vascularized normal organs such as the liver and kidney than that found in tumors, Alpha-TOS damages tumor cells but not normal cells, indicating that selective anti-tumor activity of alpha-TOS is not correlated with differences in levels in tissue accumulation [62]. Artemisinin and its derivatives that interact with iron to create free radicals are well known as anti-malarial drugs which reported that have growth inhibitory effects on cancer cells and non-toxicity to normal cells in both *in vitro* and *in vivo* studies. Cancer cells typically contain higher free iron levels than normal cells In the

**35**

effects [67].

model with their application.

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

**6. TPGS based polymers in drug delivery**

form of heme molecules, plasmodium parasites often contain a high amount of Fe2+ [63]. A time-dependent stimulation of mitochondrial hydrogen peroxide develop-

TPGS-based polymers are extensively used in the drug delivery system, which

can enhance the drug's encapsulation efficiency, intracellular cell uptake and therapeutic efficacy in vitro and in vivo [64]. The first synthesized PLA-TPGS drug delivery copolymer which produces significant antitumor efficiency. A set of TPGSbased polymers including poly(lactic-co-glycolic acid) (PLGA)-TPGS. [40] hyaluronic acid (HA)-TPGS, poly(beta-amino ester) (PBAE)-TPGS, polycaprolactone (PCL)-TPGS and chitosan-TPGS have obtained significant benefits and have been synthesized for medical applications [65, 66]. PLGA, a biocompatible polymer, is non-immunogenic and can be metabolized in nature to non-toxic products. PLGA is however, hydrophobic and can be quickly filtered and captured by the reticuloendothelial system in the liver. With the assistance of the TPGS, these shortages could be masterfully prevented. As a polymeric matrix for nanoparticles, the PLGA-TPGS polymer can be used to deliver therapeutic agents that can achieve high drug encapsulation performance, sustained-release action, and improved therapeutic

To enhance the pharmacological effects, PLGA-TPGS nanoparticles can be prepared to encapsulate these. Emodin, Tanshinone was loaded through qurecetinloading nanoparticles of PLGA-TPGS, resulting in improved antitumor activity for liver cancer [68, 69]. Gao et al. combined separately loaded heparin sodium and oleanolic acid with PLGA-TPGS nanoparticles indicating synergistic antitumor activity in the HCa-F liver cancer cells [70]. Star-shaped polymer-based drug carriers have lower hydrodynamic radius, minimize solution viscosity, increase drug loading content and increase drug encapsulation performance in comparison to the linear polymers of the same molar mass [71], in comparison to linear PLGA-b-TPGS copolymer-based nanoparticles, doxitaxil-loaded-PLGA-b-TPGS block copolymer nanoparticles present perfect cellular uptake efficiency and sufficient antitumor efficacy. **Table 2** showed that effect of polymers types and drugs loading on tumer

**6.1 TPGS based formulations to improve drug oral bioavailability**

Oral administration is an appealing drug delivery way owing to the simplicity, convenience, high patient compliance, perfect for chronic therapy, and minimize costs for industry and physicians [77]. In addition various inherent challenges, such as reduced permeability through the gastrointestinal tract, low water solubility, enzyme hydrolysis and first-pass elimination, which lead to lower absorption and bioavailability, continue to limit effective drug delivery [78]. P-gp and CYP3A4 substrates are the majority of Class IV biopharmaceutical classification system drugs, resulting in low permeability and existing class metabolism [79]. TPGS-based formulations have several advantages in enhancing the bioavailability of orally administered drugsIn addition, for the sake of a nonionic surfactant, TPGS can improve drug solubility. On the other hand, due to the P-gp inhibition effect, TPGS can enhance drug permeability [72]. Furthermore, the ability to boost drug stability by inhibiting CYP3A4 and CYP2C9-mediated metabolism was confirmed by TPGS [80]. TPGS has shown little inhibition effect on CYP3A activity in other studies [81], which may be linked to dosage [82]. Nanocrystals, nanosuspensions, the

ment was triggered by the adding of alpha-TOS to cultured cancer cells.

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

A prodrug is a drug class with minimal to no therapeutic activity and can be submitted to a set of in vivo metabolism to generate parental drugs [45]. It is designed to improve the concentration of pharmacokinetic (PK), pharmaceutical and pharmacodynamic (PD) products, such as boosting drug solubility, safety, bioavailability, permeability, efficiency of treatment and reducing adverse effects. The prodrug can be classified purely into prodrug and precursor prodrug carrier-setup. The carrier-based prodrug, which is synthesized by a temporal connector merely conjugating polymer with the drug, can easily collect itself into nanoformulation as well as provide great potential for clinical recruitment [46]. The data summerized in **Table 1** explain the role of TPGS and prodrug payload on several types of tumor

Over one natural system, stimulus-responsive prodrugs based on TPGS can be

Malaria is one of the main worldwide infectious diseases. In 2015 only, 212 million cases of malaria and 430,000 malaria deaths were reported [55]. *Plasmodium falciparum* and *P. vivax* respect the majority of the etiology of malaria and the vast majority of deaths are due to *P. falciparum* malaria [56]. *P. falciparum* infections are most likely to develop into severe symptoms such as intense anemia, difficult respiration and cerebral malaria (CM) among human-adapted Plasmodium spp. infections [57]. Several studies show that alpha-TOS inhibits the mitochondrial complex II in ROS generation, which induces selective apoptosis in several types of malignant cells, although it is mainly non-toxic to healthy cells [44, 58]. In addition, cells that lack the potency of the mitochondrial respiratory chain are resistant to alpha-TOS toxicity. Nevertheless the mechanism for alpha-TOS to remain obscure is selectively effective on cancer cells. The effect of plasmodium parasites that are highly susceptible to oxidative stress is doubtful for alpha-TOS. Alpha-Tocopheryl

TPGS is a suitable candidate for safe new anti-malarial drug, This research has shown that TPGS therapy of malaria, survival rates in mice infected with two parasites have been significantly elevated. Similarly, the severity of Evans blue staining on the brains taken from mice treated with TPGS was lower than the remedy not received by mice. This indicates that TPGS should prohibit the collapse of the BBB and the development of cerebral malaria. These data suggest that the potential candidate for malaria treatment drugs could be vitamin E-TPGS. Higher levels have been found after TPGS administration particularly in mitochondria, plasma membranes, and hepatocyte nuclei [60]. The majority of alpha-TOS in hepatocytes that can hydrolyze the esterified forms of vitamin E which may sooner or later hydrolyzed into alptocopherol [61]. In addition, the amount of alpha-tocopherol is comparatively lower in erythrocytes than in other organs such as the liver, kidney, or heart. Although the amount of TPGS is 10 times greater in well-vascularized normal organs such as the liver and kidney than that found in tumors, Alpha-TOS damages tumor cells but not normal cells, indicating that selective anti-tumor activity of alpha-TOS is not correlated with differences in levels in tissue accumulation [62]. Artemisinin and its derivatives that interact with iron to create free radicals are well known as anti-malarial drugs which reported that have growth inhibitory effects on cancer cells and non-toxicity to normal cells in both *in vitro* and *in vivo* studies. Cancer cells typically contain higher free iron levels than normal cells In the

succinate-inhibits the development of cerebral malaria in mice [59].

**4.3 TPGS based prodrugs**

model with their application.

**5. Effect of TPGS on malaria**

prepared to recognize optimum cancer therapy [54].

**34**

form of heme molecules, plasmodium parasites often contain a high amount of Fe2+ [63]. A time-dependent stimulation of mitochondrial hydrogen peroxide development was triggered by the adding of alpha-TOS to cultured cancer cells.

#### **6. TPGS based polymers in drug delivery**

TPGS-based polymers are extensively used in the drug delivery system, which can enhance the drug's encapsulation efficiency, intracellular cell uptake and therapeutic efficacy in vitro and in vivo [64]. The first synthesized PLA-TPGS drug delivery copolymer which produces significant antitumor efficiency. A set of TPGSbased polymers including poly(lactic-co-glycolic acid) (PLGA)-TPGS. [40] hyaluronic acid (HA)-TPGS, poly(beta-amino ester) (PBAE)-TPGS, polycaprolactone (PCL)-TPGS and chitosan-TPGS have obtained significant benefits and have been synthesized for medical applications [65, 66]. PLGA, a biocompatible polymer, is non-immunogenic and can be metabolized in nature to non-toxic products. PLGA is however, hydrophobic and can be quickly filtered and captured by the reticuloendothelial system in the liver. With the assistance of the TPGS, these shortages could be masterfully prevented. As a polymeric matrix for nanoparticles, the PLGA-TPGS polymer can be used to deliver therapeutic agents that can achieve high drug encapsulation performance, sustained-release action, and improved therapeutic effects [67].

To enhance the pharmacological effects, PLGA-TPGS nanoparticles can be prepared to encapsulate these. Emodin, Tanshinone was loaded through qurecetinloading nanoparticles of PLGA-TPGS, resulting in improved antitumor activity for liver cancer [68, 69]. Gao et al. combined separately loaded heparin sodium and oleanolic acid with PLGA-TPGS nanoparticles indicating synergistic antitumor activity in the HCa-F liver cancer cells [70]. Star-shaped polymer-based drug carriers have lower hydrodynamic radius, minimize solution viscosity, increase drug loading content and increase drug encapsulation performance in comparison to the linear polymers of the same molar mass [71], in comparison to linear PLGA-b-TPGS copolymer-based nanoparticles, doxitaxil-loaded-PLGA-b-TPGS block copolymer nanoparticles present perfect cellular uptake efficiency and sufficient antitumor efficacy. **Table 2** showed that effect of polymers types and drugs loading on tumer model with their application.

#### **6.1 TPGS based formulations to improve drug oral bioavailability**

Oral administration is an appealing drug delivery way owing to the simplicity, convenience, high patient compliance, perfect for chronic therapy, and minimize costs for industry and physicians [77]. In addition various inherent challenges, such as reduced permeability through the gastrointestinal tract, low water solubility, enzyme hydrolysis and first-pass elimination, which lead to lower absorption and bioavailability, continue to limit effective drug delivery [78]. P-gp and CYP3A4 substrates are the majority of Class IV biopharmaceutical classification system drugs, resulting in low permeability and existing class metabolism [79]. TPGS-based formulations have several advantages in enhancing the bioavailability of orally administered drugsIn addition, for the sake of a nonionic surfactant, TPGS can improve drug solubility. On the other hand, due to the P-gp inhibition effect, TPGS can enhance drug permeability [72]. Furthermore, the ability to boost drug stability by inhibiting CYP3A4 and CYP2C9-mediated metabolism was confirmed by TPGS [80]. TPGS has shown little inhibition effect on CYP3A activity in other studies [81], which may be linked to dosage [82]. Nanocrystals, nanosuspensions, the


**Table 2.**

*Inspired by the use of PLA-TPGS copolymer loading antitumer and their effects.*

self-emulsifying/micro emulsifying drug delivery mechanism (SEDDS/SMEDDS), solid dispersions/tablet, solid lipid nanoparticles (SLNs), liposomes and micelles and emulsified TPGS nanoparticles are included in the TPGS formulations.

#### **6.2 TPGS based formulations to improve drug oral bioavailability**

Oral administration is an appealing drug delivery way owing to the simplicity, convenience, high patient compliance, perfect for chronic therapy and minimize costs for industry and physicians [83, 84]. Furthermore, there are still different inherent challenges hampering the effective delivery of drugs, such as limited permeability through the gastrointestinal tract, low water solubility, hydrolysis by enzymes and first pass elimination, which lead to lower absorption and bioavailability [85]. In fact, a majority of biopharmaceutics classification system class IV drugs are substrates of P-gp and CYP3A4, result in poor permeability and extensive pre-systemic metabolism [86]. TPGS-based formulations have numerous advantages to improve bioavailability of orally administered drugs. In addition to, as TPGS has ability to increase drug solubility due to a nonionic surfactant. On the other aspect, TPGS can enhance drug permeation due to the P-gp inhibition effect. Furthermore, TPGS has been confirmed with the ability to improve drug stability by inhibiting the CYP3A4 and CYP2C9-mediated metabolism [87]. In other studies, TPGS showed little inhibition effect on CYP3A activity [88, 89], which may be related to the dosage [90]. The TPGS formulations involve nanocrystals, nanosupensions, self-emulsifying/microemulsifying drug delivery system (SEDDS/ SMEDDS), solid dispersions/tablet, solid lipid nanoparticles (SLNs), liposomes and micelles, TPGS emulsified nanoparticles and so on.

Vitamin E (TPGS) is a lipid-soluble organic compound and usually present in the cell membranes. This vitamin has robust antioxidant properties and inhibits the

**37**

**7. Osteoartharitis**

a oppsite agent for hydrogen peroxide [98].

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

seminiferous tubules.

lipid peroxidation formd by the free hydroxyl and superoxide radicals [91]. This vitamin save the cell membrane of sperm cells from damages of ROS. In vitro studies have demonstrated that the utilize of vitamin E -TPGS amilorate the availability, motility and fertilizing capacity of sperm in the egg penetration of animals. Likwise, in vivo research, supplementation of vitamin E was found to be effective in reducing the number and motility of sperms caused by reactive oxygen species (ROS) [92]. The administration of this vitamin during oral route has significant advantages influnce on the motility of sperms through the depression synthesis of malondialde-

hyde (MDA), which is known as the final part of lipid peroxidation [93].

The deficiency of vitamin E may spoil the reproductive organs like harm in the spermatogenesis, testicular dysfunction and seminiferous tubules shrinkage. The utilize of this vitamin boost the functions of testes in the form of excess in the weight ofepididymis and testes. In addition, the antioxidants properties of TPGS, endogenous, antioxidant enzymes like superoxide dismutase (SOD), and glutathione peroxidase are augmented due to the use of this vitamin [94]. This imbalance between the endogenous antioxidants and oxidative stress results in a situation of infertility in males. Antioxidants play an essential role in eliminating these free radicals. Vitamin E is one of the better antioxidants for the sweep of oxidative stress in the male reproductive system. Its use raise functions of the reproductive system and its effecacy. The lack of TPGS result in the declination of germinal epithelium and Leydig cells in

The use of selenium and vitamin E posses synergistic effects on the male reproductive system. More than 25% of males defeat to output functional sperms for effective insemination [94]. The over production of ROS is the main cause of infertility by damaging the genetic material and enzymes activities of [13]. ROS can be harmful or benefit according to their site as well as level of production [95]. The sperm have the capability to move after the transit stay in epididymis. They demand some physiological processes such as capacitation takes place during the female reproductive tract to fertilize the egg, through this physiological event the suffcint amount of ROS is produced [96]. In the ROS, superoxide is count as the most harmful agent. The male germ cells are susceptible to ROS due to a higher amount of polyunsaturated fatty acids within the cell membrane and cytoplasm [97].

Vitamin E is considered an essential portion of antioxidants in sperm [38] and acts as a substantial protection to minimize the production of reactive oxygen species [30]. Spermatozoa demand the ROS for natural functions like acrosome functions, capacitation, and incorporation of spermatozoa through the operation of fertilization [43]. But the production of an excess quantity of ROS leads to lipid peroxidation in the membrane of sperm [43, 44]. Vitamin E prevents the production of ROS in the sperm membrane during the various motility processes due to lipid-soluble [43]. In addition to scavenging of ROS, this vitamin has the capacity to conserve the primary reproductive organs and accessory reproductive organs in males. Feeding of vitamin E sbsquent metabolism and absorption of vitamin reduction of ROS in blood result in Increase in semen quality parameters and testosterone rise in antioxidants enzymes (Superoxide dismutase, glutathion peroxidase). Glutathion peroxidase (GPx) is considered as the asignificant antioxidant and minimize the amount of lipid peroxidation. This enzyme act potentiating to vitamin E as

Osteoarthritis (OA) of the knee is a major reason of chronic, incompetence in elderly people, the pathogenesis of this disease until now not clear understood [60].

#### *Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

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

**iRGD-TPGS** PTX Resistant lung

DTX, gold clusters

**PBAE-g-TPGS** PTX Resistant breast

**PLGA-TPGS** Zontivity Atherosclerosis

*Inspired by the use of PLA-TPGS copolymer loading antitumer and their effects.*

**PLA-PGS, Ce6-TPGS, tLyp-1-TPGS**

**Transferrin conjugated TPGS**

**Table 2.**

**Chitosan-g-TPGS** DOX Hepatoma 2.4-fold AUC, 2.0-fold

cancer

breast cancer

**4-arm-PEG-TPGS** PTX Hepatoma Significant in vivo antitumor

cancer

atheroma

DOX, Ce6 DOX-resistant

**Polymer Payload Tumor model Application Ref**

MRT vs. free drug after oral

Significant drug accumulation, downregulation of Survivin expression, and tumor apoptosis

In vivo near-infrared imaging of tumor-bearing mice and enhanced antitumor efficiency in

effect on S180 sarcoma-bearing

Stimuli-responsive release of PTX, targeted drug delivery to tumor, and remarkable MCF-7/ ADR tumor inhibition

Reduce the therapeutic dose and remove DNA damage.

[72]

[73]

[47, 74]

[75]

[66]

[66]

[76]

administration

MCF-7/ADR

Breast cancer In vivo imaging and antitumor efficacy

mice

self-emulsifying/micro emulsifying drug delivery mechanism (SEDDS/SMEDDS), solid dispersions/tablet, solid lipid nanoparticles (SLNs), liposomes and micelles and emulsified TPGS nanoparticles are included in the TPGS formulations.

Oral administration is an appealing drug delivery way owing to the simplicity, convenience, high patient compliance, perfect for chronic therapy and minimize costs for industry and physicians [83, 84]. Furthermore, there are still different inherent challenges hampering the effective delivery of drugs, such as limited permeability through the gastrointestinal tract, low water solubility, hydrolysis by enzymes and first pass elimination, which lead to lower absorption and bioavailability [85]. In fact, a majority of biopharmaceutics classification system class IV drugs are substrates of P-gp and CYP3A4, result in poor permeability and extensive pre-systemic metabolism [86]. TPGS-based formulations have numerous advantages to improve bioavailability of orally administered drugs. In addition to, as TPGS has ability to increase drug solubility due to a nonionic surfactant. On the other aspect, TPGS can enhance drug permeation due to the P-gp inhibition effect. Furthermore, TPGS has been confirmed with the ability to improve drug stability by inhibiting the CYP3A4 and CYP2C9-mediated metabolism [87]. In other studies, TPGS showed little inhibition effect on CYP3A activity [88, 89], which may be related to the dosage [90]. The TPGS formulations involve nanocrystals, nanosupensions, self-emulsifying/microemulsifying drug delivery system (SEDDS/ SMEDDS), solid dispersions/tablet, solid lipid nanoparticles (SLNs), liposomes and

Vitamin E (TPGS) is a lipid-soluble organic compound and usually present in the cell membranes. This vitamin has robust antioxidant properties and inhibits the

**6.2 TPGS based formulations to improve drug oral bioavailability**

micelles, TPGS emulsified nanoparticles and so on.

**36**

lipid peroxidation formd by the free hydroxyl and superoxide radicals [91]. This vitamin save the cell membrane of sperm cells from damages of ROS. In vitro studies have demonstrated that the utilize of vitamin E -TPGS amilorate the availability, motility and fertilizing capacity of sperm in the egg penetration of animals. Likwise, in vivo research, supplementation of vitamin E was found to be effective in reducing the number and motility of sperms caused by reactive oxygen species (ROS) [92]. The administration of this vitamin during oral route has significant advantages influnce on the motility of sperms through the depression synthesis of malondialdehyde (MDA), which is known as the final part of lipid peroxidation [93].

The deficiency of vitamin E may spoil the reproductive organs like harm in the spermatogenesis, testicular dysfunction and seminiferous tubules shrinkage. The utilize of this vitamin boost the functions of testes in the form of excess in the weight ofepididymis and testes. In addition, the antioxidants properties of TPGS, endogenous, antioxidant enzymes like superoxide dismutase (SOD), and glutathione peroxidase are augmented due to the use of this vitamin [94]. This imbalance between the endogenous antioxidants and oxidative stress results in a situation of infertility in males. Antioxidants play an essential role in eliminating these free radicals. Vitamin E is one of the better antioxidants for the sweep of oxidative stress in the male reproductive system. Its use raise functions of the reproductive system and its effecacy. The lack of TPGS result in the declination of germinal epithelium and Leydig cells in seminiferous tubules.

The use of selenium and vitamin E posses synergistic effects on the male reproductive system. More than 25% of males defeat to output functional sperms for effective insemination [94]. The over production of ROS is the main cause of infertility by damaging the genetic material and enzymes activities of [13]. ROS can be harmful or benefit according to their site as well as level of production [95]. The sperm have the capability to move after the transit stay in epididymis. They demand some physiological processes such as capacitation takes place during the female reproductive tract to fertilize the egg, through this physiological event the suffcint amount of ROS is produced [96]. In the ROS, superoxide is count as the most harmful agent. The male germ cells are susceptible to ROS due to a higher amount of polyunsaturated fatty acids within the cell membrane and cytoplasm [97].

Vitamin E is considered an essential portion of antioxidants in sperm [38] and acts as a substantial protection to minimize the production of reactive oxygen species [30]. Spermatozoa demand the ROS for natural functions like acrosome functions, capacitation, and incorporation of spermatozoa through the operation of fertilization [43]. But the production of an excess quantity of ROS leads to lipid peroxidation in the membrane of sperm [43, 44]. Vitamin E prevents the production of ROS in the sperm membrane during the various motility processes due to lipid-soluble [43]. In addition to scavenging of ROS, this vitamin has the capacity to conserve the primary reproductive organs and accessory reproductive organs in males. Feeding of vitamin E sbsquent metabolism and absorption of vitamin reduction of ROS in blood result in Increase in semen quality parameters and testosterone rise in antioxidants enzymes (Superoxide dismutase, glutathion peroxidase). Glutathion peroxidase (GPx) is considered as the asignificant antioxidant and minimize the amount of lipid peroxidation. This enzyme act potentiating to vitamin E as a oppsite agent for hydrogen peroxide [98].

#### **7. Osteoartharitis**

Osteoarthritis (OA) of the knee is a major reason of chronic, incompetence in elderly people, the pathogenesis of this disease until now not clear understood [60]. Recent guide demonstrates that oxidative stress, the event wherein oxidant levels overtake those of antioxidative agents, is one of the motives factors of OA [99–101]. ROS including oxidants that are generated under the physiological situation in the human body and controlled by cellular antioxidants, lead to functional and structural damage of cartilage cells. Several report studies of the relationship between oxidative stress and OA have been undertaken. The elevation nitrite, a stable deterioration biochemical marker of the being of nitric oxide, has been confirmed in the plasma and synovial fluid of patients with OA [102]. Vitamin E, a dietary antioxidant capable of augmenting the total cellular antioxidant ability, reportedly has a positive influence on the symptomatic therapy of arthritis [103, 104]. However, there is very little proof from high quality trials that vitamin E modifies oxidative markers and clinical signs in people with knee osteoarthritis [28, 105]. This is the primary randomized controlled trial that converge on the influence of vitamin E in end stage knee OA and entirely estimate clinical symptoms, biochemistry and histology results. We hypothesized that a sustained peroid of vitamin E administration will reduce the oxidative stress, inflammatory process and ameloriate symptoms in patients with end stage knee OA.

#### **8. Conclusions**

In this chapter, we summarized the feature and recent advancements of TPGS in drug delivery and pharmaceutical application. TPGS has been approved by FDA as a secure pharmaceutical adjuvant with top biocompatibility. In addition to TPGS can serve as an effective P-gp inhibitor for overcoming MDR. TPGS oneself can be active as an anticancer agent with selective toxicity to tumor cells. TPGS can be easily combined with nanotechnology to develop nanomedicines, which has been shown as a promising strategy in cancer treatment with increased solubility and stability of therapeutic agents, improved PK/PD, enhanced treatment efficiency, and minimize side effects. Furthermore, the impact of TPGS on the immune system, TPGS can be used as an adjuvant in vaccine development. As to TPGS based formulations, the limitations to realize the precise stimuli-responsive property and deep penetration of nanoformulations in the tumor microenvironment still remain as obstacles for the widespread application of these nanomedicines. However, the production of TPGS nanomedicines is yet on a laboratory scale and the progress in developing novel nanomedicines is comparatively slow, which hinders the effective clinical translation of TPGS based nanomedicines.

#### **Acknowledgements**

This work was supported by College of Veterinary Medicine, University of AL-Qassim green, Dr. Mohammed Jawad, Karbala university, Karbala, IRAQ., College of Veterinary Medicine.

**39**

**Author details**

Adnan M. Jasim1

\* and Mohammed J. Jawad<sup>2</sup>

2 College of Veterinary Medicine, Karbala University, Karbala, Iraq

\*Address all correspondence to: adnan.mansour81@gmail.com

provided the original work is properly cited.

1 College of Veterinary Medicine, University of AL-Qassim Green, Babylon, Iraq

© 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,

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

*Pharmaceutical Applications of Vitamin E TPGS DOI: http://dx.doi.org/10.5772/intechopen.97474*

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

patients with end stage knee OA.

clinical translation of TPGS based nanomedicines.

**8. Conclusions**

**Acknowledgements**

College of Veterinary Medicine.

Recent guide demonstrates that oxidative stress, the event wherein oxidant levels overtake those of antioxidative agents, is one of the motives factors of OA [99–101]. ROS including oxidants that are generated under the physiological situation in the human body and controlled by cellular antioxidants, lead to functional and structural damage of cartilage cells. Several report studies of the relationship between oxidative stress and OA have been undertaken. The elevation nitrite, a stable deterioration biochemical marker of the being of nitric oxide, has been confirmed in the plasma and synovial fluid of patients with OA [102]. Vitamin E, a dietary antioxidant capable of augmenting the total cellular antioxidant ability, reportedly has a positive influence on the symptomatic therapy of arthritis [103, 104]. However, there is very little proof from high quality trials that vitamin E modifies oxidative markers and clinical signs in people with knee osteoarthritis [28, 105]. This is the primary randomized controlled trial that converge on the influence of vitamin E in end stage knee OA and entirely estimate clinical symptoms, biochemistry and histology results. We hypothesized that a sustained peroid of vitamin E administration will reduce the oxidative stress, inflammatory process and ameloriate symptoms in

In this chapter, we summarized the feature and recent advancements of TPGS in drug delivery and pharmaceutical application. TPGS has been approved by FDA as a secure pharmaceutical adjuvant with top biocompatibility. In addition to TPGS can serve as an effective P-gp inhibitor for overcoming MDR. TPGS oneself can be active as an anticancer agent with selective toxicity to tumor cells. TPGS can be easily combined with nanotechnology to develop nanomedicines, which has been shown as a promising strategy in cancer treatment with increased solubility and stability of therapeutic agents, improved PK/PD, enhanced treatment efficiency, and minimize side effects. Furthermore, the impact of TPGS on the immune

system, TPGS can be used as an adjuvant in vaccine development. As to TPGS based formulations, the limitations to realize the precise stimuli-responsive property and deep penetration of nanoformulations in the tumor microenvironment still remain as obstacles for the widespread application of these nanomedicines. However, the production of TPGS nanomedicines is yet on a laboratory scale and the progress in developing novel nanomedicines is comparatively slow, which hinders the effective

This work was supported by College of Veterinary Medicine, University of AL-Qassim green, Dr. Mohammed Jawad, Karbala university, Karbala, IRAQ.,

**38**

#### **Author details**

Adnan M. Jasim1 \* and Mohammed J. Jawad<sup>2</sup>

1 College of Veterinary Medicine, University of AL-Qassim Green, Babylon, Iraq

2 College of Veterinary Medicine, Karbala University, Karbala, Iraq

\*Address all correspondence to: adnan.mansour81@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.

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**40**

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

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**44**

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[81] Mudra, D.R. and R.T. Borchardt, *Absorption barriers in the rat intestinal mucosa. 3: Effects of polyethoxylated solubilizing agents on drug permeation and metabolism.* Journal of pharmaceutical sciences, 2010. **99**(2): p. 1016-1027.

[82] Vasconcelos, T., S. Marques, and B. Sarmento, *The biopharmaceutical classification system of excipients.* Therapeutic Delivery, 2017. **8**(2): p. 65-78.

[83] XU, Wei; LING, Peixue; ZHANG, Tianmin. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. Journal of drug delivery, 2013, 2013.

[84] DE PORTU, Simona, et al. Cost analysis of capecitabine vs 5-fluorouracil-based treatment for metastatic colorectal cancer patients. *Journal of Chemotherapy*, 2010, 22.2: 125-128.

[85] Morales JO, Fathe KR, Brunaugh A, Ferrati S, Li S, Montenegro-Nicolini M. et al. Challenges and future prospects for the delivery of biologics: oral Mucosal, pulmonary, and transdermal routes. AAPS J. 2017;19:652-668

[86] Ghadi R, Dand N. BCS class IV drugs: highly notorious candidates for formulation development. J Control Release. 2017;248:71-95

[87] Christiansen A, Backensfeld T, Denner K, Weitschies W. Effects of non-ionic surfactants on cytochrome P450-mediated metabolism in vitro. Eur J Pharm Biopharm. 2011;78:166-167

[88] Mudra DR, Borchardt RT. Absorption barriers in the rat intestinal mucosa. 3: effects of polyethoxylated

solubilizing agents on drug permeation and metabolism. J Pharm Sci. 2010;99:1016-1027

[89] Johnson BM, Charman WN, Porter CJ. An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-alphatocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS PharmSci. 2002;4:193-205

[90] Vasconcelos T, Marques S, Sarmento B. The biopharmaceutical classification system of excipients. Ther Deliv. 2017;8:65-78

[91] Keskes-Ammar, L., et al., *Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men.* Archives of andrology, 2003. **49**(2): p. 83-94.

[92] Ahsan, U., et al., *Role of selenium in male reproduction—A review.* Animal reproduction science, 2014. **146**(1-2): p. 55-62.

[93] Zubair, M., *Effects of dietary vitamin E on male reproductive system.* Asian Pacific Journal of Reproduction, 2017. **6**(4): p. 145.

[94] Wang, S., et al., *Beneficial effects of vitamin E in sperm functions in the rat after spinal cord injury.* Journal of andrology, 2007. **28**(2): p. 334-341.

[95] Agarwal, A. and R.A. Saleh, *Role of oxidants in male infertility: rationale, significance, and treatment.* Urologic Clinics of North America, 2002. **29**(4): p. 817-828.

[96] Makker, K., A. Agarwal, and R. Sharma, *Oxidative stress & male infertility.* Indian Journal of Medical Research, 2009. **129**(4): p. 357.

[97] Alvarez, J.G. and B.T. Storey, *Differential incorporation of fatty acids*  *into and peroxidative loss of fatty acids from phospholipids of human spermatozoa.* Molecular reproduction and development, 1995. **42**(3): p. 334-346.

[98] Rahman, H., M. Qureshi, and R. Khan, *Influence of Dietary Zinc on Semen Traits and Seminal Plasma Antioxidant Enzymes and Trace Minerals of B eetal Bucks.* Reproduction in Domestic Animals, 2014. **49**(6): p. 1004-1007.

[99] Wieland, H.A., et al., *Osteoarthritis—an untreatable disease?* Nature reviews Drug discovery, 2005. **4**(4): p. 331-344.

[100] Sarban, S., et al., *Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis.* Clinical biochemistry, 2005. **38**(11): p. 981-986.

[101] Suantawee, T., et al., *Oxidative stress, vitamin e, and antioxidant capacity in knee osteoarthritis.* Journal of clinical and diagnostic research: JCDR, 2013. **7**(9): p. 1855.

[102] Karan, A., et al., *Synovial fluid nitric oxide levels in patients with knee osteoarthritis.* Clinical rheumatology, 2003. **22**(6): p. 397-399.

[103] Bhattacharya, I., R. Saxena, and V. Gupta, *Efficacy of vitamin E in knee osteoarthritis management of North Indian geriatric population.* Therapeutic advances in musculoskeletal disease, 2012. **4**(1): p. 11-19.

[104] Vasanthi, B., J. Komathi, and K. Arun, *Therapeutic effect of vitamin E in patients with primary osteoarthritis.* Int J Recent Adv Pharm Res, 2012. **2**: p. 46-50.

[105] Zheng, L., et al., *Nicotianamine, a novel enhancer of rice iron bioavailability to humans.* PLoS One, 2010. **5**(4): p. e10190.

**47**

**Chapter 3**

**Abstract**

*and Gennadii Telegeev*

of leukemic cells in CML.

drug resistance

**1. Introduction**

Vitamin E in Chronic Myeloid

*Lyudmyla Shvachko, Michael Zavelevich, Daniil Gluzman* 

The resistance to inhibitors of tyrosine kinase necessitates novel approaches to the therapy of chronic myeloid leukemia (CML). The progression of CML to blast crisis is associated with down-regulation of C/EBP-alpha being involved in the differentiation block in leukemic blast cells. Moreover, lowered C/EBP-alpha expression correlates with resistance to imatinib in CML. We have demonstrated that vitamin E up-regulates expression of C/EBP-alpha and down-regulates expression of Snail transcription factor in K562 cells in vitro contributing to the putative recovery of myeloid differentiation potential. In parallel with increased CEBP alpha expression, Vitamin E treatment results in the decreasing expression of placentallike alkaline phosphatase and increasing expression of tissue non-specific alkaline phosphatase. We suggest that vitamin E could be used as the plausible biological modulator to prevent the progression to blast crisis and to overcome drug resistance

**Keywords:** chronic myeloid leukemia, vitamin E, C/EBP-alpha, Snail, K562 cells,

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of *Bcr-Abl* fusion oncogene that arises from the translocation of chromosomes 9 and 22 as t (9:22) (q34;q11) [1, 2]. The BCR/ABL fusion protein with elevated ABL tyrosine kinase activity is crucial for transformation of hematopoietic stem cells (HSCs) [3]. The constitutively active P210 BCR-ABL tyrosine kinase is considered as a key player in the molecular pathogenesis of CML [3, 4]. The disease begins with an indolent chronic phase that can last for several years. If untreated, it then progresses into accelerated phase and within a year into blast crisis phase. The survival of patients in blast crisis is less than one year. Because the preeminent rearrangement driving CML is *Bcr-Abl*, only BCR-ABL tyrosine kinase inhibitors such as imatinib (or nilotinib and dasatinib) are a known curative therapy of CML with extraordinarily successful 5-year survival rates greater than 90% [5–8]. Nevertheless, the secondary mutations finally contribute to the therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML progression is now in the spotlight. The free radical scavengers like alpha-tocopherol may be effective against cancer-associated oxidative stress. The mean serum vitamin E level significantly

Leukemia (CML) Prevention

#### **Chapter 3**

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

*into and peroxidative loss of fatty acids* 

*spermatozoa.* Molecular reproduction and development, 1995. **42**(3): p.

[98] Rahman, H., M. Qureshi, and R. Khan, *Influence of Dietary Zinc on Semen Traits and Seminal Plasma Antioxidant Enzymes and Trace Minerals of B eetal Bucks.* Reproduction in Domestic Animals, 2014. **49**(6): p. 1004-1007.

*Osteoarthritis—an untreatable disease?* Nature reviews Drug discovery, 2005.

[100] Sarban, S., et al., *Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis.* Clinical biochemistry, 2005. **38**(11):

[101] Suantawee, T., et al., *Oxidative stress, vitamin e, and antioxidant capacity in knee osteoarthritis.* Journal of clinical and diagnostic research: JCDR, 2013.

[102] Karan, A., et al., *Synovial fluid nitric oxide levels in patients with knee osteoarthritis.* Clinical rheumatology,

[103] Bhattacharya, I., R. Saxena, and V. Gupta, *Efficacy of vitamin E in knee osteoarthritis management of North Indian geriatric population.* Therapeutic advances in musculoskeletal disease,

[104] Vasanthi, B., J. Komathi, and K. Arun, *Therapeutic effect of vitamin E in patients with primary osteoarthritis.* Int J

[105] Zheng, L., et al., *Nicotianamine, a novel enhancer of rice iron bioavailability to humans.* PLoS One, 2010. **5**(4):

Recent Adv Pharm Res, 2012. **2**:

2003. **22**(6): p. 397-399.

2012. **4**(1): p. 11-19.

*from phospholipids of human* 

[99] Wieland, H.A., et al.,

**4**(4): p. 331-344.

p. 981-986.

**7**(9): p. 1855.

334-346.

**46**

p. 46-50.

p. e10190.

## Vitamin E in Chronic Myeloid Leukemia (CML) Prevention

*Lyudmyla Shvachko, Michael Zavelevich, Daniil Gluzman and Gennadii Telegeev*

#### **Abstract**

The resistance to inhibitors of tyrosine kinase necessitates novel approaches to the therapy of chronic myeloid leukemia (CML). The progression of CML to blast crisis is associated with down-regulation of C/EBP-alpha being involved in the differentiation block in leukemic blast cells. Moreover, lowered C/EBP-alpha expression correlates with resistance to imatinib in CML. We have demonstrated that vitamin E up-regulates expression of C/EBP-alpha and down-regulates expression of Snail transcription factor in K562 cells in vitro contributing to the putative recovery of myeloid differentiation potential. In parallel with increased CEBP alpha expression, Vitamin E treatment results in the decreasing expression of placentallike alkaline phosphatase and increasing expression of tissue non-specific alkaline phosphatase. We suggest that vitamin E could be used as the plausible biological modulator to prevent the progression to blast crisis and to overcome drug resistance of leukemic cells in CML.

**Keywords:** chronic myeloid leukemia, vitamin E, C/EBP-alpha, Snail, K562 cells, drug resistance

#### **1. Introduction**

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of *Bcr-Abl* fusion oncogene that arises from the translocation of chromosomes 9 and 22 as t (9:22) (q34;q11) [1, 2]. The BCR/ABL fusion protein with elevated ABL tyrosine kinase activity is crucial for transformation of hematopoietic stem cells (HSCs) [3]. The constitutively active P210 BCR-ABL tyrosine kinase is considered as a key player in the molecular pathogenesis of CML [3, 4]. The disease begins with an indolent chronic phase that can last for several years. If untreated, it then progresses into accelerated phase and within a year into blast crisis phase. The survival of patients in blast crisis is less than one year. Because the preeminent rearrangement driving CML is *Bcr-Abl*, only BCR-ABL tyrosine kinase inhibitors such as imatinib (or nilotinib and dasatinib) are a known curative therapy of CML with extraordinarily successful 5-year survival rates greater than 90% [5–8]. Nevertheless, the secondary mutations finally contribute to the therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML progression is now in the spotlight.

The free radical scavengers like alpha-tocopherol may be effective against cancer-associated oxidative stress. The mean serum vitamin E level significantly decreased in CML patients that seems to be quite in agreement with free radical involvement in CML progression [9]. In contrast to antioxidant function of vitamin E in CML, we suggest new modulation mechanisms of vitamin E that could be operative in prevention of CML progression. In particular, we analyzed the modulation function of vitamin E for molecular unblocking of myeloid differentiation potential in CML cells via vitamin E-dependent induction of pivotal transcription factor CEBP alpha (CCAAT/enhancer-binding protein) as myeloid master regulator of myelopoiesis/granulopoiesis and consequently G-CSFR (granulocyte-colony stimulation factor receptor) [10]. Moreover, we have found that vitamin E could be involved in targeting epithelial-mesenchymal transition (EMT) mechanism in CML cells via SNAIL as EMT inducer [11, 12]. Therefore, we propose that vitamin E could be a therapeutic option when CML progresses in setting of imatinib therapy. Finally, since alkaline phosphatase is considered as a marker of stem cells [13], we studied the aberrant expression of placentallike alkaline phosphatase (PLAP) and discovered the potential of vitamin E in remodeling of CML-associated aberrant expression of this enzyme [14]. Vitamin E-dependent induction of tissue non-specific alkaline phosphatase (TNAP) is paralleled by restored CEBP alpha expression as myeloid master regulator in CML cells [14].

Taken together, these findings suggest that vitamin E shows ability of remodeling leukemic stem cell (LSC) phenotype in CML cells to hematopoietic stem cell (HSC) phenotype with myeloid differentiation potential development.

#### **2. Vitamin E activates expression of C/EBP alpha transcription factor and G-CSF receptor in CML blast crisis leukemic K562 cells**

C/EBPα is mainly involved in cell fate decisions for myeloid differentiation [15]. The progression of CML to blast crisis is correlated with down-modulation of C/EBP-alpha contributing to the differentiation block, enhanced proliferation, and development of acute myelogenous leukemia [16, 17]. The level of C/EBPα expression is significantly declined in CML patients [18]. Currently, the deregulation of C/EBP alpha is considered as a paradigm of leukemogenesis [19]. Therefore, C/EBPα is a critical regulator of myeloid development guiding granulocyte and monocyte differentiation.

We have studied the modulating potential of vitamin E as the possible inducer of C/EBP-alpha expression in BCR-ABL-positive CML K562 cells. K562 cell line originated from a CML patient in blast crisis progression is recognized as a model for leukemia research. We studied the effects of vitamin E in K562 cells in comparison with valproic acid with known differentiation properties towards myeloid cells [20–22].

Valproic acid in a concentration of 4 mM for 48 h reduced the growth rate and cell viability and induced apoptosis in a fraction of K562 cells (up to 30%). As to vitamin E, in the series of our preliminary experiments, no evidence of toxicity has been demonstrated when K562 cells were cultured with vitamin E in a concentration of 100 μM for 48 h. These concentrations were further used in the experiments for assaying the expression of C/EBP-alpha and G-CSFR mRNA. **Figure 1A** demonstrates that valproic acid did not change significantly the level of mRNA C/EBP expression in K562 cells. On the contrary, vitamin E proved to be an effective inducer of mRNA C/EBP with about 10-fold increase in expression as compared with nontreated K562 cells. When mRNA G-CSFR expression in K562 cells was assessed, both valproic acid and vitamin E induced mRNA of this receptor, with effect of vitamin E surpassed that of VA (**Figure 1A** and **Table 1**).

**49**

**Figure 1.**

*qRT-PCR and calculated by 2¯(ΔCt) method.*

Thease findings are quite confirmed by Tavor et al. [23] have first shown that the restoration of C/EBP-alpha expression in BCR-ABL-positive KCL22 blast cell line provided by transfection with C/EBPα plasmid vector caused a block in the G2/M phase of the cell cycle with gradual increase in apoptosis suggesting that C/EBP-alpha may be considered as a putative target in differentiation therapies in acute myeloid

*mRNA expression in CML cells modified by vitamin E. (A) The relative levels of mRNA C/EBP-alpha and G-CSFR expression in K562 cells exposed to valproic acid (2 mM) or vitamin E (100 μM) for 48 h. (B) The aberrant AP mRNA detected by qRT-PCR in leukemic cells of the patient with CML blast crisis: 1 – control without primers; 2 – primers to PAP; 3 – primers to TNAP; 4 – primers to IAP. (C) Ectopic gene expression of embryonic PLAP mRNA in peripheral blood cells of the patient with CML, acute myeloid leukemia (AML), and polycytemia vera (PV): 1 – GAPDH, reference gene; 2 – aberrant PLAP. (D) The relative levels of mRNA expression of PLAP, TNAP, and CCAAT-enhancer binding protein alpha (C/EBP*α*) in K562 cells exposed to vitamin E (100 μM) for 48 h by real time RT-PCR 2¯(ΔCt) method. (E) Relative mRNA expression level of transcription factor Snail and transcription factor CEBP*α *in CML blast crisis K562 cells exposed to vitamin E (100 μM) and metformin (4 mM) for 48 h. The relative levels of mRNA expression were analyzed by* 

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention*

*DOI: http://dx.doi.org/10.5772/intechopen.96452*

#### *Vitamin E in Chronic Myeloid Leukemia (CML) Prevention DOI: http://dx.doi.org/10.5772/intechopen.96452*

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

decreased in CML patients that seems to be quite in agreement with free radical involvement in CML progression [9]. In contrast to antioxidant function of vitamin E in CML, we suggest new modulation mechanisms of vitamin E that could be operative in prevention of CML progression. In particular, we analyzed the modulation function of vitamin E for molecular unblocking of myeloid differentiation potential in CML cells via vitamin E-dependent induction of pivotal transcription factor CEBP alpha (CCAAT/enhancer-binding protein) as myeloid master regulator of myelopoiesis/granulopoiesis and consequently G-CSFR (granulocyte-colony stimulation factor receptor) [10]. Moreover, we have found that vitamin E could be involved in targeting epithelial-mesenchymal transition (EMT) mechanism in CML cells via SNAIL as EMT inducer [11, 12]. Therefore, we propose that vitamin E could be a therapeutic option when CML progresses in setting of imatinib therapy. Finally, since alkaline phosphatase is considered as a marker of stem cells [13], we studied the aberrant expression of placentallike alkaline phosphatase (PLAP) and discovered the potential of vitamin E in remodeling of CML-associated aberrant expression of this enzyme [14]. Vitamin E-dependent induction of tissue non-specific alkaline phosphatase (TNAP) is paralleled by restored CEBP alpha expression as myeloid master regulator in CML

Taken together, these findings suggest that vitamin E shows ability of remodeling leukemic stem cell (LSC) phenotype in CML cells to hematopoietic stem cell

**2. Vitamin E activates expression of C/EBP alpha transcription factor and G-CSF receptor in CML blast crisis leukemic K562 cells**

C/EBPα is mainly involved in cell fate decisions for myeloid differentiation [15]. The progression of CML to blast crisis is correlated with down-modulation of C/EBP-alpha contributing to the differentiation block, enhanced proliferation, and development of acute myelogenous leukemia [16, 17]. The level of C/EBPα expression is significantly declined in CML patients [18]. Currently, the deregulation of C/EBP alpha is considered as a paradigm of leukemogenesis [19]. Therefore, C/EBPα is a critical regulator of myeloid development guiding granulocyte and

We have studied the modulating potential of vitamin E as the possible inducer of C/EBP-alpha expression in BCR-ABL-positive CML K562 cells. K562 cell line originated from a CML patient in blast crisis progression is recognized as a model for leukemia research. We studied the effects of vitamin E in K562 cells in comparison with valproic acid with known differentiation properties towards myeloid

Valproic acid in a concentration of 4 mM for 48 h reduced the growth rate and cell viability and induced apoptosis in a fraction of K562 cells (up to 30%). As to vitamin E, in the series of our preliminary experiments, no evidence of toxicity has been demonstrated when K562 cells were cultured with vitamin E in a concentration of 100 μM for 48 h. These concentrations were further used in the experiments for assaying the expression of C/EBP-alpha and G-CSFR mRNA. **Figure 1A** demonstrates that valproic acid did not change significantly the level of mRNA C/EBP expression in K562 cells. On the contrary, vitamin E proved to be an effective inducer of mRNA C/EBP with about 10-fold increase in expression as compared with nontreated K562 cells. When mRNA G-CSFR expression in K562 cells was assessed, both valproic acid and vitamin E induced mRNA of this receptor, with effect of vitamin E

(HSC) phenotype with myeloid differentiation potential development.

**48**

cells [14].

monocyte differentiation.

surpassed that of VA (**Figure 1A** and **Table 1**).

cells [20–22].

#### **Figure 1.**

*mRNA expression in CML cells modified by vitamin E. (A) The relative levels of mRNA C/EBP-alpha and G-CSFR expression in K562 cells exposed to valproic acid (2 mM) or vitamin E (100 μM) for 48 h. (B) The aberrant AP mRNA detected by qRT-PCR in leukemic cells of the patient with CML blast crisis: 1 – control without primers; 2 – primers to PAP; 3 – primers to TNAP; 4 – primers to IAP. (C) Ectopic gene expression of embryonic PLAP mRNA in peripheral blood cells of the patient with CML, acute myeloid leukemia (AML), and polycytemia vera (PV): 1 – GAPDH, reference gene; 2 – aberrant PLAP. (D) The relative levels of mRNA expression of PLAP, TNAP, and CCAAT-enhancer binding protein alpha (C/EBP*α*) in K562 cells exposed to vitamin E (100 μM) for 48 h by real time RT-PCR 2¯(ΔCt) method. (E) Relative mRNA expression level of transcription factor Snail and transcription factor CEBP*α *in CML blast crisis K562 cells exposed to vitamin E (100 μM) and metformin (4 mM) for 48 h. The relative levels of mRNA expression were analyzed by qRT-PCR and calculated by 2¯(ΔCt) method.*

Thease findings are quite confirmed by Tavor et al. [23] have first shown that the restoration of C/EBP-alpha expression in BCR-ABL-positive KCL22 blast cell line provided by transfection with C/EBPα plasmid vector caused a block in the G2/M phase of the cell cycle with gradual increase in apoptosis suggesting that C/EBP-alpha may be considered as a putative target in differentiation therapies in acute myeloid


#### **Table 1.**

*Fold increase C/EBP alpha and G-CSFR mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n*  ∑*(xi – x¯)2 .*

leukemia. C/EBPα directly activates G-CSFR transcription in lineage committing activation of common myeloid progenitor [24–26]. Therefore, C/EBPα loss is causally connected with early block in myeloid maturation suggesting that C/EBPα is a master regulator of hematopoietic differentiation. The transcription factor C/EBPα is known as a critical regulator of myeloid development, directing granulocyte, and monocyte differentiation [27].

Our findings gave evidence of C/EBP alpha-dependent activation to granulocytic differentiation via targeted increase in G-CSFR expression in vitamin E treated K562 cells. It should be further elucidated whether such effects of vitamin E on myeloid transcription factor C/EBP-alpha are direct or mediated indirectly due to the antioxidant properties of vitamin E. Nevertheless, our data suggest vitamin E-associated hematopoietic differentiation-like potential associated with C/EBPα and G-CSFR up-regulation. Our findings might be very important for future studies of imatinib resistance in CML clinical setting taking into account the recent report by S. Kagita et al. demonstrating correlation of C/EBPα expression with response and resistance to imatinib in CML [28].

#### **3. Aberrant expression of placental-like alkaline phosphatase in chronic myeloid leukemia cells in vitro and its modulation by vitamin E**

LSCs in CML do not depend on BCR-ABL signaling for their survival [29, 30], and their persistence remains a major obstacle to curing CML [31, 32]. The search for new biological markers of LSC phenotype is still relevant today. Placental-like alkaline phosphatase (PLAP) is expressed by many tumors. Its aberrant expression has been considered to be potentially useful as tumor marker [33]. However, the biological background of the role of this aberrant alkaline phosphatase (AP) in cancer is still unclear. The AP activity in blood serum known as nonspecific marker of bone metastasis [33] is also of potential significance for the identification of stem cell phenotype [13, 34]. Moreover, AP activity is a widely accepted marker of stem cells associated with embryonic stem cell pluripotency [35]. The expression of various forms of AP in CML cells has not yet been studied. Therefore, we aimed to analyze the expression patterns of various AP forms in cells originated from CML patients in blast crisis and to modify their expression by vitamin E (100 μM) in K562 cells. We used the primers to three known tissue AP, namely placental AP (PAP), non-specific AP (TNAP) (expressed in bone, kidney, liver) and intestinal AP (IAP) [36] to analyze the mRNA expression of these APs in CML cells by qRT-PCR. We have observed the aberrant expression of mRNA IAP in cells of CML patient in blast crisis (**Figure 1B**) that upon sequencing (data not shown) demonstrated the significant alignment with known cancer-associated PLAP sequence, while no gene homology with tissue PAP was detected. This fact gave reason to

**51**

**Table 2.**

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention*

consider revealed PLAP as embryonic-like placental AP (ELAP), to be more precise, the aberrant PLAP in blast cells of CML patients (**Figure 1C**). Indeed, such PLAP is expressed in early embryo pre-implantation period as was detected in studying mouse embryonic cell development, while tissue TNAP begins to express in postimplantation period [35]. We have not detected TNAP in cells of CML patients. Only the embryonic-like PLAP was detected, which expression also increased in acute myeloid leukemia (**Figure 1C**). Recently, TNAP recognized ultimately as mesenchymal stromal cell antigen-1 (MSCA-1) [13] was described as a biomarker associated with normal hematopoiesis as well as with terminal myeloid differentiation [37]. The decreased TNAP synthesis is a classical feature of CML used as one of diagnostic cytochemical markers in differential diagnosis [2]. We have observed vitamin E targeted decrease in aberrant embryonic-like PLAP expression at mRNA level with increased TNAP mRNA expression. Moreover, along with downregulation of aberrant PLAP the up-regulation of C/EBP alpha mRNA expression was restored by vitamin E in exposed K562 cells as we founded (**Figure 1D** and

Taken together, we have concluded that the loss of TNAP and CEBP alpha in CML may contribute to pathogenesis of this disease whereas aberrant embryoniclike PLAP may be considered as a new CML biomarker of LSC pluripotent phenotype in CML progression. Therefore, aberrant embryonic-like PLAP may be considered as a putative target in differentiation therapies in myeloid neoplasms. Our findings suggest the biomodulation role of vitamin E as the available inducer of differentiation potential of CML leukemic cells. The ectopic PLAP expression in leukemic cells of different myeloid neoplasms suggests its importance in biology of

Conclusivelly, to analyze whether ectopic PLAP expression in CMLcells *in vitro* may be modulated, we studied PLAP and TNAP expression in CML blast crisis K562 leukemic cells incubated with vitamin E for 48 h. In fact, vitamin E treatment affects expression of PLAP and TNAP in opposite ways. Namely, PLAP expression decreased significantly while TNAP expression increased. The increase in TNAP expression was paralleled with increased CEBP alpha expression (**Figure 1D** and **Table 2**). **Figure 1**, D demonstrates that vitamin E targeted aberrant PLAP expression is closely related to the restoration of CEBP alpha and TNAP expression. These key regulators tightly contribute to potential reactivation of myeloid differential as we studied in K562 leukemic cells. Therefore, we point out that vitamin E could be

To sum up, we have demonstrated increased aberrant PLAP expression in leukemic cells of myeloid origin (CML) in the setting of the decreased TNAP expression. The aberrant expression of embryonic PLAP may be considered as

1 4.088 ± 0.322 1.42 2.972 ± 1.594 1.35 6.023 ± 2.809 1.98

*The relative fold decreasing PLAP corresponding to fold increasing CEBP* α *and TNAP mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM)* 

*.*

2 6.292 ± 1.883 4.377 ± 0.117 1.690 ± 1.524 3 2.848 ± 1.561 6.207 ± 1.713 1.931 ± 1.283

**Fold increasing Standard** 

**CEBPα (M ± m)**

**deviation, σ**

**Fold increasing**

> **TNAP (M ± m)**

**Standard deviation, σ**

able to affect leukemic blast stem cell phenotype remodeling.

**Standard deviation, σ**

*DOI: http://dx.doi.org/10.5772/intechopen.96452*

**Table 2**).

these malignancies.

**N(n=3) Fold** 

**decreasing**

**PLAP (M ± m)**

*calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* ∑*(xi – x¯)2*

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

2 9.854 ± 0.023 4.626 ± 0.853 3 11.381 ± 1.506 5.134 ± 1.357

**N (n = 3) C/EBP alpha G-CSFR**

1 8.395 ± 1.481 1.219 3.930 ± 1.843 1.988

**Fold increase Standard Deviation, σ Fold increase Standard Deviation, σ**

monocyte differentiation [27].

**Table 1.**

∑*(xi – x¯)2*

*.*

and resistance to imatinib in CML [28].

leukemia. C/EBPα directly activates G-CSFR transcription in lineage committing activation of common myeloid progenitor [24–26]. Therefore, C/EBPα loss is causally connected with early block in myeloid maturation suggesting that C/EBPα is a master regulator of hematopoietic differentiation. The transcription factor C/EBPα is known as a critical regulator of myeloid development, directing granulocyte, and

*Fold increase C/EBP alpha and G-CSFR mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* 

Our findings gave evidence of C/EBP alpha-dependent activation to granulocytic differentiation via targeted increase in G-CSFR expression in vitamin E treated K562 cells. It should be further elucidated whether such effects of vitamin E on myeloid transcription factor C/EBP-alpha are direct or mediated indirectly due to the antioxidant properties of vitamin E. Nevertheless, our data suggest vitamin E-associated hematopoietic differentiation-like potential associated with C/EBPα and G-CSFR up-regulation. Our findings might be very important for future studies of imatinib resistance in CML clinical setting taking into account the recent report by S. Kagita et al. demonstrating correlation of C/EBPα expression with response

**3. Aberrant expression of placental-like alkaline phosphatase in chronic myeloid leukemia cells in vitro and its modulation by vitamin E**

LSCs in CML do not depend on BCR-ABL signaling for their survival [29, 30], and their persistence remains a major obstacle to curing CML [31, 32]. The search for new biological markers of LSC phenotype is still relevant today. Placental-like alkaline phosphatase (PLAP) is expressed by many tumors. Its aberrant expression has been considered to be potentially useful as tumor marker [33]. However, the biological background of the role of this aberrant alkaline phosphatase (AP) in cancer is still unclear. The AP activity in blood serum known as nonspecific marker of bone metastasis [33] is also of potential significance for the identification of stem cell phenotype [13, 34]. Moreover, AP activity is a widely accepted marker of stem cells associated with embryonic stem cell pluripotency [35]. The expression of various forms of AP in CML cells has not yet been studied. Therefore, we aimed to analyze the expression patterns of various AP forms in cells originated from CML patients in blast crisis and to modify their expression by vitamin E (100 μM) in K562 cells. We used the primers to three known tissue AP, namely placental AP (PAP), non-specific AP (TNAP) (expressed in bone, kidney, liver) and intestinal AP (IAP) [36] to analyze the mRNA expression of these APs in CML cells by qRT-PCR. We have observed the aberrant expression of mRNA IAP in cells of CML patient in blast crisis (**Figure 1B**) that upon sequencing (data not shown) demonstrated the significant alignment with known cancer-associated PLAP sequence, while no gene homology with tissue PAP was detected. This fact gave reason to

**50**

consider revealed PLAP as embryonic-like placental AP (ELAP), to be more precise, the aberrant PLAP in blast cells of CML patients (**Figure 1C**). Indeed, such PLAP is expressed in early embryo pre-implantation period as was detected in studying mouse embryonic cell development, while tissue TNAP begins to express in postimplantation period [35]. We have not detected TNAP in cells of CML patients. Only the embryonic-like PLAP was detected, which expression also increased in acute myeloid leukemia (**Figure 1C**). Recently, TNAP recognized ultimately as mesenchymal stromal cell antigen-1 (MSCA-1) [13] was described as a biomarker associated with normal hematopoiesis as well as with terminal myeloid differentiation [37]. The decreased TNAP synthesis is a classical feature of CML used as one of diagnostic cytochemical markers in differential diagnosis [2]. We have observed vitamin E targeted decrease in aberrant embryonic-like PLAP expression at mRNA level with increased TNAP mRNA expression. Moreover, along with downregulation of aberrant PLAP the up-regulation of C/EBP alpha mRNA expression was restored by vitamin E in exposed K562 cells as we founded (**Figure 1D** and **Table 2**).

Taken together, we have concluded that the loss of TNAP and CEBP alpha in CML may contribute to pathogenesis of this disease whereas aberrant embryoniclike PLAP may be considered as a new CML biomarker of LSC pluripotent phenotype in CML progression. Therefore, aberrant embryonic-like PLAP may be considered as a putative target in differentiation therapies in myeloid neoplasms. Our findings suggest the biomodulation role of vitamin E as the available inducer of differentiation potential of CML leukemic cells. The ectopic PLAP expression in leukemic cells of different myeloid neoplasms suggests its importance in biology of these malignancies.

Conclusivelly, to analyze whether ectopic PLAP expression in CMLcells *in vitro* may be modulated, we studied PLAP and TNAP expression in CML blast crisis K562 leukemic cells incubated with vitamin E for 48 h. In fact, vitamin E treatment affects expression of PLAP and TNAP in opposite ways. Namely, PLAP expression decreased significantly while TNAP expression increased. The increase in TNAP expression was paralleled with increased CEBP alpha expression (**Figure 1D** and **Table 2**). **Figure 1**, D demonstrates that vitamin E targeted aberrant PLAP expression is closely related to the restoration of CEBP alpha and TNAP expression. These key regulators tightly contribute to potential reactivation of myeloid differential as we studied in K562 leukemic cells. Therefore, we point out that vitamin E could be able to affect leukemic blast stem cell phenotype remodeling.

To sum up, we have demonstrated increased aberrant PLAP expression in leukemic cells of myeloid origin (CML) in the setting of the decreased TNAP expression. The aberrant expression of embryonic PLAP may be considered as


#### **Table 2.**

*The relative fold decreasing PLAP corresponding to fold increasing CEBP* α *and TNAP mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* ∑*(xi – x¯)2 .*

one of the putative markers of myeloid cell undifferentiated state. On the other hand, potential of PLAP as one of the possible target for controlling LSC phenotype should be further explored. More attention is needed to explore the potential of the bioactive molecules such as vitamin E that may induce granulopoiesis reprogramming.

#### **4. Vitamin E suppresses EMT-SNAIL transcription factor and restores CEBP alpha transcription factor as master regulator of myelopoiesis in K562 cells**

The persistence of LSC remains a major obstacle to cure CML [38, 39]. Epithelial mesenchymal transition (EMT) mechanism is known to contribute to tumor stem cell progression [40, 41]. Although EMT has been studied in relation to epithelium-derived tumors, there is increasing evidence implicating the involvement of EMT activators in hematopoietic malignancies [42, 43]. The expression of some EMT modulators has been demonstrated in Ph + leukemia cells [44]. EMT inducer Snail if of most important role in maintaining stemness properties in tumor progression [45, 46]. It was shown that Snail also drives LSC phenotype in leukemia progression [44, 47]. Earlier, we revealed that alpha-tocopherol might be an effective inducer of mRNA CEBP alpha in K562 cells *in vitro* [10]. The loss of C/EBPα contributes to leukemogenesis [16, 19] and CEBP alpha expression prevents from appearance of EMT phenotype [48].

We have determined the relationship between EMT-Snail suppression and restored CEBP alpha myeloid differentiation potential in CML blast crisis K562 cells exposed to vitamin E. Metformin as known substance mediating EMT reversal [49] was used to compare EMT suppression effect of vitamin E in K562 cells.

We have found highly detectable Snail1 mRNA expression and down-regulated CEBP alpha in K562 cells (**Figure 1E**). Vitamin E suppressed EMT-Snail mRNA expression and up-regulated myeloid master regulator CEBP alpha mRNA expression (**Figure 1E** and **Tables 3**, **4**). Such reactivation of CEBP alpha is enhanced by metformin pointing to the possible synergistic effect with alpha-tocopherol. We observed that vitamin E is a modulator of gene expression that affects Snail1 and CEBP alpha mRNA expression in K562 cells in opposite directions. One could suggest the causal relationship between EMT-Snail1 suppression and restoration of CEBP alpha expression that seems to contribute to recover myeloid differentiation potential of CML blast cells. As seen in **Figure 1E**, myelopoietic master regulator C/EBPα is also restored upon metformin treatment, although the effect of vitamin E is more pronounced (**Table 4**).

Taken together, schematic model of the Vitamin E modulation effects in CML blast crisis progression with Snail-EMT phenotype is presented (**Figure 2**).


#### **Table 3.**

*Fold increase EMT-inducer transcription factor SNAIL mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* ∑*(xi – x¯)2 .*

**53**

**5. Discussion**

**Figure 2.**

**Table 4.**

for CML prevention.

CML is characterized by an accelerated and unregulated proliferation of predominantly myeloid cells in the bone marrow with their accumulation in the blood. CML develops as a result of malignant transformation and clonal proliferation of pluripotent hematopoietic stem cells (HSCs), leading to overproduction of immature myeloid progenitor cells that results in blast cell crisis. The CML blast crisis resembles acute leukemia. Because the preeminent mutation driving CML is Bcr-ABL thyrosine kinase oncogene, the use of Bcr-Abl kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, significantly improves treatment outcomes and extends the life expectancy of CML patients. However, imatinib resistance drives blast crisis progression. The persistence of LSCs remains a major obstacle to cure CML. The clinical CML blast crisis progression with LSC phenotype is practically incurable. Therefore, the blocking of terminal myeloid differentiation and LSC phenotype development defines a putatively new strategy

*Schematic model of the vitamin E modulation in CML progression with EMT phenotype.*

The potential of vitamin E in regulation of these interdependent mechanisms in CML progression was hinted by several observations that were reported earlier. Sangodkar et al. [50] showed that vitamin E activates PP2A phosphatase resulting in Bcr-Abl thyrosine kinase inhibition and re-activation of myeloid differentiation

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention*

**deviation, σ**

**Fold increasing**

1 5.156 ± 0.328 0.232 5.564 ± 0.075 0.371 2.841 ± 0.007 0.272

*The fold increase of relative levels of the transcription factor CEBP alpha mRNA expression compared with metformin (4 mM) under decreasing of relative levels of the transcription factor Snail mRNA expression by vitamin E (analyzed in triplicates) in K562 cells line culture under 48-h vitamin E exposure (100 μM)* 

*.*

2 4.634 ± 0.194 5.00 ± 0.489 3.164 ± 0.330 3 4.696 ± 0.132 5.902 ± 0.413 2.498 ± 0.336

**Vitamin E + Metformin M ± m**

**Standard deviation, σ**

**Fold increasing**

> **Metformin M ± m**

**Standard deviation, σ**

*DOI: http://dx.doi.org/10.5772/intechopen.96452*

**Vitamin E M ± m**

*calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* ∑*(xi – x¯)2*

**N(n=3) Fold increasing Standard** 


#### **Table 4.**

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

reprogramming.

**in K562 cells**

one of the putative markers of myeloid cell undifferentiated state. On the other hand, potential of PLAP as one of the possible target for controlling LSC phenotype should be further explored. More attention is needed to explore the potential of the bioactive molecules such as vitamin E that may induce granulopoiesis

**4. Vitamin E suppresses EMT-SNAIL transcription factor and restores CEBP alpha transcription factor as master regulator of myelopoiesis** 

The persistence of LSC remains a major obstacle to cure CML [38, 39]. Epithelial mesenchymal transition (EMT) mechanism is known to contribute to tumor stem cell progression [40, 41]. Although EMT has been studied in relation to epithelium-derived tumors, there is increasing evidence implicating the involvement of EMT activators in hematopoietic malignancies [42, 43]. The expression of some EMT modulators has been demonstrated in Ph + leukemia cells [44]. EMT inducer Snail if of most important role in maintaining stemness properties in tumor progression [45, 46]. It was shown that Snail also drives LSC phenotype in leukemia progression [44, 47]. Earlier, we revealed that alpha-tocopherol might be an effective inducer of mRNA CEBP alpha in K562 cells *in vitro* [10]. The loss of C/EBPα contributes to leukemogenesis [16, 19] and CEBP alpha expression prevents from appearance of EMT phenotype [48]. We have determined the relationship between EMT-Snail suppression and restored CEBP alpha myeloid differentiation potential in CML blast crisis K562 cells exposed to vitamin E. Metformin as known substance mediating EMT reversal [49]

was used to compare EMT suppression effect of vitamin E in K562 cells.

We have found highly detectable Snail1 mRNA expression and down-regulated CEBP alpha in K562 cells (**Figure 1E**). Vitamin E suppressed EMT-Snail mRNA expression and up-regulated myeloid master regulator CEBP alpha mRNA expression (**Figure 1E** and **Tables 3**, **4**). Such reactivation of CEBP alpha is enhanced by metformin pointing to the possible synergistic effect with alpha-tocopherol. We observed that vitamin E is a modulator of gene expression that affects Snail1 and CEBP alpha mRNA expression in K562 cells in opposite directions. One could suggest the causal relationship between EMT-Snail1 suppression and restoration of CEBP alpha expression that seems to contribute to recover myeloid differentiation potential of CML blast cells. As seen in **Figure 1E**, myelopoietic master regulator C/EBPα is also restored upon metformin treatment, although the effect of vitamin E is more pronounced (**Table 4**).

Taken together, schematic model of the Vitamin E modulation effects in CML

**N(n=3) Fold decreasing Standard deviation, σ Fold decreasing Standard deviation, σ**

1 14.160 ± 0.437 0.408 1.579 ± 0.110 0.086

*Fold increase EMT-inducer transcription factor SNAIL mRNA expression (analyzed in triplicates) in gene expression in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method.* 

**Metformin/Snail M ± m**

blast crisis progression with Snail-EMT phenotype is presented (**Figure 2**).

**Vitamin E/Snail M ± m**

2 13.176 ± 0.547 1.366 ± 0.103 3 13.833 ± 0.110 1.464 ± 0.005

**52**

**Table 3.**

*Note: σ =* √ *1/n* ∑*(xi – x¯)2*

*.*

*The fold increase of relative levels of the transcription factor CEBP alpha mRNA expression compared with metformin (4 mM) under decreasing of relative levels of the transcription factor Snail mRNA expression by vitamin E (analyzed in triplicates) in K562 cells line culture under 48-h vitamin E exposure (100 μM) calculated by 2−(∆∆Ct) method. Note: σ =* √ *1/n* ∑*(xi – x¯)2 .*

#### **Figure 2.**

*Schematic model of the vitamin E modulation in CML progression with EMT phenotype.*

#### **5. Discussion**

CML is characterized by an accelerated and unregulated proliferation of predominantly myeloid cells in the bone marrow with their accumulation in the blood. CML develops as a result of malignant transformation and clonal proliferation of pluripotent hematopoietic stem cells (HSCs), leading to overproduction of immature myeloid progenitor cells that results in blast cell crisis. The CML blast crisis resembles acute leukemia. Because the preeminent mutation driving CML is Bcr-ABL thyrosine kinase oncogene, the use of Bcr-Abl kinase inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, significantly improves treatment outcomes and extends the life expectancy of CML patients. However, imatinib resistance drives blast crisis progression. The persistence of LSCs remains a major obstacle to cure CML. The clinical CML blast crisis progression with LSC phenotype is practically incurable. Therefore, the blocking of terminal myeloid differentiation and LSC phenotype development defines a putatively new strategy for CML prevention.

The potential of vitamin E in regulation of these interdependent mechanisms in CML progression was hinted by several observations that were reported earlier. Sangodkar et al. [50] showed that vitamin E activates PP2A phosphatase resulting in Bcr-Abl thyrosine kinase inhibition and re-activation of myeloid differentiation pathway. In BCR/ABL transformed cells and CML blast crisis hematopoietic progenitors, the PP2A activity is strongly inhibited, while the pharmacological activation of PP2A suppresses BCL/ABL activity and induces BCR/ABL degradation [51]. The pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. The substances of several different classes are known as PP2A activating compounds, vitamin E (α-tocopherol) and its analogues having been reported among such compounds [50, 52].

Nevertheless, the effects of vitamin E on differentiation pathways in cells of blast crisis CML, in particular those involving restoration of the expression of CCAAT-enhancer binding protein alpha (C/EBPα) and granulocyte colony-stimulating factor receptor (G-CSFR) have not been yet studied. The expression of these proteins decreases drastically in chronic phase and blast crisis of CML [53, 54]. In this regard, we evaluated the effect of vitamin E on RNA expression of crucial factors of myeloid differentiation, C/EBRα and G-CSFR, in BCR-ABL-positive CML blast crisis K562 cells. Our data demonstrate that vitamin E restores the expression of C/EBPα and concequently G-CSFR. Our results are consistent with Tavor et al. [23] who demonstrated that the restoration of C/EBPα expression in BCR-ABLpositive KCL22 blast cell line triggered a proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis suggesting the activation of differentiation. Therefore, C/EBPα stimulated by vitamin E may be considered as a putative target in differentiation therapies in myeloid leukemias.

The second effect of vitamin E potentially useful for CML treatment was reported by Nieborowska-Skorska et al. [55] who demonstrated that vitamin E prevents accumulation of imatinib-resistant BCR-ABL1 kinase mutations in mice CML xenografts. The authors stressed anti-oxidant function of vitamin E in this processes. We use vitamin E as modulating factor in CML that involves vitamin E-dependent EMT mechanism of repression taking into account the pivotal role of EMT in the development of LSC phenotype. In this connection, we observed Snail1 overexpression suggesting some features of EMT phenotype in K562 cells seemingly contributing to CML pathogenesis. Furthermore, we have determined downregulation of CEBP alpha transcription factor representing the master regulator of myelopoiesis in CML cells coinciding with Snail1 overexpression. Our findings are quite consistent with the recent report by Lourenço et al. [43] who suggest that C/ EBP α is crucial determinant of epithelial maintenance by preventing EMT. Indeed, we have found that CEBP alpha is repressed by overexpression of EMT-inducer Snail in CML blast crisis K562 cells. Consequently, the reactivation of CEBP alpha by vitamin E is paralleled by suppression of Snail.

Therefore, our findings make deeper understanding of the role of vitamin E in suppression of CML LSC phenotype. In addition, we have revealed a new marker – aberrant placental-like alkaline phosphatase (PLAP) that expressed ectopically in CML progression. Moreover, its suppression by vitamin E consequently re-activates CEBP alpha and TNAP as myeloid differentiation factors. Taken together, our findings presented in this Chapter stress the role of vitamin E in modifying expression profile of CML cells towards restoration of myeloid differentiation potential.

#### **6. Conclusion**

Vitamin E is a complex group of lipid-soluble antioxidants comprising four tocopherols and four tocotrienols. It prevents production of reactive oxygen species (ROS) that are elevated in majority of tumor cells leading to lipid peroxydation, changing signaling pathways that control cell proliferation and apoptosis, expression of several transcription factors, epigenetic modulators, resistance to treatment,

**55**

**Author details**

Lyudmyla Shvachko1

and Gennadii Telegeev1

Ukraine, Kyiv, Ukraine

\*, Michael Zavelevich<sup>2</sup>

National Academy of Sciences of Ukraine, Kyiv, Ukraine

\*Address all correspondence to: l.shvachko@ukr.net

provided the original work is properly cited.

1 Institute of Molecular Biology and Genetics, National Academy of Sciences of

2 RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology,

© 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,

, Daniil Gluzman2

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention*

etc. We have suggested the causal relationship between EMT-Snail1 suppression and restoration of CEBP-alpha myeloid master regulator expression that seems to contribute to recover myeloid differentiation potential of CML blast cells by vitamin E. We first observed that vitamin E is an effective modulator of down-regulation of transcription factor Snail EMT-inducer and up-regulation of pivotal myelopoietic transcription factor CEBP alpha resulting in restoration of TNAP expression. Taken into account the data of literature and our findings, we can postulate that vitamin E might be used as a potential pharmacopoeian biological modulator capable of preventing the onset of blast crisis development, ameliorating disease progression and possibly overcoming drug resistance of leukemic cells in CML patients.

All authors of chapter are Laureates of the National Award of the Cabinet of Ministers of Ukraine for the development and implementation of innovative

technologies in the field of Biomedicine (N289.p from May 10, 2018).

*DOI: http://dx.doi.org/10.5772/intechopen.96452*

**Additional information**

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention DOI: http://dx.doi.org/10.5772/intechopen.96452*

etc. We have suggested the causal relationship between EMT-Snail1 suppression and restoration of CEBP-alpha myeloid master regulator expression that seems to contribute to recover myeloid differentiation potential of CML blast cells by vitamin E. We first observed that vitamin E is an effective modulator of down-regulation of transcription factor Snail EMT-inducer and up-regulation of pivotal myelopoietic transcription factor CEBP alpha resulting in restoration of TNAP expression. Taken into account the data of literature and our findings, we can postulate that vitamin E might be used as a potential pharmacopoeian biological modulator capable of preventing the onset of blast crisis development, ameliorating disease progression and possibly overcoming drug resistance of leukemic cells in CML patients.

### **Additional information**

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

a putative target in differentiation therapies in myeloid leukemias.

by vitamin E is paralleled by suppression of Snail.

The second effect of vitamin E potentially useful for CML treatment was reported by Nieborowska-Skorska et al. [55] who demonstrated that vitamin E prevents accumulation of imatinib-resistant BCR-ABL1 kinase mutations in mice CML xenografts. The authors stressed anti-oxidant function of vitamin E in this processes. We use vitamin E as modulating factor in CML that involves vitamin E-dependent EMT mechanism of repression taking into account the pivotal role of EMT in the development of LSC phenotype. In this connection, we observed Snail1 overexpression suggesting some features of EMT phenotype in K562 cells seemingly contributing to CML pathogenesis. Furthermore, we have determined downregulation of CEBP alpha transcription factor representing the master regulator of myelopoiesis in CML cells coinciding with Snail1 overexpression. Our findings are quite consistent with the recent report by Lourenço et al. [43] who suggest that C/ EBP α is crucial determinant of epithelial maintenance by preventing EMT. Indeed, we have found that CEBP alpha is repressed by overexpression of EMT-inducer Snail in CML blast crisis K562 cells. Consequently, the reactivation of CEBP alpha

Therefore, our findings make deeper understanding of the role of vitamin E in suppression of CML LSC phenotype. In addition, we have revealed a new marker – aberrant placental-like alkaline phosphatase (PLAP) that expressed ectopically in CML progression. Moreover, its suppression by vitamin E consequently re-activates CEBP alpha and TNAP as myeloid differentiation factors. Taken together, our findings presented in this Chapter stress the role of vitamin E in modifying expression profile of CML cells towards restoration of myeloid differentiation potential.

Vitamin E is a complex group of lipid-soluble antioxidants comprising four tocopherols and four tocotrienols. It prevents production of reactive oxygen species (ROS) that are elevated in majority of tumor cells leading to lipid peroxydation, changing signaling pathways that control cell proliferation and apoptosis, expression of several transcription factors, epigenetic modulators, resistance to treatment,

been reported among such compounds [50, 52].

pathway. In BCR/ABL transformed cells and CML blast crisis hematopoietic progenitors, the PP2A activity is strongly inhibited, while the pharmacological activation of PP2A suppresses BCL/ABL activity and induces BCR/ABL degradation [51]. The pharmacological modulation of PP2A activity is becoming an attractive strategy for cancer treatment. The substances of several different classes are known as PP2A activating compounds, vitamin E (α-tocopherol) and its analogues having

Nevertheless, the effects of vitamin E on differentiation pathways in cells of blast crisis CML, in particular those involving restoration of the expression of CCAAT-enhancer binding protein alpha (C/EBPα) and granulocyte colony-stimulating factor receptor (G-CSFR) have not been yet studied. The expression of these proteins decreases drastically in chronic phase and blast crisis of CML [53, 54]. In this regard, we evaluated the effect of vitamin E on RNA expression of crucial factors of myeloid differentiation, C/EBRα and G-CSFR, in BCR-ABL-positive CML blast crisis K562 cells. Our data demonstrate that vitamin E restores the expression of C/EBPα and concequently G-CSFR. Our results are consistent with Tavor et al. [23] who demonstrated that the restoration of C/EBPα expression in BCR-ABLpositive KCL22 blast cell line triggered a proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis suggesting the activation of differentiation. Therefore, C/EBPα stimulated by vitamin E may be considered as

**54**

**6. Conclusion**

All authors of chapter are Laureates of the National Award of the Cabinet of Ministers of Ukraine for the development and implementation of innovative technologies in the field of Biomedicine (N289.p from May 10, 2018).

### **Author details**

Lyudmyla Shvachko1 \*, Michael Zavelevich<sup>2</sup> , Daniil Gluzman2 and Gennadii Telegeev1

1 Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

2 RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine

\*Address all correspondence to: l.shvachko@ukr.net

© 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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**59**

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*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention*

[51] Neviani P, Santhanam R, Trotta R, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005; 8: 355-368. DOI:

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2A: a novel druggable target for Alzheimer's disease. Future Medicinal Chemistry. 2011; 3: 821-833. DOI: 10.1007/s11596-020-2140-1

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[54] Chang JS, Santhanam R, Trotta R,

oncoprotein are required for the MAPhnRNP-E2-dependent suppression of C/ EBPα-driven myeloid differentiation. Blood. 2007; 10: 994-1002. DOI: 10.1182/blood-2007-03-078303.

[55] Nieborowska-Skorska M., Hoser G., Hochhaus A. et al. Anti-oxidant vitamin E prevents accumulation of imatinibresistant BCR-ABL1 kinase mutations in CML-CP xenografts in NSG mice. Leukemia. 2013, 27(11): 2253-2254.

et al. High levels of BCR-ABL

DOI : 10.1038/leu.2013.123

*DOI: http://dx.doi.org/10.5772/intechopen.96452*

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[44] Kidan NH, Ruimi N, Roitman Sh. Ectopic expression of Snail and Twist in Ph+ leukemia cells upregulates CD44 expression and alters their differentiation potential. Journal of Cancer. 2017; 8(8): 3952-3968. DOI:

[45] Wang Y, Shi J, Chai K. et al. The role of Snail in EMT and

[46] Cano A, Perez-Moreno MA,

76-83. DOI: 10.1038/35000025.

[48] Lourenço AN, Roukens MG, Seinstra D. et al. C/EBP α is crucial determinant of epithelial maintenance

by preventing epithelial-tomesenchymal transition. Nature Communication. 2020; 11: 785. DOI:

10.1038/s41467-020-14556-x

[49] Yoshida J, Ishikawa T, Endo Y, et al. Metformin inhibits TGF β1 induced epithelial mesenchymal transition and liver metastasis of pancreatic cancer cells. Oncology Reports. 2020; 44(1): 371-381. https://doi.org/10.3892/

[50] Sangodkar J, Farrington CC, McClinch K, et al. All roads lead to PP2A: Exploiting the therapeutic potential of this phosphatase. FEBS Journal. 2016; 283: 1004-1024. DOI:

tumorigenesis. Current Cancer Drug Targets. 2013; 13(9): 963-972. DOI: 10.2174/15680096113136660102.

Rodrigo I. et al. The transcription factor snail controls epithelialmesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology. 2000; 2:

[47] Carmichel CL, Goossens S, Wang J. et al. The EMT Modulator SNAI1 Drives AML Development Via Its Interaction with the Chromatin Modulator LSD1. Blood. 2016; 128 (22): 2688. DOI: 10.1182/blood.V128.22.2688.2688

10.7150/jca.19633.

*Vitamin E in Chronic Myeloid Leukemia (CML) Prevention DOI: http://dx.doi.org/10.5772/intechopen.96452*

with increased aggressiveness. Journal of Molecular Cell Biology. 2012; 4(4): 207-220. DOI: 10.1093/jmcb/mjs010

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

in the mouse embryo. Development. 1990; 110 (2): 555-564. PMID: 2133555

[37] Kim YH, Yoon DS, Kim HO, Lee JW. Characterization of different subpopulations from bone marrowderived mesenchymal stromal cells by alkaline phosphatase expression. Stem Cells and Development 2012; 21(16): 2958-2968. DOI: 10.1089/scd.2011.0349.

[38] Jamieson CH. Chronic myeloid leukemia stem cells. Hematology ASH Education Program. 2008; 436-442. DOI: 10.1182/asheducation-2008.1.436.

[39] Crews L.A., Jamiesson C.H.M. Chronic Myeloi-d Leukemia Stem Cell Biology. Current Hematological Malignancies Reports. 2012; 7(2):125- 132. DOI: 10.1007/s11899012-0121-6

[40] Liu X, Fan D. The epithelialmesenchymal transition and cancer stem cells: functional and mechanistic links. Current Pharmacology Design. 2015; 21(10):1279-1291. DOI: 10.2174/13

[41] Jolly MK, Huang B, Lu M. et al. Towards elucidating the connection between epithelial mesenchymal transitions and stemness. Journal of Royal Society Interface. 2014; 11: 20140962. DOI: 10.1098/

[42] Chen S., Liao T., Yang M. Emerging roles of epithelial-mesenchymal transition in hematological

malignancies. Journal of Biomedical Sciences. 2018; 25: 37. DOI: 10.1186/

[43] PuissantA., Dufies M., Fenouille N. et al. Imatinib triggers mesenchymallike conversion of CML cells associated

81612821666141211115611.

rsif.2014.0962.

s12929-018-0440-6.

s12291-013-0408-y.

[36] Sharma U, Pal D, Prasad R. Alkaline phosphatase: An overview. Indian Journal of Clinical Biochemistry. 2014; 29(3): 269-278. DOI: 10.1007/

Japanese Journal of Clinical Oncology. 2015; 45: 749-754. DOI:org/10.1093/

Independent Mechanisms of Resistance in Chronic Myeloid Leukemia. Frontiers in Oncology. 2019; 9: 939. DOI:10.3389/

[30] Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. Journal of Clinical Investigations. 2011; 121: 396-409. DOI: 10.1172/

[31] Chomel JC, Bonnet ML, Sorel N, et al. Leukemic stem cell persistence

patients with sustained undetectable molecular residual disease. Blood 2011; 118: 3657-3660. DOI: 10.1182/

[32] Chu S, McDonald T, Lin A, et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood. 2011; 118: 5565-5572. DOI: 10.1182/

[33] Metwalli AR, Rosner IL, Cullen J, et al. Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate resistant prostate cancer. Urological Oncology. 2014; 32(6): 761-768.DOI: 10.1016/j.

in chronic myeloid leukemia

blood-2011-02-335497.

blood-2010-12-327437.

urolonc.2014.03.024.

2015; 2015: 628368. DOI: 10.1155/2015/628368.

[34] Stefkova K, Prochazkova J, Pachernik J. Alkaline phosphatase in stem cells. Stem Cells International.

[35] Hahnel AC, Rappolee DA, Millan JL, et al. Two alkaline phosphatase genes are expressed during early development

jjco/hyv064

fonc.2019.00939

JCI35721.

[29] Loscocco F, Visani G, Galimberti S, et al. BCR-ABL

**58**

[44] Kidan NH, Ruimi N, Roitman Sh. Ectopic expression of Snail and Twist in Ph+ leukemia cells upregulates CD44 expression and alters their differentiation potential. Journal of Cancer. 2017; 8(8): 3952-3968. DOI: 10.7150/jca.19633.

[45] Wang Y, Shi J, Chai K. et al. The role of Snail in EMT and tumorigenesis. Current Cancer Drug Targets. 2013; 13(9): 963-972. DOI: 10.2174/15680096113136660102.

[46] Cano A, Perez-Moreno MA, Rodrigo I. et al. The transcription factor snail controls epithelialmesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology. 2000; 2: 76-83. DOI: 10.1038/35000025.

[47] Carmichel CL, Goossens S, Wang J. et al. The EMT Modulator SNAI1 Drives AML Development Via Its Interaction with the Chromatin Modulator LSD1. Blood. 2016; 128 (22): 2688. DOI: 10.1182/blood.V128.22.2688.2688

[48] Lourenço AN, Roukens MG, Seinstra D. et al. C/EBP α is crucial determinant of epithelial maintenance by preventing epithelial-tomesenchymal transition. Nature Communication. 2020; 11: 785. DOI: 10.1038/s41467-020-14556-x

[49] Yoshida J, Ishikawa T, Endo Y, et al. Metformin inhibits TGF β1 induced epithelial mesenchymal transition and liver metastasis of pancreatic cancer cells. Oncology Reports. 2020; 44(1): 371-381. https://doi.org/10.3892/ or.2020.7595.

[50] Sangodkar J, Farrington CC, McClinch K, et al. All roads lead to PP2A: Exploiting the therapeutic potential of this phosphatase. FEBS Journal. 2016; 283: 1004-1024. DOI: 10.1111/febs.13573.

[51] Neviani P, Santhanam R, Trotta R, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005; 8: 355-368. DOI: 10.1016/j.ccr.2005.10.015.

[52] Voronkov M, Braitwaite SP, Stockt JB. Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease. Future Medicinal Chemistry. 2011; 3: 821-833. DOI: 10.1007/s11596-020-2140-1

[53] Perrotti D, Cesi V, Trotta R, et al. BCR/ABL suppresses C/EBR expression through inhibitory action of RNPE2. Nature Genetics. 2002; 30: 48-58. DOI: 10.1038/ng791.

[54] Chang JS, Santhanam R, Trotta R, et al. High levels of BCR-ABL oncoprotein are required for the MAPhnRNP-E2-dependent suppression of C/ EBPα-driven myeloid differentiation. Blood. 2007; 10: 994-1002. DOI: 10.1182/blood-2007-03-078303.

[55] Nieborowska-Skorska M., Hoser G., Hochhaus A. et al. Anti-oxidant vitamin E prevents accumulation of imatinibresistant BCR-ABL1 kinase mutations in CML-CP xenografts in NSG mice. Leukemia. 2013, 27(11): 2253-2254. DOI : 10.1038/leu.2013.123

**61**

**Chapter 4**

**Abstract**

Health Promotion

*and Thaís Nogueira Barradas*

tions as well as favor its skin penetration.

**1. Introduction**

**Keywords:** antioxidant, tocopherols, tocotrienols, skin, health

Neurodegenerative and metabolic diseases progression is related to oxidative stress [1, 2], a condition where there is a lower ability of endogenous antioxidants to scavenge free radicals [3] resulting in free radicals increase. Most frequent free radicals are the reactive oxygen species (ROS) such as singlet oxygen, hydrogen peroxide and hydroperoxide. ROS are formed endogenously [4] and its production is raised by some environmental factors [3]. Major internal sources are mitochondrial oxidative reactions, phagocytosis by macrophages and xenobiotics metabolization [4]. Environmental factors include pollution, ultraviolet radiation and smoking [3]. Free radicals damage DNA, protein and lipids [4] and their increase is involved in diabetes progression [1] and in Alzheimer and Parkinson's diseases onset [2]. In addition, cystic fibrosis patients are more prone to oxidative stress owing to vitamin E deficiency [3]. Some endogenous antioxidants are glutathione peroxidase, vitamin C and vitamin E [4]. Vitamin E is a non-enzymatic endogenous antioxidant [4] preventing atherosclerosis due to reduction of low density lipoprotein (LDL) oxidation. Beyond from antioxidant, it has a fundamental role in neurological and immune system function [4]. Accordingly, oral intake of vitamin E would be an interesting

*Júlia Scherer Santos, Guilherme Diniz Tavares* 

Vitamin E and Derivatives in Skin

Vitamin E is fundamental for a proper function of human cells. Mostly obtained from vegetable oils, it has antioxidant and non-antioxidant actions. At times, its oral intake or skin application are employed. Oral intake is recommended in some cases. Differently, the topical application is a part of daily skin routine. Both in oral or in topical formulations, it is employed in its isoforms or derivatives. Tocopherols and tocotrienols are isoforms while derivatives are synthetic forms. In pharmaceutical and cosmetic formulations, vitamin E and its derivatives are widely used due to its antioxidant and photoprotective properties. However, the clinical success treatment is often impaired by its low skin penetration, high lipophilicity, and chemical instability. A rational formulation design in the development of novel vitamin E dosage forms is required. In this chapter, the most successful and innovative approaches towards Vitamin E and its derivatives loaded in formulations for skin health promotion are reviewed. Conventional and nanoparticle-based formulations enable vitamin E chemical stabilization, and they are suitable vehicles for its release on the skin. Further, nano-sized carriers can increase vitamin E content in formula-

#### **Chapter 4**

## Vitamin E and Derivatives in Skin Health Promotion

*Júlia Scherer Santos, Guilherme Diniz Tavares and Thaís Nogueira Barradas*

#### **Abstract**

Vitamin E is fundamental for a proper function of human cells. Mostly obtained from vegetable oils, it has antioxidant and non-antioxidant actions. At times, its oral intake or skin application are employed. Oral intake is recommended in some cases. Differently, the topical application is a part of daily skin routine. Both in oral or in topical formulations, it is employed in its isoforms or derivatives. Tocopherols and tocotrienols are isoforms while derivatives are synthetic forms. In pharmaceutical and cosmetic formulations, vitamin E and its derivatives are widely used due to its antioxidant and photoprotective properties. However, the clinical success treatment is often impaired by its low skin penetration, high lipophilicity, and chemical instability. A rational formulation design in the development of novel vitamin E dosage forms is required. In this chapter, the most successful and innovative approaches towards Vitamin E and its derivatives loaded in formulations for skin health promotion are reviewed. Conventional and nanoparticle-based formulations enable vitamin E chemical stabilization, and they are suitable vehicles for its release on the skin. Further, nano-sized carriers can increase vitamin E content in formulations as well as favor its skin penetration.

**Keywords:** antioxidant, tocopherols, tocotrienols, skin, health

#### **1. Introduction**

Neurodegenerative and metabolic diseases progression is related to oxidative stress [1, 2], a condition where there is a lower ability of endogenous antioxidants to scavenge free radicals [3] resulting in free radicals increase. Most frequent free radicals are the reactive oxygen species (ROS) such as singlet oxygen, hydrogen peroxide and hydroperoxide. ROS are formed endogenously [4] and its production is raised by some environmental factors [3]. Major internal sources are mitochondrial oxidative reactions, phagocytosis by macrophages and xenobiotics metabolization [4]. Environmental factors include pollution, ultraviolet radiation and smoking [3]. Free radicals damage DNA, protein and lipids [4] and their increase is involved in diabetes progression [1] and in Alzheimer and Parkinson's diseases onset [2]. In addition, cystic fibrosis patients are more prone to oxidative stress owing to vitamin E deficiency [3].

Some endogenous antioxidants are glutathione peroxidase, vitamin C and vitamin E [4]. Vitamin E is a non-enzymatic endogenous antioxidant [4] preventing atherosclerosis due to reduction of low density lipoprotein (LDL) oxidation. Beyond from antioxidant, it has a fundamental role in neurological and immune system function [4]. Accordingly, oral intake of vitamin E would be an interesting alternative treatment to oxidative related diseases to improve patients quality of life [5, 6]. Apart from oral intake, natural sources of this vitamin are the vegetable oils. Wheat germ oil, sunflower oil, rice bran oil, canola oil and palm oil are some representants rich in vitamin E. Nuts and fresh foods contain vitamin E, but in smaller amounts [4].

#### **1.1 Vitamin E isoforms and derivatives**

A sum of 4 tocopherols isomers and 4 tocotrienols isomers compose vitamin E. Isomers are named as alpha, beta, gamma and delta and their chemical structures are shown in **Figure 1**. Tocopherols and tocotrienols differ only in their side chain. Tocotrienols have an unsaturation on its side chain. In respect to isomers, the nomenclature is due to substitutions in R1 and R2 positions. Alpha isomers have a methyl group both at R1 and R2 while delta isomers do not have any methyl group. Instead, beta and gamma isomers have one single methyl group, in R1 or in R2. Regardless of the source, vegetables contain a mixture of isoforms and one of them is predominant [7, 8]. Isoforms are obtained through extraction from vitamin E- rich vegetables such as wheat (shown in **Figure 1**) whose principal isoform is alphatocopherol [7]. Chemical synthesis is employed to obtain alpha-tocopherol [7, 8].

Commercially, vitamin E is available mainly as alpha-tocopherol [9, 10] or tocopheryl acetate [11–13] which are used above all to oral [14, 15] and skin [10, 12, 16] applications, respectively. Among vitamin E derivatives are tocopheryl acetate, tocopheryl glucoside and tocopheryl phosphate. Tocopheryl acetate is the most used vitamin E derivative [17] also named as tocopherol acetate or vitamin E acetate [18]. It is obtained through tocopherol modification to improve stability since tocopherol is a labile form. However, tocopheryl acetate is biologically inactive and it must be converted to tocopherol in skin and intestine. Often, there is no mention about tocopheryl acetate isomer as alpha-tocopheryl acetate is the most used [8].

Regarding human use, there is no standardization about vitamin E dose neither in oral intake [14, 15] nor in skin formulations [10, 19, 20]. Although its deficiency in adults is unusual [4], its oral intake may be recommended in cystic fibrosis

#### **Figure 1.**

*Extraction of vitamin E isoforms, chemical structure of Tocopherols, Tocotrienols and Tocopheryl acetate. Created in BioRender and ACD/ChemSketch.*

**63**

**Table 1.**

diseases treatments.

**2. Vitamin E in skin care formulations**

*Vitamin E and Derivatives in Skin Health Promotion DOI: http://dx.doi.org/10.5772/intechopen.99466*

patients [21]. Oral supplementation is equally used to reduce ultraviolet damage to skin [14, 15]. Furthermore, its combination with other antioxidants is a common approach. Vitamin C is the most used one [15, 19, 20] because it regenerates oxidized vitamin E [22]. Oxidized vitamin E if not properly regenerated may promote lipid peroxidation instead of preventing it [4]. The association of several antioxi-

**Skin effect Mechanism of action References** Photoprotection Lipid peroxidation reduction [23–25]

Cancer prevention Pyrimidine dimers reduction [30] Reduction of melanoma progression Apoptosis induction [31, 32]

Improvement of melasma Reduction of tyrosinase activity [33, 34]

Reduction of Skin Aging Increased collagen expression [36, 37]

*\*TYR: Tyrosinase, TYRP-1: tyrosinase-related protein-1, TYRP-2: tyrosinase-related protein- 2.*

Endogenous antioxidants protection [24–26] Erythema decrease [27, 28] Inflammation reduction [29]

Cell cycle arrest [32]

Down-regulation of TYRP-2 expression [34] Down-regulation of TYR, TYRP-1, TYRP-2\* [35]

Decrease metalloproteinases expression [37]

The knowledge about vitamin E effects is essential to guide its use in dermatological treatments. **Table 1** shows some skin effects and mechanisms of action to vitamin E isoforms and derivatives. Photoprotection was approached mostly in earlier studies [23, 27, 28] while current ones approach mostly skin diseases [31, 35]. The antioxidant activity accounts for many skin effects including photoprotection [23–25], skin aging reduction [36, 37] and pyrimidine dimers reduction. The latter effect is important to prevent cancer onset [30]. Moreover, as reactive oxygen species are involved in the pathogenesis of psoriasis and atopic dermatitis [38–40], the topical application

dants is then extremely important to reduce oxidative stress.

of vitamin E isoforms would be likewise beneficial in these diseases.

In relation to isomers, earlier researches were directed mainly to alphatocopherol whose action is lipid peroxidation reduction [24]. Nowadays, research is focused on tocotrienols [31] and tocotrienol-rich fraction [35–37] which are able to reduce melanoma progression [31, 32], melanogenesis [35] and skin aging [36, 37]. Tocotrienol-rich fraction (TRF) is a mixture of tocotrienols and alpha-tocopherol [41] allowing to combine the pharmacological benefits of several isomers. Further studies over tocotrienols and TRF are required to prove their efficacy in skin

Conventional formulations [42] and nanotechnological-based formulations [16, 43] have been used to deliver vitamin E and its derivatives into the skin due

**1.2 Benefits on skin health and dermatological diseases**

*General skin effects and mechanisms of vitamin E isoforms and derivatives.*



#### **Table 1.**

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

smaller amounts [4].

**1.1 Vitamin E isoforms and derivatives**

alpha-tocopheryl acetate is the most used [8].

alternative treatment to oxidative related diseases to improve patients quality of life [5, 6]. Apart from oral intake, natural sources of this vitamin are the vegetable oils. Wheat germ oil, sunflower oil, rice bran oil, canola oil and palm oil are some representants rich in vitamin E. Nuts and fresh foods contain vitamin E, but in

A sum of 4 tocopherols isomers and 4 tocotrienols isomers compose vitamin E. Isomers are named as alpha, beta, gamma and delta and their chemical structures are shown in **Figure 1**. Tocopherols and tocotrienols differ only in their side chain. Tocotrienols have an unsaturation on its side chain. In respect to isomers, the nomenclature is due to substitutions in R1 and R2 positions. Alpha isomers have a methyl group both at R1 and R2 while delta isomers do not have any methyl group. Instead, beta and gamma isomers have one single methyl group, in R1 or in R2. Regardless of the source, vegetables contain a mixture of isoforms and one of them is predominant [7, 8]. Isoforms are obtained through extraction from vitamin E- rich vegetables such as wheat (shown in **Figure 1**) whose principal isoform is alphatocopherol [7]. Chemical synthesis is employed to obtain alpha-tocopherol [7, 8]. Commercially, vitamin E is available mainly as alpha-tocopherol [9, 10] or tocopheryl acetate [11–13] which are used above all to oral [14, 15] and skin [10, 12, 16] applications, respectively. Among vitamin E derivatives are tocopheryl acetate, tocopheryl glucoside and tocopheryl phosphate. Tocopheryl acetate is the most used vitamin E derivative [17] also named as tocopherol acetate or vitamin E acetate [18]. It is obtained through tocopherol modification to improve stability since tocopherol is a labile form. However, tocopheryl acetate is biologically inactive and it must be converted to tocopherol in skin and intestine. Often, there is no mention about tocopheryl acetate isomer as

Regarding human use, there is no standardization about vitamin E dose neither in oral intake [14, 15] nor in skin formulations [10, 19, 20]. Although its deficiency in adults is unusual [4], its oral intake may be recommended in cystic fibrosis

*Extraction of vitamin E isoforms, chemical structure of Tocopherols, Tocotrienols and Tocopheryl acetate.* 

**62**

**Figure 1.**

*Created in BioRender and ACD/ChemSketch.*

*General skin effects and mechanisms of vitamin E isoforms and derivatives.*

patients [21]. Oral supplementation is equally used to reduce ultraviolet damage to skin [14, 15]. Furthermore, its combination with other antioxidants is a common approach. Vitamin C is the most used one [15, 19, 20] because it regenerates oxidized vitamin E [22]. Oxidized vitamin E if not properly regenerated may promote lipid peroxidation instead of preventing it [4]. The association of several antioxidants is then extremely important to reduce oxidative stress.

#### **1.2 Benefits on skin health and dermatological diseases**

The knowledge about vitamin E effects is essential to guide its use in dermatological treatments. **Table 1** shows some skin effects and mechanisms of action to vitamin E isoforms and derivatives. Photoprotection was approached mostly in earlier studies [23, 27, 28] while current ones approach mostly skin diseases [31, 35]. The antioxidant activity accounts for many skin effects including photoprotection [23–25], skin aging reduction [36, 37] and pyrimidine dimers reduction. The latter effect is important to prevent cancer onset [30]. Moreover, as reactive oxygen species are involved in the pathogenesis of psoriasis and atopic dermatitis [38–40], the topical application of vitamin E isoforms would be likewise beneficial in these diseases.

In relation to isomers, earlier researches were directed mainly to alphatocopherol whose action is lipid peroxidation reduction [24]. Nowadays, research is focused on tocotrienols [31] and tocotrienol-rich fraction [35–37] which are able to reduce melanoma progression [31, 32], melanogenesis [35] and skin aging [36, 37]. Tocotrienol-rich fraction (TRF) is a mixture of tocotrienols and alpha-tocopherol [41] allowing to combine the pharmacological benefits of several isomers. Further studies over tocotrienols and TRF are required to prove their efficacy in skin diseases treatments.

#### **2. Vitamin E in skin care formulations**

Conventional formulations [42] and nanotechnological-based formulations [16, 43] have been used to deliver vitamin E and its derivatives into the skin due to its moisturizing, photoprotective, antioxidant [44, 45] and anticancer properties [46]. Some formulations applied to skin care are summarized in **Table 2**. Mainly sunscreens and anti-aging commercial products contain this vitamin [42]. Additionally, some cosmetic brands have explored the "anti-pollution" claim in their labels. As pollution triggers oxidative stress, the "anti-pollution" effect prevents skin damage induced by pollutants [19].

Nevertheless, several limitations impact vitamin E isoforms and derivatives bioavailability. Their bioactivity in different target sites, such as the skin is affected. Vitamin E is an unstable molecule because it undergoes oxidation, especially the light-triggered phenomena [60]. In this sense, novel drug delivery systems have been extensively investigated to improve vitamin E bioavailability, solubility, stability and biodistribution. Consequently, a better skin penetration can be accomplished [61, 62].

#### **2.1 Conventional formulations**

Emulsions and hydroalcoholic gel are the most common conventional formulations bearing either tocopherol, tocopheryl acetate or other esters (succinate, nicotinate, linoleate, and phosphate). The isoform α-tocopherol is the one with the best cost–benefit ratio [42]. One single α-tocopherol molecule is capable of neutralizing 2 peroxidil radicals which is responsible for lipid oxidation initiation. Then, a delay in the development of several oxidation-based disorders could be achieved [38]. Despite being less effective than tocopherol, tocopheryl acetate is widely used in formulations intended to skin delivery [42].

In sunscreens formulations, vitamin E and its derivatives increase the sun protection factor [47] and contribute to the photostabilization of chemical filters [49]. After skin permeation, they can minimize the oxidative stress harmful effects


#### **Table 2.**

*Vitamin E isoforms and derivatives in conventional forms and nanotechnology-based systems.*

**65**

*Vitamin E and Derivatives in Skin Health Promotion DOI: http://dx.doi.org/10.5772/intechopen.99466*

**2.2 Nanotechnology-based formulations**

some nanocarriers used to deliver vitamin E into skin.

nanoparticles [54].

volunteers [48].

caused by UV radiation [48, 63]. In the latter case, an adequate vehicle is important since it can influence its permeation. In this regard, especially o/w (oil- in-water) emulsions have been used as the vehicle of choice [64]. From this perspective, a report showed that o/w emulsion containing vitamin E prevented erythema induction and reduced inflammatory damage caused by UV exposure in healthy

In anti-aging formulations, vitamin E and its derivatives act as antioxidants, scavenging free radicals, the principal accelerators of skin aging [65]. As regards to α-tocopherol, it decreased expression lines, wrinkles, and freckles induced by photoaging in a study performed *in vivo* [66]. In addition, α-tocopherol smooths the skin, increases the stratum corneum ability to maintain its humidity and accelerates the epithelialization process [67]. For these purposes of use, most commercially

Furthermore, the association of vitamin E and its derivatives with other ingredients increased the effectiveness of different dermocosmetic treatments [45]. In this sense, the application of a lotion combining α-tocopherol phosphate, ascorbyl 2-phosphate 6-palmitate, and glyceryl-octyl-ascorbic acid reduced the complications of acne vulgaris [52]. On the other hand, in a randomized controlled trial, a cream containing hydroquinone, buffered glycolic acid, vitamins C and E, and sunscreen was safe and effective in melasma treatment [50]. Recently, a serum containing vitamin C, tocopheryl acetate and raspberry leaf cell culture extract had anti-aging and brightening effects on the skin, with significant improvement of skin color, elasticity, and radiance. The smoothness, scaliness, and wrinkles were also improved by topical use of the product once a day, during eight weeks [51].

Bioactives molecules and lipophilic vitamins release on or into the skin by topical products comprise a challenging task owing to the characteristics of the stratum corneum barrier. Thereby, the drug accumulates on the skin surface. Besides, vitamin E low stability by its direct exposure to UV radiation can limit conventional formulations effectiveness [58]. Therefore, when it comes to topical administration, nanostructured drug vehicles have shown advantages over conventional delivery systems. The most investigated nanostructured carriers for vitamin E comprise liposomes, nanoemulsions, polymer nanoparticles and lipid-based

Liposomes are self-assembled vesicles composed by one or more hydrophobic bilayers constituted by amphiphilic phospholipids which originate an aqueous core domain. Phospholipids contain phosphorus in their composition [68]. Diversely, nanoemulsions are thermodynamically unstable surfactant-stabilized systems composed of nano-sized micelles bearing an oily nucleus [69]. Polymer nanoparticles, whether nanocapsules or nanospheres, are colloidal artificially prepared spherical carriers surrounded by a polymer membrane. Nanocapsules contain an oily core and nanospheres contain a polymeric matrix [70]. Besides, chitosan obtained from shrimp and crab shells [71] is employed to form polymeric nanoparticles. In these nanoparticles, there is a matrix formed by chitosan and tripolyphosphate. The latter is used as a crosslinking agent [58]. Elseways, lipid nanoparticles either solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) have a lipophilic bioactive entrapped. SLN are formed by a solid lipid-based core while NLC are formed by a mixture of solid and liquid lipids [72]. **Figure 2** shows the general structures of

Concerning liposomes, an optimized composition [73], a proper selection of preparation methods and a suitable particle size range [74] are essential as skin

available formulations are emulsions o/w, both in creams and lotions.

#### *Vitamin E and Derivatives in Skin Health Promotion DOI: http://dx.doi.org/10.5772/intechopen.99466*

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

prevents skin damage induced by pollutants [19].

in formulations intended to skin delivery [42].

**Skin formulation Skin care** 

accomplished [61, 62].

**2.1 Conventional formulations**

to its moisturizing, photoprotective, antioxidant [44, 45] and anticancer properties [46]. Some formulations applied to skin care are summarized in **Table 2**. Mainly sunscreens and anti-aging commercial products contain this vitamin [42]. Additionally, some cosmetic brands have explored the "anti-pollution" claim in their labels. As pollution triggers oxidative stress, the "anti-pollution" effect

Nevertheless, several limitations impact vitamin E isoforms and derivatives bioavailability. Their bioactivity in different target sites, such as the skin is affected. Vitamin E is an unstable molecule because it undergoes oxidation, especially the light-triggered phenomena [60]. In this sense, novel drug delivery systems have been extensively investigated to improve vitamin E bioavailability, solubility, stability and biodistribution. Consequently, a better skin penetration can be

Emulsions and hydroalcoholic gel are the most common conventional formula-

tions bearing either tocopherol, tocopheryl acetate or other esters (succinate, nicotinate, linoleate, and phosphate). The isoform α-tocopherol is the one with the best cost–benefit ratio [42]. One single α-tocopherol molecule is capable of neutralizing 2 peroxidil radicals which is responsible for lipid oxidation initiation. Then, a delay in the development of several oxidation-based disorders could be achieved [38]. Despite being less effective than tocopherol, tocopheryl acetate is widely used

In sunscreens formulations, vitamin E and its derivatives increase the sun protection factor [47] and contribute to the photostabilization of chemical filters [49]. After skin permeation, they can minimize the oxidative stress harmful effects

Conventional formulations Photoprotection α-tocopherol [10, 47]

Nanotechnology-based systems Photoprotection Tocopheryl acetate [43, 53]

*Vitamin E isoforms and derivatives in conventional forms and nanotechnology-based systems.*

**Vitamin E isoform or** 

Tricotrienol-rich fraction

Tocopheryl acetate [48, 49]

α-tocopherol [54, 55]

γ-tocotrienol [59]

α-tocopherol [9]

**Reference**

[25]

**derivative**

Melasma Tocopheryl acetate [50] Anti-pollution α-tocopherol [19] Skin aging Tocopheryl acetate [51] Acne vulgaris Tocopheryl phosphate [52]

Wound healing Tocopheryl acetate [56, 57] Dermatitis α-tocopherol [58, 59]

Skin aging α-tocopherol [9] Moisturization Tocopheryl acetate [16]

**application**

**64**

**Table 2.**

caused by UV radiation [48, 63]. In the latter case, an adequate vehicle is important since it can influence its permeation. In this regard, especially o/w (oil- in-water) emulsions have been used as the vehicle of choice [64]. From this perspective, a report showed that o/w emulsion containing vitamin E prevented erythema induction and reduced inflammatory damage caused by UV exposure in healthy volunteers [48].

In anti-aging formulations, vitamin E and its derivatives act as antioxidants, scavenging free radicals, the principal accelerators of skin aging [65]. As regards to α-tocopherol, it decreased expression lines, wrinkles, and freckles induced by photoaging in a study performed *in vivo* [66]. In addition, α-tocopherol smooths the skin, increases the stratum corneum ability to maintain its humidity and accelerates the epithelialization process [67]. For these purposes of use, most commercially available formulations are emulsions o/w, both in creams and lotions.

Furthermore, the association of vitamin E and its derivatives with other ingredients increased the effectiveness of different dermocosmetic treatments [45]. In this sense, the application of a lotion combining α-tocopherol phosphate, ascorbyl 2-phosphate 6-palmitate, and glyceryl-octyl-ascorbic acid reduced the complications of acne vulgaris [52]. On the other hand, in a randomized controlled trial, a cream containing hydroquinone, buffered glycolic acid, vitamins C and E, and sunscreen was safe and effective in melasma treatment [50]. Recently, a serum containing vitamin C, tocopheryl acetate and raspberry leaf cell culture extract had anti-aging and brightening effects on the skin, with significant improvement of skin color, elasticity, and radiance. The smoothness, scaliness, and wrinkles were also improved by topical use of the product once a day, during eight weeks [51].

#### **2.2 Nanotechnology-based formulations**

Bioactives molecules and lipophilic vitamins release on or into the skin by topical products comprise a challenging task owing to the characteristics of the stratum corneum barrier. Thereby, the drug accumulates on the skin surface. Besides, vitamin E low stability by its direct exposure to UV radiation can limit conventional formulations effectiveness [58]. Therefore, when it comes to topical administration, nanostructured drug vehicles have shown advantages over conventional delivery systems. The most investigated nanostructured carriers for vitamin E comprise liposomes, nanoemulsions, polymer nanoparticles and lipid-based nanoparticles [54].

Liposomes are self-assembled vesicles composed by one or more hydrophobic bilayers constituted by amphiphilic phospholipids which originate an aqueous core domain. Phospholipids contain phosphorus in their composition [68]. Diversely, nanoemulsions are thermodynamically unstable surfactant-stabilized systems composed of nano-sized micelles bearing an oily nucleus [69]. Polymer nanoparticles, whether nanocapsules or nanospheres, are colloidal artificially prepared spherical carriers surrounded by a polymer membrane. Nanocapsules contain an oily core and nanospheres contain a polymeric matrix [70]. Besides, chitosan obtained from shrimp and crab shells [71] is employed to form polymeric nanoparticles. In these nanoparticles, there is a matrix formed by chitosan and tripolyphosphate. The latter is used as a crosslinking agent [58]. Elseways, lipid nanoparticles either solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) have a lipophilic bioactive entrapped. SLN are formed by a solid lipid-based core while NLC are formed by a mixture of solid and liquid lipids [72]. **Figure 2** shows the general structures of some nanocarriers used to deliver vitamin E into skin.

Concerning liposomes, an optimized composition [73], a proper selection of preparation methods and a suitable particle size range [74] are essential as skin

**Figure 2.**

*Structure of some vitamin E nanocarriers. SLN: Solid lipid nanoparticles. NLC: Nanostructured lipid carriers. TPP: Tripolyphosphate. Created in BioRender.*

penetration will be affected by these factors. Regarding biological activity, vitamin E-loaded liposomes inhibited lipid peroxidation more effectively than free vitamin E [74]. Lately, tocopherol acetate-loaded transferosomes optimized wound healing process [56]. As transferosomes are elastic liposome-like ultra-deformable vesicles, a higher diffusion across the stratum corneum can be accomplished [75, 76]. Topical administration of vitamin E-loaded liposomes are also interesting to enable a high drug penetration and transdermal release into skin tumors [68].

Lipid nanoparticles ability to increase sunscreens efficacy was previously shown [53, 55]. Tocopherol acetate-loaded SLN increased sunscreen UV-blocking effect [53]. Moreover, alpha-tocopherol and sunscreens loaded in NLC and SLN increased vitamin E photostability. Additionally, nanoencapsulated vitamin E promoted a better photoprotection than nanoparticle-based formulation without Vitamin E [55]. Besides, tocopheryl acetate and idebenone loaded in NLC provided a skin hydration increase because lipids have occlusive properties. Vitamin E loaded in NLC reduced skin pigmentation which was attributed to the photoprotective effect of Vitamin E [43].

An innovative nanocomposite dressing for burn wound healing containing vitamin E- loaded polymer nanoparticles allowed a vitamin controlled release [57]. In another report, α-tocopherol loaded to nanospheres was crosslinked to cellulose fiber to obtain a novel cosmetic fabric with potential application to atopic dermatitis patients [58]. As to nanoemulsions, tocopherol-loaded nanoemulsions increased skin delivery *in vitro* and they protected vitamin E from UV-triggered degradation [54]. More recently, α-tocopherol and γ-tocotrienol were loaded in nanoemulsions to treat dermatitis as an attempt to avoid the use of steroid anti-inflammatory drugs. This nanotechnological formulation could be in the future an alternative to dermatitis patients [59].

Lastly, clinical trials are essential to complement in *vitro assays*. According to human experiments, different nanosystems could be employed to ensure a more immediate or a more prolonged skin hydration [16]. Beyond skin moisturization, lipid nanoparticles improved human skin elasticity and firmness [9]. Importantly, a protocol clinical trial proposes the use of a formulation containing vitamin E-loaded NLC to reduce radiodermatitis in breast cancer patients. Since radiodermatitis is a recurrent radiotherapy side effect, the use of this topical formulation could improve cancer treatment as there would be lower patients quitting radiotherapy treatment [77].

**67**

**Author details**

of Juiz de Fora, Juiz de Fora, Brazil

provided the original work is properly cited.

Júlia Scherer Santos\*, Guilherme Diniz Tavares and Thaís Nogueira Barradas Faculty of Pharmacy, Department of Pharmaceutical Sciences, Federal University

© 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: julia\_scherer\_santos@hotmail.com

*Vitamin E and Derivatives in Skin Health Promotion DOI: http://dx.doi.org/10.5772/intechopen.99466*

treatment, their skin effects are not fully understood.

Reactive oxygen species are implicated in systemic and skin diseases pathogenesis. Hence, topical use as well as oral intake of antioxidants should be encouraged to reduce stress oxidative effects. Vitamin E isomers and derivatives are widely known for their antioxidant activity. Tocopherols and tocotrienols isomers are found in vegetable oils. Elseways, vitamin E derivatives are synthetic forms obtained from natural isomers. Endogenously, alpha-tocopherol scavanges reactive oxygen species and owed to this effect, the oral supplementation of vitamin E is beneficial to prevent the appearance and progression of diseases. In relation to cutaneous effects, both oral and topical formulations provide a photoprotection against harmful ultraviolet radiation. Moreover, despite tocotrienols potential application in melanoma

Majority of skin care formulations contain alpha-tocopherol isoform or tocopherol acetate derivative whose effects are mainly due to their scavenging ROS ability. Therefore, the reduction of skin aging, melasma and cancer prevention can be achieved by different vitamin E pathways on the skin. As conventional forms and nanotechnology-based systems bearing vitamin E are useful in skin diseases treatment, their use is essential to skin health promotion and maintenance. Nevertheless, its therapeutic effectiveness is limited. Vitamin E loaded in nanostructured delivery systems can significantly increase antioxidant-based therapy effectiveness. In the future, there will be a need for well-designed controlled trials to support the benefits of nanotechnology-based products containing this vitamin.

**3. Conclusion**

### **3. Conclusion**

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

penetration will be affected by these factors. Regarding biological activity, vitamin E-loaded liposomes inhibited lipid peroxidation more effectively than free vitamin E [74]. Lately, tocopherol acetate-loaded transferosomes optimized wound healing process [56]. As transferosomes are elastic liposome-like ultra-deformable vesicles, a higher diffusion across the stratum corneum can be accomplished [75, 76]. Topical administration of vitamin E-loaded liposomes are also interesting to enable a high

*Structure of some vitamin E nanocarriers. SLN: Solid lipid nanoparticles. NLC: Nanostructured lipid carriers.* 

Lipid nanoparticles ability to increase sunscreens efficacy was previously shown [53, 55]. Tocopherol acetate-loaded SLN increased sunscreen UV-blocking effect [53]. Moreover, alpha-tocopherol and sunscreens loaded in NLC and SLN increased vitamin E photostability. Additionally, nanoencapsulated vitamin E promoted a better photoprotection than nanoparticle-based formulation without Vitamin E [55]. Besides, tocopheryl acetate and idebenone loaded in NLC provided a skin hydration increase because lipids have occlusive properties. Vitamin E loaded in NLC reduced skin pigmentation which was attributed to the photoprotective effect

An innovative nanocomposite dressing for burn wound healing containing vitamin E- loaded polymer nanoparticles allowed a vitamin controlled release [57]. In another report, α-tocopherol loaded to nanospheres was crosslinked to cellulose fiber to obtain a novel cosmetic fabric with potential application to atopic dermatitis patients [58]. As to nanoemulsions, tocopherol-loaded nanoemulsions increased skin delivery *in vitro* and they protected vitamin E from UV-triggered degradation [54]. More recently, α-tocopherol and γ-tocotrienol were loaded in nanoemulsions to treat dermatitis as an attempt to avoid the use of steroid anti-inflammatory drugs. This nanotechnological formulation could be in the future an alternative to

Lastly, clinical trials are essential to complement in *vitro assays*. According to human experiments, different nanosystems could be employed to ensure a more immediate or a more prolonged skin hydration [16]. Beyond skin moisturization, lipid nanoparticles improved human skin elasticity and firmness [9]. Importantly, a protocol clinical trial proposes the use of a formulation containing vitamin E-loaded NLC to reduce radiodermatitis in breast cancer patients. Since radiodermatitis is a recurrent radiotherapy side effect, the use of this topical formulation could improve cancer treatment as there would be lower patients quitting radio-

drug penetration and transdermal release into skin tumors [68].

**66**

of Vitamin E [43].

**Figure 2.**

*TPP: Tripolyphosphate. Created in BioRender.*

dermatitis patients [59].

therapy treatment [77].

Reactive oxygen species are implicated in systemic and skin diseases pathogenesis. Hence, topical use as well as oral intake of antioxidants should be encouraged to reduce stress oxidative effects. Vitamin E isomers and derivatives are widely known for their antioxidant activity. Tocopherols and tocotrienols isomers are found in vegetable oils. Elseways, vitamin E derivatives are synthetic forms obtained from natural isomers. Endogenously, alpha-tocopherol scavanges reactive oxygen species and owed to this effect, the oral supplementation of vitamin E is beneficial to prevent the appearance and progression of diseases. In relation to cutaneous effects, both oral and topical formulations provide a photoprotection against harmful ultraviolet radiation. Moreover, despite tocotrienols potential application in melanoma treatment, their skin effects are not fully understood.

Majority of skin care formulations contain alpha-tocopherol isoform or tocopherol acetate derivative whose effects are mainly due to their scavenging ROS ability. Therefore, the reduction of skin aging, melasma and cancer prevention can be achieved by different vitamin E pathways on the skin. As conventional forms and nanotechnology-based systems bearing vitamin E are useful in skin diseases treatment, their use is essential to skin health promotion and maintenance. Nevertheless, its therapeutic effectiveness is limited. Vitamin E loaded in nanostructured delivery systems can significantly increase antioxidant-based therapy effectiveness. In the future, there will be a need for well-designed controlled trials to support the benefits of nanotechnology-based products containing this vitamin.

### **Author details**

Júlia Scherer Santos\*, Guilherme Diniz Tavares and Thaís Nogueira Barradas Faculty of Pharmacy, Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil

\*Address all correspondence to: julia\_scherer\_santos@hotmail.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.

### **References**

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from lab to industrial scale.

ijpharm.2019.118817

jowc.2021.30.sup6.s44

2020;573:118817. DOI: 10.1016/j.

[76] Fernández-García R, Lalatsa A,

Technology & Research. 2011;2:138-143.

International Journal of Pharmaceutics.

[77] Schmidt FMQ, Serna González C V., Mattar RC, Lopes LB, dos Santos MF, de Gouveia Santos VLC. Topical cream containing nanoparticles with Vitamin E to prevent radiodermatitis in women with breast cancer: A clinical trial protocol. Journal of Wound Care. 2021;30:S44–S50. DOI: 10.12968/

Development of vitamin loaded topical liposomal formulation using factorial design approach: Drug deposition and stability. International Journal of Pharmaceutics. 2006;320:37-44. DOI:

[66] Gensler HL, Aickin M, Peng Y, Xu M. Importance of the form of topical

photocarcinogenesis. Nutrition and Cancer. 1996;26:183-191. DOI: 10.1080/01635589609514474

[67] Ganceviciene R, Liakou AI, Theodoridis A, Makrantonaki E, Zouboulis CC. Skin anti-aging strategies. Dermato-Endocrinology. 2012;4:308-319. DOI: 10.4161/

[68] Koudelka S, Turanek Knotigova P, Masek J, Prochazka L, Lukac R, Miller AD, et al. Liposomal delivery systems for anti-cancer analogues of vitamin E. Journal of Controlled Release. 2015;207:59-69. DOI: 10.1016/j.

[69] Barradas TN, de Holanda e Silva KG. Nanoemulsions of essential oils to improve solubility, stability and permeability: a review. Environmental Chemistry Letters. 2021;19:1153-1171. DOI: 10.1007/s10311-020-01142-2

derm.22804

jconrel.2015.04.003

[70] Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, et al. Polymeric Nanoparticles: Production, Characterization, Toxicology and

Ecotoxicology. Molecules. 2020;25:3731. DOI: 10.3390/

[71] Nwe N, Furuike T, Tamura H. Isolation and Characterization of Chitin and Chitosan from Marine Origin. In: Kim S-K, editor. Advances in Food and Nutrition Research. 1st ed. London; San Diego;Oxford: Elsevier; 2014. p. 1-15. DOI: 10.1016/B978-0-12-800269-8.

[72] Kakadia P, Conway B. Lipid Nanoparticles for Dermal Drug Delivery. Current Pharmaceutical Design. 2015;21:2823-2829. DOI: 10.2174

/1381612821666150428143730

molecules25163731

vitamin E for prevention of

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

on cellulosic fabric for potential antibacterial and antioxidant cosmetotextiles. Cellulose. 2020;27:1717-1731. DOI: 10.1007/

[59] Harun MS, Wong TW, Fong CW. Advancing skin delivery of α-tocopherol

[60] Yap SP, Yuen KH, Lim AB. Influence of route of administration on the absorption and disposition of α,- γ- and

and γ-tocotrienol for dermatitis treatment via nanotechnology and microwave technology. International Journal of Pharmaceutics. 2021; 593:120099. DOI: 10.1016/j. ijpharm.2020.120099

δ-tocotrienols in rats. Journal of Pharmacy and Pharmacology. 2003;55:53-58. DOI: 10.1111/j.2042-

[61] Lohani A, Verma A, Joshi H, Yadav N, Karki N. Nanotechnology-Based Cosmeceuticals. ISRN

Dermatology. 2014;2014:843687. DOI:

[62] Zoabi A, Touitou E, Margulis K. Recent advances in nanomaterials for dermal and transdermal applications. Colloids and Interfaces. 2021;5:18. DOI:

Mudiyanselage S. Vitamin E in human skin: Organ-specific physiology and

dermatology. Molecular Aspects of Medicine. 2007;28:646-667. DOI: 10.1016/j.mam.2007.06.001

[64] Rangarajan M, Zatz JL. Effect of formulation on the topical delivery of o-tocopherol. Journal of cosmetic

[65] Masaki H. Role of antioxidants in the skin: Anti-aging effects. Journal of Dermatological Science. 2010;58:85-90. DOI: 10.1016/j.jdermsci.2010.03.003

7158.2003.tb02433.x

10.1155/2014/843687

10.3390/colloids5010018

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considerations for its use in

science. 2003;54:161-174.

s10570-019-02862-7

ascorbyl 2-phosphate 6-palmitate/ DL-α-tocopherol phosphate complex treatment for postinflammatory hyperpigmentation, postinflammatory erythema and atrophic scar in acne vulgaris. The Journal of Dermatology.

[53] Wissing SA, Müller RH. A novel sunscreen system based on tocopherol acetate incorporated into solid lipid nanoparticles. International Journal of Cosmetic Science. 2001;23:233-243. DOI: 10.1046/j.1467-2494.2001.00087.x

[54] Abla MJ, Banga AK. Formulation of tocopherol nanocarriers and in vitro delivery into human skin. International

Journal of Cosmetic Science. 2014;36:239-246. DOI: 10.1111/

[55] Niculae G, Lacatusu I, Bors A, Stan R. Photostability enhancement by encapsulation of α-tocopherol into lipid-based nanoparticles loaded with a UV filter. Comptes Rendus Chimie. 2014;17:1028-1033. DOI: 10.1016/j.

[56] Caddeo C, Manca ML, Peris JE, Usach I, Diez-Sales O, Matos M, et al. Tocopherol-loaded transfersomes: In vitro antioxidant activity and efficacy in skin regeneration. International Journal of Pharmaceutics. 2018;551:31-41. DOI:

10.1016/j.ijpharm.2018.09.009

[58] Raza ZA, Abid S, Azam A, Rehman A. Synthesis of alphatocopherol encapsulated chitosan nano-assemblies and their impregnation

Balducci AG, Rondelli V, Colombo P, Guterres SS, et al. Hyaluronate

nanoparticles included in polymer films for the prolonged release of vitamin E for the management of skin wounds. European Journal of Pharmaceutical Sciences. 2016;83:203-211. DOI: 10.1016/j.ejps.2016.01.002

[57] Pereira GG, Detoni CB,

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**72**

[66] Gensler HL, Aickin M, Peng Y, Xu M. Importance of the form of topical vitamin E for prevention of photocarcinogenesis. Nutrition and Cancer. 1996;26:183-191. DOI: 10.1080/01635589609514474

[67] Ganceviciene R, Liakou AI, Theodoridis A, Makrantonaki E, Zouboulis CC. Skin anti-aging strategies. Dermato-Endocrinology. 2012;4:308-319. DOI: 10.4161/ derm.22804

[68] Koudelka S, Turanek Knotigova P, Masek J, Prochazka L, Lukac R, Miller AD, et al. Liposomal delivery systems for anti-cancer analogues of vitamin E. Journal of Controlled Release. 2015;207:59-69. DOI: 10.1016/j. jconrel.2015.04.003

[69] Barradas TN, de Holanda e Silva KG. Nanoemulsions of essential oils to improve solubility, stability and permeability: a review. Environmental Chemistry Letters. 2021;19:1153-1171. DOI: 10.1007/s10311-020-01142-2

[70] Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, et al. Polymeric Nanoparticles: Production, Characterization, Toxicology and Ecotoxicology. Molecules. 2020;25:3731. DOI: 10.3390/ molecules25163731

[71] Nwe N, Furuike T, Tamura H. Isolation and Characterization of Chitin and Chitosan from Marine Origin. In: Kim S-K, editor. Advances in Food and Nutrition Research. 1st ed. London; San Diego;Oxford: Elsevier; 2014. p. 1-15. DOI: 10.1016/B978-0-12-800269-8. 00001-4

[72] Kakadia P, Conway B. Lipid Nanoparticles for Dermal Drug Delivery. Current Pharmaceutical Design. 2015;21:2823-2829. DOI: 10.2174 /1381612821666150428143730

[73] Padamwar M, Pokharkar V. Development of vitamin loaded topical liposomal formulation using factorial design approach: Drug deposition and stability. International Journal of Pharmaceutics. 2006;320:37-44. DOI: 10.1016/j.ijpharm.2006.04.001

[74] Natsuki R, Morita Y, Osawa S, Takeda Y. Effects of Liposome Size on Penetration of dl-Tocopherol Acetate into Skin. Biological & Pharmaceutical Bulletin. 1996;19:758-761. DOI: 10.1248/ bpb.19.758

[75] Rajan R, Vasudevan D, Biju Mukund V, Jose S. Transferosomes - A vesicular transdermal delivery system for enhanced drug permeation. Journal of Advanced Pharmaceutical Technology & Research. 2011;2:138-143. DOI: 10.4103/2231-4040.85524

[76] Fernández-García R, Lalatsa A, Statts L, Bolás-Fernández F, Ballesteros MP, Serrano DR. Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to industrial scale. International Journal of Pharmaceutics. 2020;573:118817. DOI: 10.1016/j. ijpharm.2019.118817

[77] Schmidt FMQ, Serna González C V., Mattar RC, Lopes LB, dos Santos MF, de Gouveia Santos VLC. Topical cream containing nanoparticles with Vitamin E to prevent radiodermatitis in women with breast cancer: A clinical trial protocol. Journal of Wound Care. 2021;30:S44–S50. DOI: 10.12968/ jowc.2021.30.sup6.s44

**75**

**Chapter 5**

Elderly

*and Saheb Ali*

**1. Introduction**

vitamin E in preventing coronary heart diseases.

**Abstract**

Role of Vitamin E in Boosting

the Immunity from Neonates to

*Mariyappan Kowsalya, Mohan Prasanna Rajeshkumar,* 

*Thangavel Velmurugan, Kattakgounder Govindaraj Sudha* 

The vitamin E is a fat-soluble vitamin which occurs as a tocopherol component abundant in humans. The vitamin E supplements in humans and animals have provided numerous health benefits. The vitamin E is rich in antioxidants which slow the aging process and reduce the free radical damage. Vitamin E isoforms play an important role in respiratory health. It is also important in health and well-being of preterm neonates. Vitamin E deficiency in new born includes hemolytic anemia, disease of retina, bronchopulmonary dysplasia. Further, in vitro studies, vitamin E has increased the oxidative resistance and prevents the atherosclerotic plaque. The consumption of vitamin E rich foods reduces coronary heart diseases. This chapter focuses on the treatment of vitamin E deficiency in preterm babies and the role of

**Keywords:** Vitamin E, neonates, immunity, preterm infants, -tocopherol

Vitamins are defined as "organic compounds required in diet in little quantity to execute specific biological functions for normal protection of ideal growth and health of the organism" [1]. In 1922, vitamin E was discovered by Evans and Bishop named it as "X-factor" and got its name after the classification of other vitamins [2]. Vitamin E is generally used as a common word for four tocopherols (, β, and ) and tocotrienols (, β, and ) present in food. The main component of the group of compounds in vitamin-E is α-tocopherols. The tocopherols are products of 6-hydroxy chromane (tocol) ring with isoprenoid side chain. Vitamin E with the aid of selenium prevents the non-enzymatic oxidation of cellular components and free radical formation. Vitamin is lipophilic in nature and present on association with derivatives of lipids and cell membranes [1]. The synthetic - tocopherol is called as *all-rac-* -tocopherol and naturally available form is RRR- -tocopherol [3]. The key characteristics of vitamin-E was identified as scavenger of free radical and it is the foremost fat-soluble vitamin responsible for protecting cell membranes against peroxidation [4]. In early stages of life, vitamins are extremely important. Vitamin -E supplies the essential antioxidant protection and stimulates the development of the

#### **Chapter 5**

## Role of Vitamin E in Boosting the Immunity from Neonates to Elderly

*Mariyappan Kowsalya, Mohan Prasanna Rajeshkumar, Thangavel Velmurugan, Kattakgounder Govindaraj Sudha and Saheb Ali*

#### **Abstract**

The vitamin E is a fat-soluble vitamin which occurs as a tocopherol component abundant in humans. The vitamin E supplements in humans and animals have provided numerous health benefits. The vitamin E is rich in antioxidants which slow the aging process and reduce the free radical damage. Vitamin E isoforms play an important role in respiratory health. It is also important in health and well-being of preterm neonates. Vitamin E deficiency in new born includes hemolytic anemia, disease of retina, bronchopulmonary dysplasia. Further, in vitro studies, vitamin E has increased the oxidative resistance and prevents the atherosclerotic plaque. The consumption of vitamin E rich foods reduces coronary heart diseases. This chapter focuses on the treatment of vitamin E deficiency in preterm babies and the role of vitamin E in preventing coronary heart diseases.

**Keywords:** Vitamin E, neonates, immunity, preterm infants, -tocopherol

#### **1. Introduction**

Vitamins are defined as "organic compounds required in diet in little quantity to execute specific biological functions for normal protection of ideal growth and health of the organism" [1]. In 1922, vitamin E was discovered by Evans and Bishop named it as "X-factor" and got its name after the classification of other vitamins [2]. Vitamin E is generally used as a common word for four tocopherols (, β, and ) and tocotrienols (, β, and ) present in food. The main component of the group of compounds in vitamin-E is α-tocopherols. The tocopherols are products of 6-hydroxy chromane (tocol) ring with isoprenoid side chain. Vitamin E with the aid of selenium prevents the non-enzymatic oxidation of cellular components and free radical formation. Vitamin is lipophilic in nature and present on association with derivatives of lipids and cell membranes [1]. The synthetic - tocopherol is called as *all-rac-* -tocopherol and naturally available form is RRR- -tocopherol [3]. The key characteristics of vitamin-E was identified as scavenger of free radical and it is the foremost fat-soluble vitamin responsible for protecting cell membranes against peroxidation [4]. In early stages of life, vitamins are extremely important. Vitamin -E supplies the essential antioxidant protection and stimulates the development of the

#### **Figure 1.**

*The low level of serum -tocopherols was observed in certain disease was mentioned which cause high rate of morbidity in neonates. And also, elderly patients have diseases associated with low level of vitamin E and other micronutrients in their diet.*

immune system in new-borns [5]. Our human system does not synthesize Vitamin E and it is obtained through dietary intake. Vitamin E rich foods are wheat germ oil, sunflower oils, soybean oil, sunflower seeds, cotton seed, walnut, hazel nuts, peanut butter, corn, palm, spinach, broccoli, kiwi fruit, mango, raspberries, blackberries, blackcurrant, avocado and tomato [6–8]. The vitamin E deficiency was known as the cause of foetal death. Early high dose of vitamin E either through intravenous or intramuscular route decreases the chance of hemorrhage, bronchopulmonary dysplasia, haemolytic anemia, retrolental fibroplasia and retinopathy of prematurity [9]. The low level of vitamin E in serum was observed in certain diseases which was depicted in **Figure 1**.

The antioxidant potential of vitamin E could protect the polyunsaturated fatty acids in the membrane from oxidation, regulating the production of reactive oxygen species, reactive nitrogen species and modulates signal transduction [10]. The effect of antioxidant activity of vitamin E was based on the number of methyl group in its chromane ring. The -tocopherol have three methyl group whereas the - tocopherol has only one methyl group in it [2]. Vitamin E also has anti-cancer potential by stimulating the p53 gene, down regulation of mutant p53 gene and activates the heat shock proteins. Production of PKC and collagenase was inhibited by -tocopherol. In milieu, - tocopherol has effective anti-cancer activity than the -tocopherol [5]. Intrauterine growth restriction (IUGR) is one of the major causes of neonatal morbidity and mortality. Some studies shows that -tocopherol aids in the intrauterine development of foetus. 15 million babies are born premature every year and they need special care just to stay alive [11]. During gestational period, the maternal oral intake of vitamin E increases the weight of foetus [12]. The oral administration of vitamin E was given to children to combat malabsorption disorders. Some of the compounds used as vitamin E therapy in newborn and preterm infants are -tocopherol, tocofersolan, dl- -tocopherol, dl--tocopheryl acetate [13]. In 2000, the institute of medicine (IOM) chose the hydrogen peroxide induced

**77**

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

erythrocyte haemolysis test as a marker to determine the vitamin E status. Because, erythrocyte fragility and anemia with higher erythrocyte was observed in children. In adults, vitamin E deficiency occurs due to genetic disorders in α-tocopherol transfer protein (TTP) which causes ataxia. Further, fat malabsorption also leads to vitamin E deficiency due to genetic disorder in TG transfer protein [14]. The people with ataxia are provided with 800-1200 mg of vitamin E as a supplement to prevent the progression of disease [6]. Orally, vitamin E was given in the form of dl- -tocopherol acetate. Supplementation of -tocopherol increases insulin sensitivity and decreases the oxidative stress [15]. Oxidative stress was due to the disturbance in balance between generation of free radicals and their exclusion by free radical scavenging activity of the system [16]. Vitamin E supplementation has enhanced the host defense system by heightening the humoral and cell mediated immune system. In elderly people, vitamin E has boosted the resistance against viral diseases and also stimulates immune response to distinctive antigen [5]. Immunostimulatory property of Vitamin E provides enhanced resistance to many pathogens [9]. Earlier studies show that vitamin E possess neuroprotective activity in both foetus and adult rats [17]. The vitamin E supplementation has numerous biological activity

*Vitamin E supplementation has many biological activities and it enhances the immune response.*

**2. Immunological functions of vitamin E in different stages of life**

Preterm birth was defined as parturition prior to 37 weeks of gestation, the leading cause of mortality and morbidity in neonates. The rate of prematurity complications increases with decreased gestational age and birth weight [10]. Newborns are one of the risk groups of vitamin E deficiency. The limited transfer of -tocopherol through the placenta which results in low level of vitamin-E in tissues and serum at the time of birth in premature infants than in full term infants [18]. The preterm infants' blood vessels are exposed to high oxygen tension due to the deficient amount of vitamin E [19]. Preterm infants are born with low body weight and have less stored fat-soluble vitamins. The level of -tocopherol is low at their time of birth was shown by the elevated erythrocyte haemolysis in the presence

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

which was depicted in the **Figure 2**.

**2.1 Preterm infants**

**Figure 2.**

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

#### **Figure 2.**

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

immune system in new-borns [5]. Our human system does not synthesize Vitamin E and it is obtained through dietary intake. Vitamin E rich foods are wheat germ oil, sunflower oils, soybean oil, sunflower seeds, cotton seed, walnut, hazel nuts, peanut butter, corn, palm, spinach, broccoli, kiwi fruit, mango, raspberries, blackberries, blackcurrant, avocado and tomato [6–8]. The vitamin E deficiency was known as the cause of foetal death. Early high dose of vitamin E either through intravenous or intramuscular route decreases the chance of hemorrhage, bronchopulmonary dysplasia, haemolytic anemia, retrolental fibroplasia and retinopathy of prematurity [9]. The low level of vitamin E in serum was observed in certain diseases which

*The low level of serum -tocopherols was observed in certain disease was mentioned which cause high rate of morbidity in neonates. And also, elderly patients have diseases associated with low level of vitamin E and other* 

The antioxidant potential of vitamin E could protect the polyunsaturated fatty acids in the membrane from oxidation, regulating the production of reactive oxygen species, reactive nitrogen species and modulates signal transduction [10]. The effect of antioxidant activity of vitamin E was based on the number of methyl group in its chromane ring. The -tocopherol have three methyl group whereas the - tocopherol has only one methyl group in it [2]. Vitamin E also has anti-cancer potential by stimulating the p53 gene, down regulation of mutant p53 gene and activates the heat shock proteins. Production of PKC and collagenase was inhibited by -tocopherol. In milieu, - tocopherol has effective anti-cancer activity than the -tocopherol [5]. Intrauterine growth restriction (IUGR) is one of the major causes of neonatal morbidity and mortality. Some studies shows that -tocopherol aids in the intrauterine development of foetus. 15 million babies are born premature every year and they need special care just to stay alive [11]. During gestational period, the maternal oral intake of vitamin E increases the weight of foetus [12]. The oral administration of vitamin E was given to children to combat malabsorption disorders. Some of the compounds used as vitamin E therapy in newborn and preterm infants are -tocopherol, tocofersolan, dl- -tocopherol, dl--tocopheryl acetate [13]. In 2000, the institute of medicine (IOM) chose the hydrogen peroxide induced

**76**

was depicted in **Figure 1**.

**Figure 1.**

*micronutrients in their diet.*

*Vitamin E supplementation has many biological activities and it enhances the immune response.*

erythrocyte haemolysis test as a marker to determine the vitamin E status. Because, erythrocyte fragility and anemia with higher erythrocyte was observed in children. In adults, vitamin E deficiency occurs due to genetic disorders in α-tocopherol transfer protein (TTP) which causes ataxia. Further, fat malabsorption also leads to vitamin E deficiency due to genetic disorder in TG transfer protein [14]. The people with ataxia are provided with 800-1200 mg of vitamin E as a supplement to prevent the progression of disease [6]. Orally, vitamin E was given in the form of dl- -tocopherol acetate. Supplementation of -tocopherol increases insulin sensitivity and decreases the oxidative stress [15]. Oxidative stress was due to the disturbance in balance between generation of free radicals and their exclusion by free radical scavenging activity of the system [16]. Vitamin E supplementation has enhanced the host defense system by heightening the humoral and cell mediated immune system. In elderly people, vitamin E has boosted the resistance against viral diseases and also stimulates immune response to distinctive antigen [5]. Immunostimulatory property of Vitamin E provides enhanced resistance to many pathogens [9]. Earlier studies show that vitamin E possess neuroprotective activity in both foetus and adult rats [17]. The vitamin E supplementation has numerous biological activity which was depicted in the **Figure 2**.

#### **2. Immunological functions of vitamin E in different stages of life**

#### **2.1 Preterm infants**

Preterm birth was defined as parturition prior to 37 weeks of gestation, the leading cause of mortality and morbidity in neonates. The rate of prematurity complications increases with decreased gestational age and birth weight [10]. Newborns are one of the risk groups of vitamin E deficiency. The limited transfer of -tocopherol through the placenta which results in low level of vitamin-E in tissues and serum at the time of birth in premature infants than in full term infants [18]. The preterm infants' blood vessels are exposed to high oxygen tension due to the deficient amount of vitamin E [19]. Preterm infants are born with low body weight and have less stored fat-soluble vitamins. The level of -tocopherol is low at their time of birth was shown by the elevated erythrocyte haemolysis in the presence

of hydrogen peroxide. The enteral dose of vitamin E is given at 50 IU/kg within 4 hours of birth and it increases the serum -tocopherol level [20]. The preterm infants those less than 1000 g in NICU were given 1.5 ml of vitamin E per day through infuvite pediatric as a portion of parental nutrition. And infants in 1000 g to 3000 g obtain 3.5 ml of vitamin E per day. Each vial (1 ml) of infuvite encompasses 7 mg of -tocopheryl acetate [3].

The preterm infants administering the oral dose of vitamin E helps in treating the vitamin E deficiency syndromes like anemia, retinopathy, thrombocytosis and congenital malformation [21]. The retrolental fibroplasia occurs often in preterm infants because the last portion of the retinal blood vessel continues to develop till the end of eight month of gestation. The blood vessels of the preterm infants might not be developed well and they need an appropriate environment with arterial oxygen tension, blood supply, nutrient, disposal of wastes and exposure to visible light [18]. The haemolytic anemia was frequently observed in preterm infants, where their intake of fortified iron is higher along with linolenic acids. Nowadays, the formula for preterm babies had increased the vitamin E and reduces their iron content so that this helps to prevent the development of haemolytic anemia [22]. The vitamin E supplements in preterm infants increases the hemoglobin level after 8–10 weeks of birth [23]. Previous studies reported that preterm infants born below 2000 g, when supplemented with 16.5 mg of -tocopherol acetate per day for about ten days has improved the hemoglobin level and decreases the reticulocyte count. Supplementing 16.5 mg concentration of vitamin E is higher in their study compared to regular dose of 1.5 mg/day but it shows betterment of disease condition, however their consequences have to be studied [24].

The bronchopulmonary dysplasia (BPD) was observed among preterm infants due to free radicals which injures the lung cells. It was generally noticed in preterm infants particularly born before 28 weeks of gestation. Oral supplementation of vitamin E is tolerable in pregnancy and infancy. They are present routinely in the total parenteral nutrition (TPN) which is used in the treatment of BPD. And also, the -tocopherol plays a key role as anti-inflammatory factor in neonatal lungs [15]. A study with 133 preterm infants were grouped into 68 preterm infants with confirmed case of BPD, 65 preterm infants without BDP. It was observed that as the condition of BPD increases with vitamin E deficiency. The involvement of vitamin E in BDP was confirmed and their supplementation would become a therapy to BPD [25].

#### **2.2 Neonates**

The adequate intake of Vitamin E is essential in neonates as they are born with low stores of it. The routine recommended intake of vitamin E is 2.8 IU/kg per day (Maximum 7 IU/kg per day) [8]. The term babies gestational age was between 37 and 41 weeks and their weight at the time of birth was 2500 g -3700 g [26]. It was observed that very low birth weight in infants were deficient in Vitamin E. Hence, vitamin E supplementation is required to enhance the weight gain in infants [27]. The yellow coloration of the skin and sclera of new born babies are referred to as neonatal jaundice which is the result of bilirubin deposition. Vitamin -E is supplemented along with phototherapy of the full-term neonates [28]. In an extrauterine environment, vitamin E acts as defense against oxygen toxicity and their placental transfer to the foetus is limited during gestational period. Hence, maternal milk is important to supply this vitamin to the neonates in their initial period and during lactation, thus, protecting it from haemolytic anemia, bronchopulmonary dysplasia, neurological dysfunction and increased neonatal mortality. The studies show that vitamin E in maternal milk decreases with increase in lactation period i.e., colostrum (40.5 ± 15 μmol/L) provides the highest content of vitamin E to infants.

**79**

adolescence [38].

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

Whereas it gradually decreases in transitional (13.9 ± 5.2 μmol/L) and mature (8.0 ± 3.8 μmol/L) milk of lactation. The higher concentration of alpha-tocopherol in colostrum acts as complementary mechanism [29]. Hyperbilirubinemia was observed in neonates which was treated with phototherapy and vitamin E supplementation [30]. The world health organization WHO has issued a global public health recommendation that infants should exclusively breastfed for 6 months to attain optimal growth and development as the maternal milk was the infant's best source of nutrients. The average amount of vitamin E in maternal milk is 2.5–2.9 mg it contributes to prevention of free radical propagation in numerous lipid structures within the system [31]. The Dietary Reference Intake (DRI) recommends the intake of 4 mg/day of vitamin E for children between 0 and 6 months. The vitamin E supplementation in children is essential to the development of the immune system, lungs, extracellular matrix of the vascular system and mental development [29].

Vitamin E enhances the immune responses of the children. Cardiomyopathy was observed as a symptom in children with critical deficiency of vitamin E. The prescribed amount of vitamin E supplementation in children is 1000 mg/d [13]. Low level of maternal plasma -tocopherol increase the chance of asthma in children within their first ten years [32]. The antioxidant intake of vitamin E during pregnancy and their effect on development of wheezing and eczema in children is needed to be confirmed with the follow up investigation on the children's growth and their dietary intake [33]. In previous report, the association of vitamin E intake during pregnancy and chance of asthma in children was observed in 2000 pregnant women. The -tocopherol level in plasma was examined during gestation and cord blood after delivery. Their intake of anti-oxidant vitamins are also examined. Then follow up studies was performed up to five-year age of children. The symptoms of asthma, wheezing and dietary intake was collected for 1253 children and 797 children were participated in hospital evaluation. They have concluded that low level of serum vitamin E during pregnancy was observed among the children with phenotypic symptoms of asthma. Though, vitamin E does not directly improve the conditions of asthma patients their deficiency in early stage of life was perceived in

The children suffering from chronic kidney disease are at high risk of micronutrient deficiency. The concentration of vitamin A and vitamin B12 was within the range of reference while vitamin E shows major changes as the kidney disease worsens hence advance studies are essential to determine the required concentration of vitamin supplements in infants and children with this disease [35]. In children, respiratory tract infection is common cause of the morbidity. The vitamin E supplementation helps to treat this disease. A substantial amount of plasma vitamin E improves the hemolytic uremic syndrome in children. Which was due to the defect in production of prostacyclin and thus preventing the mortality and morbidity rate [36]. Supplementation of vitamin E (100 IU/ day) has increased the glutathione level and decreased the lipid peroxidation and concentration of HBA1C in the erythrocytes of type 1 diabetics children [37]. The childhood obesity was growing and it may be due to imbalance in the oxidant and antioxidant level. The obese children were observed with increased level of oxidants like isoprostanes and decreased level of antioxidant like vitamin E. Oxidative stress markers were decreased by vitamin E supplementation in obesed children with liver steatosis. Hence, early implementation of vitamin E will reduce the risk of cardiovascular and metabolic changes connected with non-alcoholic fatty liver disease in children and

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

children be inflicted with asthma [34].

**2.3 Children**

#### *Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

Whereas it gradually decreases in transitional (13.9 ± 5.2 μmol/L) and mature (8.0 ± 3.8 μmol/L) milk of lactation. The higher concentration of alpha-tocopherol in colostrum acts as complementary mechanism [29]. Hyperbilirubinemia was observed in neonates which was treated with phototherapy and vitamin E supplementation [30]. The world health organization WHO has issued a global public health recommendation that infants should exclusively breastfed for 6 months to attain optimal growth and development as the maternal milk was the infant's best source of nutrients. The average amount of vitamin E in maternal milk is 2.5–2.9 mg it contributes to prevention of free radical propagation in numerous lipid structures within the system [31]. The Dietary Reference Intake (DRI) recommends the intake of 4 mg/day of vitamin E for children between 0 and 6 months. The vitamin E supplementation in children is essential to the development of the immune system, lungs, extracellular matrix of the vascular system and mental development [29].

#### **2.3 Children**

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

passes 7 mg of -tocopheryl acetate [3].

however their consequences have to be studied [24].

of hydrogen peroxide. The enteral dose of vitamin E is given at 50 IU/kg within 4 hours of birth and it increases the serum -tocopherol level [20]. The preterm infants those less than 1000 g in NICU were given 1.5 ml of vitamin E per day through infuvite pediatric as a portion of parental nutrition. And infants in 1000 g to 3000 g obtain 3.5 ml of vitamin E per day. Each vial (1 ml) of infuvite encom-

The preterm infants administering the oral dose of vitamin E helps in treating the vitamin E deficiency syndromes like anemia, retinopathy, thrombocytosis and congenital malformation [21]. The retrolental fibroplasia occurs often in preterm infants because the last portion of the retinal blood vessel continues to develop till the end of eight month of gestation. The blood vessels of the preterm infants might not be developed well and they need an appropriate environment with arterial oxygen tension, blood supply, nutrient, disposal of wastes and exposure to visible light [18]. The haemolytic anemia was frequently observed in preterm infants, where their intake of fortified iron is higher along with linolenic acids. Nowadays, the formula for preterm babies had increased the vitamin E and reduces their iron content so that this helps to prevent the development of haemolytic anemia [22]. The vitamin E supplements in preterm infants increases the hemoglobin level after 8–10 weeks of birth [23]. Previous studies reported that preterm infants born below 2000 g, when supplemented with 16.5 mg of -tocopherol acetate per day for about ten days has improved the hemoglobin level and decreases the reticulocyte count. Supplementing 16.5 mg concentration of vitamin E is higher in their study compared to regular dose of 1.5 mg/day but it shows betterment of disease condition,

The bronchopulmonary dysplasia (BPD) was observed among preterm infants due to free radicals which injures the lung cells. It was generally noticed in preterm infants particularly born before 28 weeks of gestation. Oral supplementation of vitamin E is tolerable in pregnancy and infancy. They are present routinely in the total parenteral nutrition (TPN) which is used in the treatment of BPD. And also, the -tocopherol plays a key role as anti-inflammatory factor in neonatal lungs [15]. A study with 133 preterm infants were grouped into 68 preterm infants with confirmed case of BPD, 65 preterm infants without BDP. It was observed that as the condition of BPD increases with vitamin E deficiency. The involvement of vitamin E in BDP was confirmed and their supplementation would become a therapy to BPD [25].

The adequate intake of Vitamin E is essential in neonates as they are born with low stores of it. The routine recommended intake of vitamin E is 2.8 IU/kg per day (Maximum 7 IU/kg per day) [8]. The term babies gestational age was between 37 and 41 weeks and their weight at the time of birth was 2500 g -3700 g [26]. It was observed that very low birth weight in infants were deficient in Vitamin E. Hence, vitamin E supplementation is required to enhance the weight gain in infants [27]. The yellow coloration of the skin and sclera of new born babies are referred to as neonatal jaundice which is the result of bilirubin deposition. Vitamin -E is supplemented along with phototherapy of the full-term neonates [28]. In an extrauterine environment, vitamin E acts as defense against oxygen toxicity and their placental transfer to the foetus is limited during gestational period. Hence, maternal milk is important to supply this vitamin to the neonates in their initial period and during lactation, thus, protecting it from haemolytic anemia, bronchopulmonary dysplasia, neurological dysfunction and increased neonatal mortality. The studies show that vitamin E in maternal milk decreases with increase in lactation period i.e., colostrum (40.5 ± 15 μmol/L) provides the highest content of vitamin E to infants.

**78**

**2.2 Neonates**

Vitamin E enhances the immune responses of the children. Cardiomyopathy was observed as a symptom in children with critical deficiency of vitamin E. The prescribed amount of vitamin E supplementation in children is 1000 mg/d [13]. Low level of maternal plasma -tocopherol increase the chance of asthma in children within their first ten years [32]. The antioxidant intake of vitamin E during pregnancy and their effect on development of wheezing and eczema in children is needed to be confirmed with the follow up investigation on the children's growth and their dietary intake [33]. In previous report, the association of vitamin E intake during pregnancy and chance of asthma in children was observed in 2000 pregnant women. The -tocopherol level in plasma was examined during gestation and cord blood after delivery. Their intake of anti-oxidant vitamins are also examined. Then follow up studies was performed up to five-year age of children. The symptoms of asthma, wheezing and dietary intake was collected for 1253 children and 797 children were participated in hospital evaluation. They have concluded that low level of serum vitamin E during pregnancy was observed among the children with phenotypic symptoms of asthma. Though, vitamin E does not directly improve the conditions of asthma patients their deficiency in early stage of life was perceived in children be inflicted with asthma [34].

The children suffering from chronic kidney disease are at high risk of micronutrient deficiency. The concentration of vitamin A and vitamin B12 was within the range of reference while vitamin E shows major changes as the kidney disease worsens hence advance studies are essential to determine the required concentration of vitamin supplements in infants and children with this disease [35]. In children, respiratory tract infection is common cause of the morbidity. The vitamin E supplementation helps to treat this disease. A substantial amount of plasma vitamin E improves the hemolytic uremic syndrome in children. Which was due to the defect in production of prostacyclin and thus preventing the mortality and morbidity rate [36]. Supplementation of vitamin E (100 IU/ day) has increased the glutathione level and decreased the lipid peroxidation and concentration of HBA1C in the erythrocytes of type 1 diabetics children [37]. The childhood obesity was growing and it may be due to imbalance in the oxidant and antioxidant level. The obese children were observed with increased level of oxidants like isoprostanes and decreased level of antioxidant like vitamin E. Oxidative stress markers were decreased by vitamin E supplementation in obesed children with liver steatosis. Hence, early implementation of vitamin E will reduce the risk of cardiovascular and metabolic changes connected with non-alcoholic fatty liver disease in children and adolescence [38].

#### **2.4 Adults**

The reactive oxygen species include (ROS) like hydrogen peroxide, hydroxyl radicals, and superoxide were studied exclusively. The formation of ROS during electron transport chain was presumed due to increased ingestion of oxygen by mitochondria in the cell. Some recent studies reported that exercises increased the ROS production. The studies revealed that vitamin-E supplementation in athlete improved the muscle performance and protects the cell membrane from damage through oxidative stress. This study augment that vitamin E would strengthen the skeletal muscle of the older people [39].

In the previous research, Women with the possibility of pre-eclampsia during pregnancy was provided with 400 IU of vitamin E and 1 g of vitamin C per day. As a result, very low birth weight infants were born to supplemented group compared to placebo group. Hence, the vitamin E concentration should not be exceeded above the required dietary allowances [40]. Furthermore, the greater the concentration of serum vitamin E during pregnancy then there is a chance of macrosomia [41]. Recently, a study with 897 girls in their adolescence found that vitamin E aids in the inflammatory response and oxidative stress during menstrual cycle [42].

Cystic fibrosis was one the genetic disorder which leads to deterioration of pulmonary functions in children and adults, partially due to oxidative stress. The vitamin E supplementation greater than required dietary allowances has enhanced the serum -tocopherol [43]. In USA, the higher acceptable level of vitamin E per day was 1000 mg/day [44].

#### **2.5 Elderly**

Vitamin E group has tocopherol and tocotrienol groups each with identical isomers but with alteration in hydrophobic tridecyl chain saturation point. The tocotrienol was recently discovered to be more effective than tocopherol in the treatment of age-related cardiovascular diseases [45]. The low intake of vitamin E in childhood and adulthood leads possibly to hypertension than those who have taken an adequate amount of vitamin E. The cardiovascular disease risk can be decreased by - -tocopherol which inhibits LDL oxidation and reduces the inflammatory responses [46]. The intake of antioxidants could prevent the lipid peroxidation [47]. The epidemiological study with 27271 men who were smokers and by no records of myocardial infraction in the age group 50–69 was divided into group and supplemented with vitamin E, placebo and beta-carotene. The groups were keenly monitored to detect the possible effect of vitamin E supplementation in cardiovascular disorder. The results revealed that 50 mg/day supplementation of vitamin E has prevented the occurrence of nonfatal myocardial infraction by 4% and fatal coronary heart disease by 8%. The vitamin E (-tocopherol) supplemented group has lessened the chance of coronary heart disorder in human trails followed up to six years related to the placebo group. The beta-carotene supplementation has no effect on non-fatal myocardial infraction disease [48].

Immunological function especially cell-mediated immune response will decrease with age and hence elders are prone to infectious diseases. The 200-800 mg supplementation of vitamin E enhances the production of antibody to a primary immunization [49]. In the in vivo study, healthy elderly people in the age group greater than 60 years are supplemented with 800 mg of vitamin E per day and the fasting blood sample was collected for the duration of 6 months and this study has evidenced the increase of -tocopherol level in serum and increase in delayed

**81**

with vitamin E [58].

people [57].

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

type hypersensitivity was observed [50]. In four month of clinical trials, vitamin E supplementation greater than RDA in elderly people had enhanced production of antibodies against various diseases like tetanus, hepatitis B and DTH vaccines [51]. The oxidative stress was one of the reasons for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and processes in cells related to aging. The brain cells were easily damaged by free radicals due to its consumption of high amount of oxygen along with certainly peroxidable lipid membranes and comparatively lesser enzymes with antioxidant potential. The vitamin E and vitamin C were the antioxidant rich supplements which will scavenge the reactive oxygen species and helps in regeneration of neurons [52]. Vitamin E also protects the nervous system with aging [13]. Neurological abnormalities are observed in children and adults when the serum -tocopherol level is less than 0.5 mg. Vitamin E deficiency manifests as neuropathic and myopathic disorders. Spinocerebellar syndrome, ataxia, hyporeflexia, vibratory sensation was commonly observed clinically. Moreover, skeletal myopathy and pigmented retinopathy also occurs due to the vitamin E deficiency [6]. Further, Vitamin E supplementation has upgraded the cognitive function and vascular dementia in elderly [53]. The higher level of -tocopherol in the brain generates an anti-inflammatory milieu to decrease the density of microglial cells. It also protects from the Alzheimer's disease [54]. A study group involved 39,876 women in US, in which 6377 women were greater than 65 years. It was evidenced that vitamin E supplementation in 600 IU alternative days with the follow up for 4 years had enhanced cognitive development. Because the oxidative stress was the major cause for dementia pathogenesis and numerous reports proved that vitamin E has decreased the lipid peroxidation in brain and also prevent the

Previous studies reported that intervention of Vitamin E improves the lymphocyte proliferation and delayed type hypersensitivity was enhanced with higher production of Il-2 and lesser production of Il-6 [9]. An intervention of 200 mg of vitamin E has enhanced immune response of elderly people [56]. When the older mice supplemented with vitamin E has enhanced the cell mediated immune response, production of IL-2 and delayed type hyper sensitivity. In elder human subjects also vitamin E supplementation progresses both the innate and adaptive immunity. The phagocytic capability of leucocyte was improved but declined the bactericidal activity which might be due to the antioxidant potential of vitamin and lesser production of hydrogen peroxide. Further, the optimal concentration of vitamin E supplementation is 200 IU per day than the 60 and 800 IU per day of vitamin E supplementation has increased the T-cell proliferation in elder

In vivo studies of both animals and human have evident that immunity decreases with aging process. It was observed by decreased antibody response, delayed-type hypersensitivity, proliferation of T cell in response to mitogens. Research has proved that antioxidants have helped to improve the immunity in aging process [50]. Aging is a gradual and typical loss of the physiological system along with its immune response. The elderly people are prone to infections and other diseases like cancer due to the age related decrease of immunity. One of the widely consented reason for aging was oxidative stress. The previous study suggested that supplementation of both vitamin C (500 mg/day) and vitamin E (200 mg/day) to the elderly people has improved their immune function by enhancing the humoral and cell- mediated immune response. The -tocopherol acts as immunomodulator and enhances the cytokine levels in older population of group. Level of INF- has increased in tested groups of older people supplemented

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

occurrence of Alzheimer's disease [55].

#### *Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

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

skeletal muscle of the older people [39].

The reactive oxygen species include (ROS) like hydrogen peroxide, hydroxyl radicals, and superoxide were studied exclusively. The formation of ROS during electron transport chain was presumed due to increased ingestion of oxygen by mitochondria in the cell. Some recent studies reported that exercises increased the ROS production. The studies revealed that vitamin-E supplementation in athlete improved the muscle performance and protects the cell membrane from damage through oxidative stress. This study augment that vitamin E would strengthen the

In the previous research, Women with the possibility of pre-eclampsia during pregnancy was provided with 400 IU of vitamin E and 1 g of vitamin C per day. As a result, very low birth weight infants were born to supplemented group compared to placebo group. Hence, the vitamin E concentration should not be exceeded above the required dietary allowances [40]. Furthermore, the greater the concentration of serum vitamin E during pregnancy then there is a chance of macrosomia [41]. Recently, a study with 897 girls in their adolescence found that vitamin E aids in the inflammatory response and oxidative stress during men-

Cystic fibrosis was one the genetic disorder which leads to deterioration of pulmonary functions in children and adults, partially due to oxidative stress. The vitamin E supplementation greater than required dietary allowances has enhanced the serum -tocopherol [43]. In USA, the higher acceptable level of vitamin E per

Vitamin E group has tocopherol and tocotrienol groups each with identical isomers but with alteration in hydrophobic tridecyl chain saturation point. The tocotrienol was recently discovered to be more effective than tocopherol in the treatment of age-related cardiovascular diseases [45]. The low intake of vitamin E in childhood and adulthood leads possibly to hypertension than those who have taken an adequate amount of vitamin E. The cardiovascular disease risk can be decreased by - -tocopherol which inhibits LDL oxidation and reduces the inflammatory responses [46]. The intake of antioxidants could prevent the lipid peroxidation [47]. The epidemiological study with 27271 men who were smokers and by no records of myocardial infraction in the age group 50–69 was divided into group and supplemented with vitamin E, placebo and beta-carotene. The groups were keenly monitored to detect the possible effect of vitamin E supplementation in cardiovascular disorder. The results revealed that 50 mg/day supplementation of vitamin E has prevented the occurrence of nonfatal myocardial infraction by 4% and fatal coronary heart disease by 8%. The vitamin E (-tocopherol) supplemented group has lessened the chance of coronary heart disorder in human trails followed up to six years related to the placebo group. The beta-carotene supplementation has no

Immunological function especially cell-mediated immune response will decrease

with age and hence elders are prone to infectious diseases. The 200-800 mg supplementation of vitamin E enhances the production of antibody to a primary immunization [49]. In the in vivo study, healthy elderly people in the age group greater than 60 years are supplemented with 800 mg of vitamin E per day and the fasting blood sample was collected for the duration of 6 months and this study has evidenced the increase of -tocopherol level in serum and increase in delayed

effect on non-fatal myocardial infraction disease [48].

**2.4 Adults**

strual cycle [42].

**2.5 Elderly**

day was 1000 mg/day [44].

**80**

type hypersensitivity was observed [50]. In four month of clinical trials, vitamin E supplementation greater than RDA in elderly people had enhanced production of antibodies against various diseases like tetanus, hepatitis B and DTH vaccines [51].

The oxidative stress was one of the reasons for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and processes in cells related to aging. The brain cells were easily damaged by free radicals due to its consumption of high amount of oxygen along with certainly peroxidable lipid membranes and comparatively lesser enzymes with antioxidant potential. The vitamin E and vitamin C were the antioxidant rich supplements which will scavenge the reactive oxygen species and helps in regeneration of neurons [52]. Vitamin E also protects the nervous system with aging [13]. Neurological abnormalities are observed in children and adults when the serum -tocopherol level is less than 0.5 mg. Vitamin E deficiency manifests as neuropathic and myopathic disorders. Spinocerebellar syndrome, ataxia, hyporeflexia, vibratory sensation was commonly observed clinically. Moreover, skeletal myopathy and pigmented retinopathy also occurs due to the vitamin E deficiency [6]. Further, Vitamin E supplementation has upgraded the cognitive function and vascular dementia in elderly [53]. The higher level of -tocopherol in the brain generates an anti-inflammatory milieu to decrease the density of microglial cells. It also protects from the Alzheimer's disease [54]. A study group involved 39,876 women in US, in which 6377 women were greater than 65 years. It was evidenced that vitamin E supplementation in 600 IU alternative days with the follow up for 4 years had enhanced cognitive development. Because the oxidative stress was the major cause for dementia pathogenesis and numerous reports proved that vitamin E has decreased the lipid peroxidation in brain and also prevent the occurrence of Alzheimer's disease [55].

Previous studies reported that intervention of Vitamin E improves the lymphocyte proliferation and delayed type hypersensitivity was enhanced with higher production of Il-2 and lesser production of Il-6 [9]. An intervention of 200 mg of vitamin E has enhanced immune response of elderly people [56]. When the older mice supplemented with vitamin E has enhanced the cell mediated immune response, production of IL-2 and delayed type hyper sensitivity. In elder human subjects also vitamin E supplementation progresses both the innate and adaptive immunity. The phagocytic capability of leucocyte was improved but declined the bactericidal activity which might be due to the antioxidant potential of vitamin and lesser production of hydrogen peroxide. Further, the optimal concentration of vitamin E supplementation is 200 IU per day than the 60 and 800 IU per day of vitamin E supplementation has increased the T-cell proliferation in elder people [57].

In vivo studies of both animals and human have evident that immunity decreases with aging process. It was observed by decreased antibody response, delayed-type hypersensitivity, proliferation of T cell in response to mitogens. Research has proved that antioxidants have helped to improve the immunity in aging process [50]. Aging is a gradual and typical loss of the physiological system along with its immune response. The elderly people are prone to infections and other diseases like cancer due to the age related decrease of immunity. One of the widely consented reason for aging was oxidative stress. The previous study suggested that supplementation of both vitamin C (500 mg/day) and vitamin E (200 mg/day) to the elderly people has improved their immune function by enhancing the humoral and cell- mediated immune response. The -tocopherol acts as immunomodulator and enhances the cytokine levels in older population of group. Level of INF- has increased in tested groups of older people supplemented with vitamin E [58].


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

**Table 1.**

**83**

**S. No**

1 2 3 4 5 6 7 8 **Table 2.**

*Role of vitamin E in improving immune system in various disease conditions of children, infants and elderly.*

29133

50–69

Pneumoniae

alpha -tocopherol

50 mg/

Decrease the risk

[75]

day

Elders

184

—

Cardiovascular

alpha -tocopheryl acetate

400 IU

disease

23

—

Oxidative stress

Vitamin E

Adults

716

Gestation

HIV infected

period

141

≤ 14.5 years

Cystic fibrosis

Vitamin E

alpha -tocopherol acetate

30 mg/

Improves vitamin status in

infants

Prevents exercise induced

[73]

oxidative stress

Reduces lipid per oxidation

[74]

day

400 IU

—

Enhances vitamin E level

[71]

[72]

61

≤10 years

Acute

pyelonephritis

Children

2372

16

—

≤ 5 years

Kwashiorkor

Chronic

Cholestasis

Vitamin E, riboflavin, Se

d- alpha -tocopheryl polyethylene glycol

1000 succinate (TPGS)

Vitamin E

—

—

20–25 IU

No data on morbidity

Improves neurological

development

Reduces Renal scarring

[70]

[68]

[69]

**Groups**

**No. of participants**

**Age**

**Disease Condition**

**Dosage form of Vitamin E**

**Quantity**

**Outcome**

**Reference**

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

 *Role of vitamin E in improving immune system in various disease condition of preterm infants and neonates.*


#### *Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

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

**82**

**S.**

**Groups**

**No. of** 

**Age**

**Disease Condition**

**Dosage form of Vitamin E**

**Quantity**

**Outcome**

**Reference**

**Participants**

**No**

1

Preterm

12

28–30 week

Very low Birth

dl-alpha-tocopheryl-acetate

3.5 mg/dl

Reduce the risk of

[62]

Retinopathy

Reduce cholestasis

[63]

weight

Very low Birth

Soybean oil-based lipid emulsion

—

weight

Very Low Birth

alpha-tocopheryl acetate

16.5 mg/

Increases Hemoglobin

[64]

concentration

Prevent retrolental fibroplasia

[65]

day

3.3 mg/day

Weight

Very Low Birth

Vitamin E

Weight

Very Low Birth

dl-alpha-tocopheryl acetate

25 mg

Enhances serum

[66]

alpha-tocopherol

Increased serum

[67]

alpha-tocopherol

Decreases the bilirubin level

[33]

Ephynal

3.17 mg/

day

50 mg/kg

Weight

Very Low Birth

Mixed vitamins in parenteral

solution

alpha- tocopherol

Weight

Very Low Birth

Weight

—

RRR-alpha- tocopheryl acetate;

20 IU;

Infants discriminates natural

[15]

and synthetic vitamin E

Faster Recovery

[23]

13.5 IU

*all*-rac-alpha-tocopheryl acetate

Phototherapy & Vitamin E

4 mg/day

gestation

Infants

2 3 4 5 6 7 8 9 **Table 1.**

80

—

*Role of vitamin E in improving immune system in various disease condition of preterm infants and neonates.*

Hyperbilirubinemia

Neonates

77

37–42 week

gestation

151

< 35

36

25.5 week

gestation

25

< 30 week

gestation

168

≤ 30 week

gestation

34

≤ 35 week

gestation

215

28–30 week

gestation

**Table 2.**

*Role of vitamin E in improving immune system in various disease conditions of children, infants and elderly.*

#### **3. Immunological functions of vitamin E in infections**

#### **3.1 Pneumoniae**

The in vivo studies on older mice affected with pneumonia was supplemented with vitamin E at the concentration of 500 mg per kg for four weeks and found that it has help to improve the lung functions. It was observed that migration of neutrophil and production of inflammatory cytokines was reduced with the intake of vitamin E. In human subjects, the older people supplemented with 200 IU of vitamin E per day has subsided the necessary to re-hospitalization of older people with pneumoniae up to 63% and it aids in faster recovery [57].

#### **3.2 Human immunodeficiency virus**

The vitamin E possess the anti-inflammatory property and people infected with HIV was found be lack of it and weakened immune system. Vitamin E supplementation in 400 IU per day has reinstate the delayed type hypersensitivity, production of IL-2 and TH cells. The higher level of -tocopherol in serum had blocked the advancement of infection. The murine model with HIV infection supplemented with increase in fifteen-fold of dietary vitamin E regularize the distorted immune system caused by infection to normal state [5]. Further, there was greater incidence of non-alcoholic steatohepatitis in HIV infected patients. The previous studies with 27 HIV patients with NASH reported that vitamin E supplementation was a most effective treatment as it has enhanced the ALT level, ck-18 and CAP score. Moreover, it does not cause any adverse effects in participated individuals [59].

#### **3.3 Influenza virus**

Influenza virus cause severe damage to lungs and also inflammation leads to greater oxidative stress. The vitamin E acts as an effective antioxidant therapy in influenza diseases. Thus, vitamin E supplementation protects the respiratory system and prevents the occurrence of oxidative damage due to influenza [60].

#### **3.4 Others**

The mouse models were infected with coxsackievirus which induces myocarditis. And in vitamin E deficient group the virulence of this virus is greater. In human studies, the coxsackie virus was isolated from infected individual, which was called as keshan an endemic disease commonly observed among children and women. The affected individuals were deficient in vitamin E and Se hence their supplementation in diet can prevent the viral infection [61]. The role of vitamin E in boosting immune system in various diseases in infants, children and elderly are depicted in **Tables 1** and **2**.

#### **4. Discussion**

The vitamin E was present in many natural foods which should be taken in adequate amount because the fortified or supplementation of vitamin E does not provide greater health benefits. The natural form of vitamin E rich foods should be incorporated into the diet. The healthy foods should be added to the diet for the efficient action of antioxidants in the human system [47]. The mother's milk

**85**

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

safety and longer healthy life to the preterm babies [81].

system and prevents the development of infection [84].

to have healthy and youthful glowing skin in later stages of life. [85].

the brain disorders associated with oxidative damage of brain cells.

Vitamin E was one of the efficacious nutrients which could modulate the immune system. The concentration of vitamin E is higher in immune cells than other cells in the blood. It has been observed that deficiency of vitamin E worsens the immune system in both animals and humans. Thus, vitamin E supplementation exceeding the required dietary recommendation has contributed to enhance the immune system. It has intensifies the differentiation and proliferation of T cell,

especially colostrum contains higher concentration of vitamin E which prevents the infants from oxidative damage and develops their immune system. Since, very less amount of vitamin E is transferred through the placenta, maternal milk plays a crucial role in enhancing the serum -tocopherol level in new born [76]. The babies born with lesser gestational age was highly prone to oxidative stress and the maternal milk is the best source of antioxidants than the formulas to protect the new born infants [77]. Still today, -tocopherol level in the serum was frequently measured through HPLC analysis. A novel method should be developed

The preterm infants were susceptible to oxygen radical disease and it can treat with antioxidant therapy in which the well-known antioxidant nutrient vitamin E can be used to treat this condition in preterm infants [78]. The formula fed preterm infants have the risk of developing high oxidative stress but in the study with 31 healthy preterm infants shows that long chain poly unsaturated fatty acid supplemented group does not affect the solubility of and - tocopherol [79]. Another research also suggest that both the breast fed and formula fed preterm infants possess the ability to tolerate oxidative stress. It was confirmed by the presence of malonaldehyde (MDA) in the urine which was measured by HPLC analysis [80]. The vitamin E supplementation is required in preterm infants to improve certain disease conditions like haemolytic anemia, retrolental fibroplasia, bronchopulmonary dysplasia but their long-term high dosage leads to sepsis, necro colitis and in some cases even death of premature infants. Hence the ideal dosage of vitamin E is prerequisite to treat the disease in preterm infants on the other hand to ensure the

In children, vitamin E deficiency results in the development of chronic cholestasis. In this case, the children have normal serum -tocopherol level but decreased ratio to the total lipid content [82]. The vitamin E deficiency could be combated by intaking fortified foods can enhance the vitamin E and it was one of the best methods to reach daily requirements of vitamin E [83]. Vitamin E supplementation along with other micronutrients and trace elements increases our defense barrier

The oxidative stress in the human body was mainly originated from the free radicals produced by mitochondria and other cellular components. The external factor for oxidative stress includes UV light rays from sun, ozone, pollutants, smoke from cigarette and smog. These factors contribute to the aging process. The antioxidant rich foods would help to balance the oxidant- antioxidant level in human body. The foods enriched with vitamin E are a good choice to delay the aging process and

Further, vitamin E supplementation also improves the cognitive function when their dietary intake is higher at the earlier stage of Alzheimer's disease. And also in the later stages of this disease their admission to centre is greatly reduced but it does not improve any cognitive functions [52]. The vitamin E is an effective antioxidant which shows beneficial report in preventing the progression of Alzheimer's disease, Parkinson's disease and dementia [55]. Though, there was no significant cognitive improvement in healthy individuals supplemented with vitamin E, it helped in the diseased condition We suggest that vitamin E has positive impact in improving

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

for their measurements.

#### *Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

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

**3. Immunological functions of vitamin E in infections**

with pneumoniae up to 63% and it aids in faster recovery [57].

**3.2 Human immunodeficiency virus**

pated individuals [59].

**3.3 Influenza virus**

**3.4 Others**

**Tables 1** and **2**.

**4. Discussion**

The in vivo studies on older mice affected with pneumonia was supplemented with vitamin E at the concentration of 500 mg per kg for four weeks and found that it has help to improve the lung functions. It was observed that migration of neutrophil and production of inflammatory cytokines was reduced with the intake of vitamin E. In human subjects, the older people supplemented with 200 IU of vitamin E per day has subsided the necessary to re-hospitalization of older people

The vitamin E possess the anti-inflammatory property and people infected with HIV was found be lack of it and weakened immune system. Vitamin E supplementation in 400 IU per day has reinstate the delayed type hypersensitivity, production of IL-2 and TH cells. The higher level of -tocopherol in serum had blocked the advancement of infection. The murine model with HIV infection supplemented with increase in fifteen-fold of dietary vitamin E regularize the distorted immune system caused by infection to normal state [5]. Further, there was greater incidence of non-alcoholic steatohepatitis in HIV infected patients. The previous studies with 27 HIV patients with NASH reported that vitamin E supplementation was a most effective treatment as it has enhanced the ALT level, ck-18 and CAP score. Moreover, it does not cause any adverse effects in partici-

Influenza virus cause severe damage to lungs and also inflammation leads to greater oxidative stress. The vitamin E acts as an effective antioxidant therapy in influenza diseases. Thus, vitamin E supplementation protects the respiratory system and prevents the occurrence of oxidative damage due to influenza [60].

The mouse models were infected with coxsackievirus which induces myocarditis. And in vitamin E deficient group the virulence of this virus is greater. In human studies, the coxsackie virus was isolated from infected individual, which was called as keshan an endemic disease commonly observed among children and women. The affected individuals were deficient in vitamin E and Se hence their supplementation in diet can prevent the viral infection [61]. The role of vitamin E in boosting immune system in various diseases in infants, children and elderly are depicted in

The vitamin E was present in many natural foods which should be taken in adequate amount because the fortified or supplementation of vitamin E does not provide greater health benefits. The natural form of vitamin E rich foods should be incorporated into the diet. The healthy foods should be added to the diet for the efficient action of antioxidants in the human system [47]. The mother's milk

**3.1 Pneumoniae**

**84**

especially colostrum contains higher concentration of vitamin E which prevents the infants from oxidative damage and develops their immune system. Since, very less amount of vitamin E is transferred through the placenta, maternal milk plays a crucial role in enhancing the serum -tocopherol level in new born [76]. The babies born with lesser gestational age was highly prone to oxidative stress and the maternal milk is the best source of antioxidants than the formulas to protect the new born infants [77]. Still today, -tocopherol level in the serum was frequently measured through HPLC analysis. A novel method should be developed for their measurements.

The preterm infants were susceptible to oxygen radical disease and it can treat with antioxidant therapy in which the well-known antioxidant nutrient vitamin E can be used to treat this condition in preterm infants [78]. The formula fed preterm infants have the risk of developing high oxidative stress but in the study with 31 healthy preterm infants shows that long chain poly unsaturated fatty acid supplemented group does not affect the solubility of and - tocopherol [79]. Another research also suggest that both the breast fed and formula fed preterm infants possess the ability to tolerate oxidative stress. It was confirmed by the presence of malonaldehyde (MDA) in the urine which was measured by HPLC analysis [80]. The vitamin E supplementation is required in preterm infants to improve certain disease conditions like haemolytic anemia, retrolental fibroplasia, bronchopulmonary dysplasia but their long-term high dosage leads to sepsis, necro colitis and in some cases even death of premature infants. Hence the ideal dosage of vitamin E is prerequisite to treat the disease in preterm infants on the other hand to ensure the safety and longer healthy life to the preterm babies [81].

In children, vitamin E deficiency results in the development of chronic cholestasis. In this case, the children have normal serum -tocopherol level but decreased ratio to the total lipid content [82]. The vitamin E deficiency could be combated by intaking fortified foods can enhance the vitamin E and it was one of the best methods to reach daily requirements of vitamin E [83]. Vitamin E supplementation along with other micronutrients and trace elements increases our defense barrier system and prevents the development of infection [84].

The oxidative stress in the human body was mainly originated from the free radicals produced by mitochondria and other cellular components. The external factor for oxidative stress includes UV light rays from sun, ozone, pollutants, smoke from cigarette and smog. These factors contribute to the aging process. The antioxidant rich foods would help to balance the oxidant- antioxidant level in human body. The foods enriched with vitamin E are a good choice to delay the aging process and to have healthy and youthful glowing skin in later stages of life. [85].

Further, vitamin E supplementation also improves the cognitive function when their dietary intake is higher at the earlier stage of Alzheimer's disease. And also in the later stages of this disease their admission to centre is greatly reduced but it does not improve any cognitive functions [52]. The vitamin E is an effective antioxidant which shows beneficial report in preventing the progression of Alzheimer's disease, Parkinson's disease and dementia [55]. Though, there was no significant cognitive improvement in healthy individuals supplemented with vitamin E, it helped in the diseased condition We suggest that vitamin E has positive impact in improving the brain disorders associated with oxidative damage of brain cells.

Vitamin E was one of the efficacious nutrients which could modulate the immune system. The concentration of vitamin E is higher in immune cells than other cells in the blood. It has been observed that deficiency of vitamin E worsens the immune system in both animals and humans. Thus, vitamin E supplementation exceeding the required dietary recommendation has contributed to enhance the immune system. It has intensifies the differentiation and proliferation of T cell,

production of IL2, activity of TH cells, macrophages and phagocytic cells [57]. The vitamin E supplementation in elderly has improved their immune response towards improved antibody response, delayed type hypersensitivity and also T-cell was proliferated was stimulated in response to mitogens. And Vitamin E in combination with vitamin C has also shows an enhanced immune response in elderly group than with the study group administered with vitamin E alone [50]. The higher level of vitamin E (-tocopherol) in serum the greater the ability to resist viral infection in elder population [5]. Furthermore, the dietary intake of vitamin E enhances the immunity in elders and immunocompromised persons [86].

The vitamin E supplementation has modulated the immune system in both direct and indirect way. Directly it has maintained the cellular integrity and protected the cells from damage caused by oxidative stress. While indirectly it has aid the modulation of inflammatory intermediaries like proinflammatory cytokines and prostaglandin E2. The studies in mice suggests that inflammatory lung disease can be treated with the combination of probiotic strain *Bifidobacterium lactis* and vitamin E, C to lessen the lung inflammation due to air polluting agents [87]. In animal models, the -tocopherol possess the anti-inflammatory and - tocopherol with pro-inflammatory property it could be used in the treatment of asthma [88].

The elderly people in the age group of 65 years and above was investigated for the association of vitamin E supplementation and respiratory tract infection. The study results shows that the vitamin E supplantation does not show any statistical difference among the lower respiratory infection among the supplemented and placebo group. However, the vitamin E supplementation group has a remarkable result in preventing the upper respiratory tract infection and against common cold [89]. Acute and chronic lung injuries was observed in new-borns due to oxidative damage. Usually, surfactant lipids protect the type II alveolar cells of lungs from air-borne pathogens. The vitamin E supplementation enhance surfactants and prevent the development of lung diseases like bronchopulmonary dysplasia [90]. Thus, based on these results vitamin E supplementation in our diet would prevent the upper respiratory tract infection and strengthens the lungs alveolar cells which might help us to combat the Covid-19 infection and help us to build a stronger immunity in current pandemic situation.

#### **5. Conclusion**

In past decades, vitamin E deficiency was frequently observed in preterm infants and neonates leading to various diseases like bronchopulmonary dysplasia, retrolental fibroplasia, hyperbilirubinemia, haemolytic anemia. Most often, the very low birth weight infants are at the high risk of developing vitamin E deficiency. The adequate amount of vitamin E supplementation has prevented the development of these disease conditions. The alpha tocopherol and alpha tocopheryl acetate are the most common form of vitamin E supplemented to preterm infants and new born infants. Vitamin E supplementation has prevented the development of asthma in children but not in patients with chronic severe asthma. Hence, the mechanism of vitamin E involved in preventing the disease in juvenile stage in children is need to be investigated. Vitamin E also possess numerous health benefits along with its antioxidant property. The aging process decreases the immunological response and increases the chances of infection in elder population. Thus, vitamin E supplementation has improved the T-cell mediated immune response and prevented the progression of Parkinson's disease and dementia in older people. Further, vitamin E is an important micronutrient which plays a crucial role in the early stage of our life to lead a healthy life. Many reports proved that vitamin E supplementation

**87**

**Author details**

Mariyappan Kowsalya, Mohan Prasanna Rajeshkumar\*, Thangavel Velmurugan,

© 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,

Kattakgounder Govindaraj Sudha and Saheb Ali

Tiruchengode, Tamil Nadu, India

provided the original work is properly cited.

K. S. Rangasamy College of Arts and Science (Autonomous),

\*Address all correspondence to: prasanna4d@gmail.com

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly*

has enhanced the immunity and prevented many diseases in infants. However, the optimal dosage amount, isoform and duration of vitamin E supplementation in each disease conditions in preterm infants and newborn is still need to be validated. Indeed, the mechanism behind the vitamin E in curing the infectious diseases and improving the immune response is little-known and future research will bring to light the unknown mechanism of vitamin E in boosting immune response in

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

The authors declare no conflict of interest.

infants.

**Conflict of interest**

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

has enhanced the immunity and prevented many diseases in infants. However, the optimal dosage amount, isoform and duration of vitamin E supplementation in each disease conditions in preterm infants and newborn is still need to be validated. Indeed, the mechanism behind the vitamin E in curing the infectious diseases and improving the immune response is little-known and future research will bring to light the unknown mechanism of vitamin E in boosting immune response in infants.

### **Conflict of interest**

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

immunity in elders and immunocompromised persons [86].

immunity in current pandemic situation.

**5. Conclusion**

production of IL2, activity of TH cells, macrophages and phagocytic cells [57]. The vitamin E supplementation in elderly has improved their immune response towards improved antibody response, delayed type hypersensitivity and also T-cell was proliferated was stimulated in response to mitogens. And Vitamin E in combination with vitamin C has also shows an enhanced immune response in elderly group than with the study group administered with vitamin E alone [50]. The higher level of vitamin E (-tocopherol) in serum the greater the ability to resist viral infection in elder population [5]. Furthermore, the dietary intake of vitamin E enhances the

The vitamin E supplementation has modulated the immune system in both direct and indirect way. Directly it has maintained the cellular integrity and protected the cells from damage caused by oxidative stress. While indirectly it has aid the modulation of inflammatory intermediaries like proinflammatory cytokines and prostaglandin E2. The studies in mice suggests that inflammatory lung disease can be treated with the combination of probiotic strain *Bifidobacterium lactis* and vitamin E, C to lessen the lung inflammation due to air polluting agents [87]. In animal models, the -tocopherol possess the anti-inflammatory and - tocopherol with pro-inflammatory property it could be used in the treatment of asthma [88]. The elderly people in the age group of 65 years and above was investigated for the association of vitamin E supplementation and respiratory tract infection. The study results shows that the vitamin E supplantation does not show any statistical difference among the lower respiratory infection among the supplemented and placebo group. However, the vitamin E supplementation group has a remarkable result in preventing the upper respiratory tract infection and against common cold [89]. Acute and chronic lung injuries was observed in new-borns due to oxidative damage. Usually, surfactant lipids protect the type II alveolar cells of lungs from air-borne pathogens. The vitamin E supplementation enhance surfactants and prevent the development of lung diseases like bronchopulmonary dysplasia [90]. Thus, based on these results vitamin E supplementation in our diet would prevent the upper respiratory tract infection and strengthens the lungs alveolar cells which might help us to combat the Covid-19 infection and help us to build a stronger

In past decades, vitamin E deficiency was frequently observed in preterm infants and neonates leading to various diseases like bronchopulmonary dysplasia, retrolental fibroplasia, hyperbilirubinemia, haemolytic anemia. Most often, the very low birth weight infants are at the high risk of developing vitamin E deficiency. The adequate amount of vitamin E supplementation has prevented the development of these disease conditions. The alpha tocopherol and alpha tocopheryl acetate are the most common form of vitamin E supplemented to preterm infants and new born infants. Vitamin E supplementation has prevented the development of asthma in children but not in patients with chronic severe asthma. Hence, the mechanism of vitamin E involved in preventing the disease in juvenile stage in children is need to be investigated. Vitamin E also possess numerous health benefits along with its antioxidant property. The aging process decreases the immunological response and increases the chances of infection in elder population. Thus, vitamin E supplementation has improved the T-cell mediated immune response and prevented the progression of Parkinson's disease and dementia in older people. Further, vitamin E is an important micronutrient which plays a crucial role in the early stage of our life to lead a healthy life. Many reports proved that vitamin E supplementation

**86**

The authors declare no conflict of interest.

### **Author details**

Mariyappan Kowsalya, Mohan Prasanna Rajeshkumar\*, Thangavel Velmurugan, Kattakgounder Govindaraj Sudha and Saheb Ali K. S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, Tamil Nadu, India

\*Address all correspondence to: prasanna4d@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.

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[16] Stone CA, McEvoy CT, Aschner JL, Kirk A, Ross-salazar C, Cook- Mills JM, Moore PE, Walsh WF, Hartert TV. Update on vitamin E and its potential role in preventing or treating bronchopulmonary dysplasia. Neonatology. 2018; 113, 366-378. Doi: 10.1159/000487388.

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[21] Ribeiro KD, Lima MSR, Medeirost JFP, Reboucas AS, Dantas RCS, Bezerra DS, Osorio MM, Dimenstein R. Association between maternal Vitamin E and alpha tocopherol levels in the new born and colostrum. Maternal & Child Nutrition. 2016; 12, 801-807. Doi: 10.1111/ mcn.12232.

[22] Bieri JG, Corash L, Hubbard VS. *Medical Uses of Vitamin E*. New England Journal of Medicine. 1983; 308(18), 1063-1071. doi:10.1056/ nejm198305053081805.

[23] Abrams BA, Gutteridge MC, Stocks J, Friedman M, Dormandy TL. Vitamin E in neonatal hyperbilirubinaemia. Archieves of Disease in childhood. 1973; 48, 721.

[24] Jansson L, Holmberg L, Nilsson B, Johansson. Vitamin E requirements for preterm infants. Acta paediatrica. 1978; 67 (4), 459-463. https://doi. org/10.1111/j.1651-2227.1978.tb16354.x.

[25] Ge H, Liu W, Li H, Zhang M, Liu C, Qiao Y. The association of vitamin D and vitamin E levels at birth with bronchopulmonary dysplasia in preterm infants. *Pediatr Pulmonol*. 2021; 1- 6. https://doi.org/10.1002/ppul.25414.

[26] Baydas G, Canatan H, Turkoglu A. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. JPR. 2002; https://doi.org/10.1034/j. 1600-079X.2002.01856.x.

[27] Kositamongkol S, Suthutvoravut U, Chongviriyaphan N, Feungpean B and Nuntnarumit p. Vitamin A and E status in very low birth weight infants. *Journal of Perinatology*. 2011; 31, 471-476.

[28] Al-Banna SM, Riad AN, Anes SS. Fenofibrate and antioxidant vitamins [D, E, and C] as novel approach in treatment of uncomplicated neonatal hyperbilirubinemia. MJMR. 2019; 30 (3), 206-210.

[29] Silva ALC, Ribeiro KDS, Rayanne L, Melo M, Bezerra DF, Queiroz JLC, Lima ASR, Pries JF, Bezerra DS, Osorio MM, Dimenstein. Vitamin E in human milk and its retention to the nutritional requirement of the term newborn. Rey Paul Pediatr. 2017; 36(2), 58-164.

[30] El Mashad GM, El Sayed HM, El Refaey NAS. Role of vitamin E supplementation in neonates with hyperbilirubinemia. Faculty of Medicine, Menouiia University. 2021; IP: 223.182.216.4.

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**88**

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[12] Parraguez VH, Sales F, Peralta OA,

Gonzalex-Bulnes A. Supplementation of underfed twin-bearing Ewes woth herbal vitamic C and E: Impacts on birth weight, postnatal growth and preweaning survival of the lambs. Animals. 2020; 10,652. Doi: 10.3390/ani10040652.

[13] Westergren T, and Kalikstad B. Dosage and formulation issues: Oral vitamin E therapy in children. 2010; 66,

[14] Traber MG. Vitamin E inadequancy in humans: causes and consequences. American society for nutrition. Adv. Nutr. 2014; 5, 503-514. Doi: 10.3945/

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Neonatology. 2018; 113, 366-378. Doi:

[17] Erdemli Z, Erdemli ME, Turkoz Y, Yigitcan B, Aladag MA, Cigremis Y, *et al.* Vitamin E effects on developmental disorders in fetuses and cognitive

role in preventing or treating bronchopulmonary dysplasia.

[15] Du O, Luo Z-C, Nuyt AM, Audibert F, Julein P, Wei S-Q, Zhang D-L, Fraser W, Levy E. Vitamin A and E Nutritional status in relation to leptin, adiponectin, IGF-I and IGF-II iin early life – a birth cohort study. Scientific reports. 2018; 8, 100. Doi: 10.1038/

109-118. Doi: 10.1007/ s00228-009-0729-1.

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s41598-017-18531-3.

10.1159/000487388.

Narbona E, Lira R, Reyes MD,

10.3390/ph13070145.

[1] Satyanarayana U, Chakrapani U. Essentials of Biochemistry. 2nd edition. Books and Allied P Ltd., 57-65p. ISBN:

[2] Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T. Vitamin E: Regulatory Redox Interactions. IUBMB Journal. 2019. https://doi.org/10.1002/

[3] Han SN, & Meydani SN. Impact of vitamin E on immune function and its clinical implications. Expert Review of Clinical Immunology. 2006; 2(4), 561-567. doi:10.1586/1744666x.2.4.561.

[4] Gomez-Pomar E, Hatfield E, Garlitz K, Westgate PM, Bada HS. Vitamin E in preterm infant: A forgotten cause of hemolytic anemia. Ammerican Journal of Perinatology. 2017. Doi: http:

10.1055/s-0037-160728.

90 (5), 440-480.

[5] Lima MSR, Dimenstein R,

Ribeiro KDS. Vitamin E concentration in human milk and associated factors: a literature review. J. Pediatr (Rio J). 2014;

[6] Rizvi S, Raza ST, Ahmed F, Abbas S, Mahdi F. Role of vitamin E in human health and some diseases. SQU Medical Journal. 2014; vol-14, Issue2, e157-165.

[7] Morsy TA, and Alanazi AD. A mini-overview of vitamin E. J. Egypt. Soc. Parasitol. 2020; 50(2), 247-257.

[8] How does vitamin E supports your immune system? [Internet] https:// betteryou.com/blogs/health-hub/ vitamin-e-immune-system-support.

[9] Andrea SV. Effects of Vitamin E in

[10] Lee GY and Han SN. The role of vitamin E in Immunity. Nutrients. 2018; 10(11): 1614. Doi: 10.3390/nu10111614.

neonates and young infants. International Journal of pediatrics. 2016; 4 (5), 1745-1757. 10.22038/

IJP.2016.6736.

81-87134-82-8.

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[43] Woestenenk JW, Broos N, Stellato RK, Arets GM *et al*. Vitamin E intake, -tocopherol levels and pulmonary functions in children and adolescents with cystic fibrosis. British Journal of Nutrition. 2015; 113, 1096-1101.

[44] Han SN, Adolfsson O, Lee CK, Prolla TA, Ordovas J, Meydani SN. Age and vitamin E-induced changes in gene expression profiles of T cells. J. Immunol. 2006; 177:6052-6061. doi: 10.4049/jimmunol.177.9.6052.

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[56] Graat JM, Schouten EG, Kok FJ. Effect of vitamin E and multivitaminmineral supplementation on acute respiratory tract infection in elderly. JAMA. 2002; 288(6), 715-721. Doi:

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[58] Funte MD, Sánchez C, Vellejo C, Cerro ED, Arnalich F, Hernanz A. Vitamin C and vitamin C plus E improve the immune function in the elderly. Experimental Grenology, 2020. https:// doi.org/10.1016/j.exger.2020.111118.

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[48] Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D, Huttunen JK. Effect of Vitamin E and Beta Carotene on the Incidence of Primary Nonfatal Myocardial Infarction and Fatal Coronary Heart Disease. *Arch Intern Med.* 1998;158(6):668-675. doi:10.1001/archinte.158.6.668.

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Journal of Nutrition. 2015; 113,

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[49] High KP. Micronutrient supplementation and Immune function in the eldely. Infectious disease society of Ammerica. 1999; 28, 717-22.

[50] Rall L, Meydani SN. Vitamin E, Vitamin C and Immune Response: Recent Advances. Institute of Medicine (US) Committee on Military Nutrition Research. Military Strategies for Sustainment of Nutrition and Immune Function in the Field. Washington (DC): National Academies Press (US). 1999; 13. https://www.ncbi.nlm.nih. gov/books/NBK230984/

[51] Meydani SN, Meydani M, Blumberg JB, Leka LS, Siber G, Loszewski, 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.1997.03540410058031.

[52] Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol*.* 2002; 59 (7), 1125-1132. doi:10.1001/archneur.59.7.1125.

[53] Masaki KH, Losonczy KG, Izmirlian G, Foley DG, Ross GW, Petrovitch H, Havlik R, White LR. Association of Vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 2000; 54(6). Doi: http://doi. org/10.1212/WNL.54.6.1265.

[54] de Leeuw FA, Schneider, JA, Agarwal S, Leurgans SE, Morris MC. Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex. Translational research & Clinical interventions. 2020. https://doi.org/10.1002/trc2.12021.

[55] Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A Randomized Trial of Vitamin E Supplementation and Cognitive Function in Women. *Arch Intern Med.* 2006;166(22):2462-2468. doi:10.1001/archinte.166.22.2462.

[56] Graat JM, Schouten EG, Kok FJ. Effect of vitamin E and multivitaminmineral supplementation on acute respiratory tract infection in elderly. JAMA. 2002; 288(6), 715-721. Doi: 10.1001/jama.288.6.715.

[57] Lewis ED, Meydani SN, Wu D. Regulatory Role of Vitamin E in the Immune System and Inflammation. International Union of Biochemistry and Molecular Biology. 2019; 71(4), 487-494. DOI 10.1002/iub.1976.

[58] Funte MD, Sánchez C, Vellejo C, Cerro ED, Arnalich F, Hernanz A. Vitamin C and vitamin C plus E improve the immune function in the elderly. Experimental Grenology, 2020. https:// doi.org/10.1016/j.exger.2020.111118.

[59] Giada S, Sahar S, Bertrand L, Alexandra P, Jason S, Louis-Patrick H, Jean-Pierre R, Philip W, Marc D, Peter G, Marina K. Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients. AIDS. 2020; 34(2), 237-244. doi: 10.1097/QAD.0000000000002412.

[60] Mileva M, Galabov AS. Vitamin E and Influenza virus Infection. IntechOpen. 2018. Doi: 10.5772/ intechopen.80954.

[61] Beck MA. Increased Virulence of Coxsackievirus B3 in Mice Due to Vitamin E or Selenium Deficiency. The Journal of Nutrition. 1997; 127(5), 966S–970S. https://doi.org/10.1093/ jn/127.5.966S.

[62] Brion L, Bell E, Raghuveer T. *et al.* What Is The Appropriate Intravenous Dose Of Vitamin E For Very-Low-Birth-Weight Infants?. *J Perinatol.* 2004; 24, 205-207. https://doi.org/10.1038/ sj.jp.7211078

[63] Franco S, Goriacko P, Rosen O, Morgan-Joseph T. The incidence of complications associated with parenteral nutrition in preterm infants < 32 weeks with a mixed oil lipid emulsion versus a soybean oil lipid emulsion in a level IV neonatal intensive care unit. Journal of Parenteral and Enteral Nutrition. 2020; doi:10.1002/jpen.2011.

[64] Maria Pacifici G. Effects of Vitamin E in Neonates and Young Infants. Int J Pediatr 2016; 4(5): 1745-57.

[65] Hittner HM, Speer, ME, Rudolph AJ, Blifield C, Chadda P, Holbein B, Godio LB, Kretzer FL. Retrolental Fibroplasia and Vitamin E in the Preterm Infant—Comparison of Oral Versus Intramuscular:Oral Administration. Pediatrics. 1984; 73 (2), 238-249.

[66] Jansson L, Lindreoth M, Tyoppoen J. Intestinal Absorption of Vitamin E in Low Birth Weight Infants. Acta Paediatrica. 1984; 73(3), 329-332. doi:10.1111/j.1651-2227.1994.tb17743.x.

[67] Porcelli PJ, Greene H, Adcock E. A Modified Vitamin Regimen for Vitamin B2, A, and E Administration in Very-Low–Birth-Weight Infants. Journal of Pediatric Gastroenterology and Nutrition. 2004; 38 (4), 392-400.

[68] Odigwe CC, Smedslund G, Ejemot-Nwadiaro RI, Anyanechi CC, Krawinkel MB. Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries. Cocharance Database of Systematic reviews. 2010; 4. Doi: 10.1002/14651858. CD008147.pub2.

[69] Sokol R J, Butler-Simon N, Conner C, Heubi JE, Sinatra FR, Suchy FJ, *et al.* Multicenter trial of d-α-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis. Gastroenterology. 1993; 104(6), 1727-1735. doi: 10.1016/ 0016-5085(93)90652-s.

[70] Sobouti B, Hooman N, Movahed M. The effect of vitamin E or vitamin A on the prevention of renal scarring in children with acute pyelonephritis. *Pediatric Nephrology*. 2013; 28, 277-283. https://doi.org/10.1007/ s00467-012-2308-4.

[71] Okebukola PO, Kansra S, Barrett. Vitamin E supplementation in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2017; Issue 3. Doi: 10.1002/14651858.CD0094.pub3.

[72] Baylin A, Villamor E, Rifai N, Msamanga G, Fawzi WW. Effect of vitamin supplementation to HIVinfected pregnant women on the micronutrient status of their infants. *European Journal of Clinical Nutrition*. 2005; **59**, 960-968. https://doi. org/10.1038/sj.ejcn.1602201.

[73] Goldfarb AH, McKenzie MJ, Bloomer RJ. Gender comparision of exercise-induced oxidative stress:

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exclusive formula or breast milk feeding on oxidative stress in healthy preterm infants. *Archives of Disease in Childhood*.

[81] Mino M. Use and safety of elevated dosages of vitamin E in infants and children. International Journal of vitamin and Nutrition research. 1989;

[82] Sokol RJ, Heubi JE, Iannaccone ST, Bove, KE and Balistreri, WF. Vitamin E Deficiency with Normal Serum Vitamin E Concentrations in Children with Chronic Cholestasis. N Engl J Med. 1984; 310, 1209-1212. Doi: 10.1056/

2006; 91, 327-329. http://dx.doi. org/10.1136/adc.2005.084798.

30, 69-80. PMID: 2507708.

NEJM1984051031011901.

vitaminol. 2013; 59, 576-583.

S0007114507832971.

5408.2001.00142.x.

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[85] Meydani M. Effect of functional food ingredients: vitamin E modulation of cardiovascular diseases and immune status in the elderly. *The American Journal of Clinical Nutrition*. 2000; 71(6), 1665S-1668S. https://doi. org/10.1093/ajcn/71.6.1665S.

[86] Gay R, Meydani SN. The effect of vitamin, vitamin B6 and vitamin B12 on immune function. Nutrition in clinical care. 2002; 4(4), 188-198. https://doi.org/10.1046/j.1523-

[83] Utsugi MT, Nakade M, Imai E, Kasaoka NT, Nozue M, et al.

Distribution of vitamin E intake among Japanese Dietary supplement and fortified food users: A secondary analysis from the nutritional health and nutrition survey,2003-2009. J. Nutr.Sci.

*DOI: http://dx.doi.org/10.5772/intechopen.98553*

supplementation. Applied physiology, Nutrition and Metabolism. 2007; 32(6): 1124-1131. https://doi.org/10.1139/

[74] Huang, H, Appel LJ, Croft KD, Miller ER, Moru TA, Puddey IB. Effects of vitamin C and vitamin E on in vivo

[75] Hemila H, Virtamo J, Albanes D, Kaprio J. Vitamin E and Beta-carotene supplementation and hospital treated pneumonia incidence in male smokers.

[76] Debier C. Vitamin E During Preand Postnatal Periods. Vitamins & Hormones. 2007; 357-373. doi:10.1016/

[77] Oveisi MR, Sadeghi N, Jannat B, Hajimahmoodi M, Behfar A, Jannat F, MohktariNasab. Human Breast milk provides better antioxidant capacity than infant formula. Iran J Res. 2010; 9

[78] Katti K, Ayasolla KR, Lurcotta T, Potak D, Codipilly C, Weinberger B. Lipid peroxidation products as

predictors of oxidant-mediated disease in preterm infants. The Journal of Maternal-Fetal & Neonatal Medicine. 2020; https://doi.org/10.1080/14767058.

[79] Kaempf-Rotzoll, Hellstern and Linderamp. Influence of Long-Chain Polyunsaturated Fatty Acid Formula Feeds on Vitamin E Status in Preterm. International Journal of vitamin and nutrition research. 2013; 73 (5), 377-387. https://doi.org/10.1024/0300-9831.

[80] Korchazhkina O, Jones E, Czauderna M*,* Spencer SA. Effects of

CHEST. 2004; 125(2), 557-565.

s0083-6729(07)76013-2.

(4) 445-449.PMID: 24381611.

2020.1869934.

lipid peroxidation: results of a randomized controlled trial. *The American Journal of Clinical Nutrition*. 2002; 76(3), 549-555. https://doi. org/10.1093/ajcn/76.3.549.

influence of antioxidant

H07-078.

*Role of Vitamin E in Boosting the Immunity from Neonates to Elderly DOI: http://dx.doi.org/10.5772/intechopen.98553*

influence of antioxidant supplementation. Applied physiology, Nutrition and Metabolism. 2007; 32(6): 1124-1131. https://doi.org/10.1139/ H07-078.

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

[67] Porcelli PJ, Greene H, Adcock E. A Modified Vitamin Regimen for Vitamin B2, A, and E Administration in Very-Low–Birth-Weight Infants. Journal of Pediatric Gastroenterology and Nutrition. 2004; 38 (4), 392-400.

[68] Odigwe CC, Smedslund G, Ejemot-Nwadiaro RI, Anyanechi CC, Krawinkel MB. Supplementary vitamin E, selenium, cysteine and riboflavin for preventing kwashiorkor in preschool children in developing countries. Cocharance Database of Systematic reviews. 2010; 4. Doi: 10.1002/14651858.

[69] Sokol R J, Butler-Simon N, Conner C, Heubi JE, Sinatra FR, Suchy FJ, *et al.* Multicenter trial of d-α-tocopheryl polyethylene glycol 1000 succinate for treatment of vitamin E deficiency in children with chronic cholestasis. Gastroenterology. 1993; 104(6), 1727-1735. doi: 10.1016/

0016-5085(93)90652-s.

https://doi.org/10.1007/ s00467-012-2308-4.

[70] Sobouti B, Hooman N, Movahed M. The effect of vitamin E or vitamin A on the prevention of renal scarring in children with acute pyelonephritis. *Pediatric Nephrology*. 2013; 28, 277-283.

[71] Okebukola PO, Kansra S, Barrett. Vitamin E supplementation in people with cystic fibrosis. Cochrane Database of Systematic Reviews. 2017; Issue 3. Doi: 10.1002/14651858.CD0094.pub3.

[72] Baylin A, Villamor E, Rifai N, Msamanga G, Fawzi WW. Effect of vitamin supplementation to HIVinfected pregnant women on the micronutrient status of their infants. *European Journal of Clinical Nutrition*.

2005; **59**, 960-968. https://doi. org/10.1038/sj.ejcn.1602201.

[73] Goldfarb AH, McKenzie MJ, Bloomer RJ. Gender comparision of exercise-induced oxidative stress:

CD008147.pub2.

Jean-Pierre R, Philip W, Marc D, Peter G, Marina K. Vitamin E is an effective treatment for nonalcoholic steatohepatitis in HIV mono-infected patients. AIDS. 2020; 34(2), 237-244. doi: 10.1097/QAD.0000000000002412.

[60] Mileva M, Galabov AS. Vitamin E

[61] Beck MA. Increased Virulence of Coxsackievirus B3 in Mice Due to Vitamin E or Selenium Deficiency. The Journal of Nutrition. 1997; 127(5), 966S–970S. https://doi.org/10.1093/

[62] Brion L, Bell E, Raghuveer T. *et al.* What Is The Appropriate Intravenous Dose Of Vitamin E For Very-Low-Birth-Weight Infants?. *J Perinatol.* 2004; 24, 205-207. https://doi.org/10.1038/

[63] Franco S, Goriacko P, Rosen O, Morgan-Joseph T. The incidence of complications associated with

parenteral nutrition in preterm infants < 32 weeks with a mixed oil lipid emulsion versus a soybean oil lipid emulsion in a level IV neonatal intensive care unit. Journal of Parenteral and Enteral Nutrition. 2020; doi:10.1002/jpen.2011.

[64] Maria Pacifici G. Effects of Vitamin E in Neonates and Young Infants. Int J

[65] Hittner HM, Speer, ME, Rudolph AJ,

Administration. Pediatrics. 1984; 73 (2),

Tyoppoen J. Intestinal Absorption of Vitamin E in Low Birth Weight Infants. Acta Paediatrica. 1984; 73(3), 329-332. doi:10.1111/j.1651-2227.1994.tb17743.x.

Pediatr 2016; 4(5): 1745-57.

Versus Intramuscular:Oral

[66] Jansson L, Lindreoth M,

Blifield C, Chadda P, Holbein B, Godio LB, Kretzer FL. Retrolental Fibroplasia and Vitamin E in the Preterm Infant—Comparison of Oral

and Influenza virus Infection. IntechOpen. 2018. Doi: 10.5772/

intechopen.80954.

jn/127.5.966S.

sj.jp.7211078

**92**

238-249.

[74] Huang, H, Appel LJ, Croft KD, Miller ER, Moru TA, Puddey IB. Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. *The American Journal of Clinical Nutrition*. 2002; 76(3), 549-555. https://doi. org/10.1093/ajcn/76.3.549.

[75] Hemila H, Virtamo J, Albanes D, Kaprio J. Vitamin E and Beta-carotene supplementation and hospital treated pneumonia incidence in male smokers. CHEST. 2004; 125(2), 557-565.

[76] Debier C. Vitamin E During Preand Postnatal Periods. Vitamins & Hormones. 2007; 357-373. doi:10.1016/ s0083-6729(07)76013-2.

[77] Oveisi MR, Sadeghi N, Jannat B, Hajimahmoodi M, Behfar A, Jannat F, MohktariNasab. Human Breast milk provides better antioxidant capacity than infant formula. Iran J Res. 2010; 9 (4) 445-449.PMID: 24381611.

[78] Katti K, Ayasolla KR, Lurcotta T, Potak D, Codipilly C, Weinberger B. Lipid peroxidation products as predictors of oxidant-mediated disease in preterm infants. The Journal of Maternal-Fetal & Neonatal Medicine. 2020; https://doi.org/10.1080/14767058. 2020.1869934.

[79] Kaempf-Rotzoll, Hellstern and Linderamp. Influence of Long-Chain Polyunsaturated Fatty Acid Formula Feeds on Vitamin E Status in Preterm. International Journal of vitamin and nutrition research. 2013; 73 (5), 377-387. https://doi.org/10.1024/0300-9831. 73.5.377.

[80] Korchazhkina O, Jones E, Czauderna M*,* Spencer SA. Effects of exclusive formula or breast milk feeding on oxidative stress in healthy preterm infants. *Archives of Disease in Childhood*. 2006; 91, 327-329. http://dx.doi. org/10.1136/adc.2005.084798.

[81] Mino M. Use and safety of elevated dosages of vitamin E in infants and children. International Journal of vitamin and Nutrition research. 1989; 30, 69-80. PMID: 2507708.

[82] Sokol RJ, Heubi JE, Iannaccone ST, Bove, KE and Balistreri, WF. Vitamin E Deficiency with Normal Serum Vitamin E Concentrations in Children with Chronic Cholestasis. N Engl J Med. 1984; 310, 1209-1212. Doi: 10.1056/ NEJM1984051031011901.

[83] Utsugi MT, Nakade M, Imai E, Kasaoka NT, Nozue M, et al. Distribution of vitamin E intake among Japanese Dietary supplement and fortified food users: A secondary analysis from the nutritional health and nutrition survey,2003-2009. J. Nutr.Sci. vitaminol. 2013; 59, 576-583.

[84] Maggini S, Wintergerst ES, Beveridge S, Horning DH. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. British Journal of Nutrition. 2007; 98(S1), s29-s35. http://doi.org/10.1017/ S0007114507832971.

[85] Meydani M. Effect of functional food ingredients: vitamin E modulation of cardiovascular diseases and immune status in the elderly. *The American Journal of Clinical Nutrition*. 2000; 71(6), 1665S-1668S. https://doi. org/10.1093/ajcn/71.6.1665S.

[86] Gay R, Meydani SN. The effect of vitamin, vitamin B6 and vitamin B12 on immune function. Nutrition in clinical care. 2002; 4(4), 188-198. https://doi.org/10.1046/j.1523- 5408.2001.00142.x.

[87] Panebianco C, Bou Nasser EF, Forlani G, Palmiweri G, Tatangelo L, Villani A, Xu L, Accolla R, Pazienza V. Probiotic *Bifidobacterium lactis*, antioxidant vitamin E/C and antiinflammatory dha attenuate lung inflammation due to pm2.5 exposure in mice. Beneficial Microbes. 2019; 10 (1), 69-75(7). https://doi.org/10.3920/ BM2018.0060.

[88] Cook-Mills JM, Avila PC. Vitamin E and D regulation of allergic asthma immunopathogenesis. International Immunopharmacology. 2014; 23(1), 364-372. doi:10.1016/j. intimp.2014.08.007.

[89] Meydani SN, Leka LS, Fine BC, Dallal GE, Keusch GT, Singh MF, Hamer DH. Vitamin E and Respiratory Tract Infections in Elderly Nursing Home Residents: A Randomized Controlled Trial. JAMA*.* 2004; 292(7); 828-836. doi:10.1001/jama.292.7.828

[90] Kolleck I, Sinha P, Rustow B. Vitamin E as an antioxidant of the lung mechanisms of vitamin E delivery to alveolar type II cells. American Journal of Respiratory and Critical care medicine. 2002; 166 (1), s62-s66. https://doi.org/10.1164/rccm.2206019.

**95**

**Chapter 6**

**Abstract**

**1. Introduction**

Medicine [5–7].

Role of Vitamin E in Pregnancy

Vitamins play important roles in female health. They are essential for many functions, including menstruation and ovulation, oocyte (egg) quality and maturation. Vitamin E was first discovered in 1922 as a substance necessary for reproduction. It has become widely known as a powerful lipid-soluble antioxidant. There are various reports on the benefits of vitamin E on health in general. Vitamin E helps your body create and maintain red blood cells, healthy skin, eyes and strengthens your natural immune system. However, despite it being initially discovered as a vitamin necessary for reproduction, to date studies relating to its effects in this area are lacking. Vitamin E supplementation may help reduce the risk of pregnancy complications involving oxidative stress, such as pre-eclampsia. This chapter is written

Vitamin E is an important micronutrient in the human body. Vitamin E maintains various body functions. It plays a very important role in maternal health and child development [1]. Vitamin E is an essential fat-soluble micronutrient for higher mammals and functions as an antioxidant for lipids [2]. American scientists Herbert McLean Evans and Katherine Scott Bishop discovered vitamin E in 1922. Vitamin E is an essential lipid-soluble vitamin. It was initially denoted as an "antisterility factor X" that was necessary for reproduction. The vital role of vitamin E in reproduction was first investigated 80 years ago [3]. It was named according to a consecutive alphabetical order preceded by the discovery of vitamins A to D. Later vitamin E was called alpha-tocopherol, according to the Greek term "tokos" childbirth, "phero" to bear, and -ol indicating alcohol. Vitamin E is also called the "protecting vitamin" [4]. The amount of vitamin E is determined by age. For adults, the safest dose of vitamin E supplements is 1,500 IU/day for natural forms and 1,000 IU/day for man-made (synthetic) forms. **Table 1** shows the average daily prescribed doses as determined by the Food and Nutrition Board of the Institute of

Some vitamin E containing foods include wheat, rice bran, barley, oat, coconut, palm, and annatto [8–9]. Other sources include rye, amaranth, walnut, hazelnut, poppy, sunflower, maize and the seeds of grape and pumpkins [10]. The richest sources are nuts, spinach, whole grains, olive oil, and sunflower oil [11]. Vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues

*Mohd Aftab Siddiqui, Usama Ahmad, Asad Ali,* 

to provide a review of the known roles of vitamin E in pregnancy.

**Keywords:** Vitamin E, Pregnancy, Oxidative stress, Tocopherol

*Farogh Ahsan and Md. Faheem Haider*

#### **Chapter 6**

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

[87] Panebianco C, Bou Nasser EF, Forlani G, Palmiweri G, Tatangelo L, Villani A, Xu L, Accolla R, Pazienza V. Probiotic *Bifidobacterium lactis*, antioxidant vitamin E/C and antiinflammatory dha attenuate lung inflammation due to pm2.5 exposure in mice. Beneficial Microbes. 2019; 10 (1), 69-75(7). https://doi.org/10.3920/

[88] Cook-Mills JM, Avila PC. Vitamin E and D regulation of allergic asthma immunopathogenesis. International Immunopharmacology. 2014; 23(1),

[89] Meydani SN, Leka LS, Fine BC, Dallal GE, Keusch GT, Singh MF, Hamer DH. Vitamin E and Respiratory Tract Infections in Elderly Nursing Home Residents: A Randomized Controlled Trial. JAMA*.* 2004; 292(7); 828-836. doi:10.1001/jama.292.7.828

[90] Kolleck I, Sinha P, Rustow B. Vitamin E as an antioxidant of the lung mechanisms of vitamin E delivery to alveolar type II cells. American Journal of Respiratory and Critical care medicine. 2002; 166 (1), s62-s66. https://doi.org/10.1164/rccm.2206019.

BM2018.0060.

364-372. doi:10.1016/j. intimp.2014.08.007.

**94**
