**Abstract**

Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and neuroimaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. It is the commonest neurological problem that results in significant disability, but awareness of it remains poor. It affects over half of people over 65 years old and inflicts up to third of acute strokes, over 40% of dementia, and a significant decline in physical ability in otherwise asymptomatic, aging individuals. Moreover, the unifying theory for the pathomechanism of the disease remains elusive and hence the apparent ineffective therapeutic approaches. Given the growing literature for natural vitamin E (tocopherols and tocotrienols) as a potent antioxidant, this chapter attempts to consolidate the contemporary evidence to shed plausible insights on the neuroprotective potentials of natural vitamin E in addressing the heterogenous CSVD spectrum, in health and in disease.

**Keywords:** cerebral small vessel diseases, vitamin E, antioxidants, dementia, aging

#### **1. Introduction**

The recognition of vitamin E for its nutritive value was first linked to reproductive health in laboratory rats, then coined as factor X [1]. While alpha-tocopherol was the first vitamin E isomer to be recognized, there are now eight chemically distinct isomers known, consisting of alpha (α), beta (β), gamma (γ), and delta (δ)-isoforms of tocopherols and tocotrienols [2]. Current recommendations for adequate intake values are established based on α-tocopherol alone, whereas other forms of vitamin E need to meet other criteria [3]. Nature affords tocopherols in abundance, particularly in plants such as peanuts, sunflower seeds, and sesame seeds. The major dietary source of tocopherol is largely from corn and soybean oil consumption [4]. In contrast, the less ubiquitous tocotrienols are found in certain cereals and vegetables such as palm oil and annatto. A non-food source of tocotrienols is also recognized, namely, the latex of the rubber plant [2].

The well-established bioactivity of vitamin E is its antioxidant property by means of lipid peroxidation of cellular membranes [2]. As such, this property lends vitamin E the roles in promoting vascular health in arterial compliance studies and endothelial dysfunction biomarker. Pertinent to this, vitamin E

involvement is the vascular endothelium, which lines the intraluminal surface of blood vessels and is involved in the regulation of vascular tone, platelet activity, thrombosis, and the overriding pathogenesis of atherosclerosis [5, 6]. Vitamin E engages with the production of nitric oxide (NO) that relaxes the vascular smooth muscle while limiting free radicals to maintain arterial compliance [7]. More recently, vitamin E has been linked with anti-atherogenic effects that decrease low-density lipoprotein (LDL) oxidation and downstream inhibition of protein kinase C (PKC), adhesion molecules, monocyte transmigration, and vascular smooth muscle cell proliferation [8].

Therefore, the foregoing facts on vascular health and vitamin E profiles offer interrelated perspectives for a largely unexplored neurological condition termed cerebral small vessel diseases (CSVD). CSVD variable manifestations inflict small blood vessels or microcirculation at the subcortical and deeper parts of the brain. It has been widely reported to cause cerebral ischemic stroke or lacunar stroke that accounts for nearly a third of all stroke subtypes worldwide [9–12]. The pathological consequences of small vessel disease on the brain parenchyma rather than the underlying diseases of the vessels is frequently viewed as the basis of CSVD [13]. Notably, CSVD lesions can be silent, and the affected individual may not have any apparent clinical symptoms. This silent (subclinical) lesion, with higher numbers (single or multiple), poses as a risk for vascular cognitive impairment, dementia, Alzheimer's disease, and full-blown stroke [14, 15].

Furthermore, aging and chronic hypertension are known to accelerate CSVD, as the two conditions (physiological and pathological, respectively) may result in less efficient ability to self-regulate cerebral blood flow (cBF) from the concurrent varying systemic blood pressure levels and increased arterial stiffness which increases the speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to cause variable degrees of endothelial damage in the blood-brain barrier (BBB) and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis feature of CSVD [17–19].

In addition, there is an elevated production of reactive oxygen species (ROS) in CSVD that ultimately leads to endothelium dysfunctions [20, 21]. This is mainly due to the cumulative reactions and processes (i.e., high blood pressure, very low density of lipoproteins, diabetes mellitus, homocysteinemia, and smoking) that trigger and escalate the inflammatory responses and oxidative stress [20, 21]. This, in turn, heightens the release of adhesion molecules and recruits leukocytes, causing higher leukocyte-endothelial cell (EC) adhesion and reduced cBF. Accordingly, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases intensify the oxidative stress (a major source of ROS in vessel wall) and the consequent destructive impact on EC-dependent NO signaling [22, 23].

Collectively, this chapter focuses on highlighting the contemporary evidence on vitamin E, especially α-tocopherol and α-tocotrienol, their neuroprotective potential in relation to the heterogenous spectrum of CSVD manifestations, in promoting health as we age, and in mitigating disease.

#### **2. Natural sources of vitamin E**

#### **2.1 Forms and structure**

Vitamin E was first discovered in 1922 by Herbert Evans and Katherine Bishop at the University of California in Berkeley when they studied nutritive dependencies in reproduction [1]. They observed that rats fed with a purified diet of casein 18%,

**187**

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

–*ol* because it behaves chemically like an alcohol) [25, 26].

cornstarch 54%, lard 15%, butterfat 9%, and salts 4% and adequate vitamin A (as cod liver oil), vitamin B (as yeast), and vitamin C (as orange juice) did not reproduce. They observed in females defective placental function, whereas the ovaries, ovulation, and implantation were unimpaired; and in males, there was a complete atrophy of the seminiferous epithelium [24, 25]. The addition of lettuce to the diet prevented embryo resorption during rodent gestation, and healthy pups were born again, thus, leading to the discovery of an anti-sterility factor, then termed as factor X. Wheat germ oil was later found to be a rich source of factor X. It was not until some 10 years later that Evans successfully isolated the components of vitamin E family and named them tocopherols (Greek: *toc* (child), *phero* (to bring forth), and

Meanwhile, tocotrienol was named by Bunyan and colleagues, when they identified the unsaturated derivatives of tocols, isolated from the latex of the rubber plant (*Hevea brasiliensis*) [27]. The structure of tocotrienols was further described by Pennock and colleagues, who found that palm oil was a rich source of this "new tocopherol" [28]. Palm oil derived from *Elaeis guineensis* (African oil palm) now represents the richest source of the lesser characterized vitamin E, α-tocotrienol. α-Tocopherol is currently the only form of vitamin E recognized to meet human

requirements, and recommended adequate intake values are established based on α-tocopherol alone. Other forms of vitamin E must fulfill the following to be recognized as vitamin E: (1) converted to α-tocopherol in humans and (2) recognized by the α-tocopherol transfer protein. Plasma α-tocopherol concentrations in humans range from 11 to 37 μmol/L, whereas γ-tocopherol concentrations are roughly 2–5 μmol/L, and tocotrienol concentrations are less than 1 μmol/L in non-

Tocopherols are widely found in nature, predominantly in plant seeds such as peanuts, sunflower seeds, almonds, walnuts, and sesame seeds. The major dietary source of tocopherol comes from the widespread use of corn and soybean oil [4]. Tocotrienols, which are less ubiquitous, are found in certain cereals and vegetables such as palm oil, rice bran oil, and annatto. Lower levels of tocotrienols can be found in grapefruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flaxseed oil, poppy seed oil, and sunflower oil [3]. A non-food source of tocotrienols is the latex of the rubber plant. While it has been shown that the different vitamin E forms are interconvertible by plants, there has been no convincing

While alpha-tocopherol was the first vitamin E isomer to be recognized, there are now eight chemically distinct isomers known, consisting of alpha (α), beta (β), gamma (γ), and delta (δ)-isoforms of tocopherols and tocotrienols [2], as shown in **Figure 1**. The molecular structure of vitamin E is based on a chromanol ring with a side chain at the C2 position. While the lipophilic tail of tocopherols is completely saturated, tocotrienols have three double bonds, at the 3′, 7′, and 11′ positions. Plants synthesize eight different forms of vitamin E, tocopherols and tocotrienols, which include α, β, γ, and δ forms that differ in the number of methyl groups on the chromanol ring [29]. The slight difference in structure between isoforms translates into striking variations in activity. Compared with tocopherols, tocotrienols are more efficiently incorporated into membranes and cultured cells [30], thus giving

Upon oral administration, vitamin E, a lipid-soluble vitamin, requires biliary and pancreatic secretions in order to form micelles for the subsequent uptake by intestinal epithelial cells [3]. Therefore, the absorption of vitamin E is enhanced if

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

supplemented humans [3].

evidence that the same is true for animals [29].

rise to more potent antioxidant activities.

**2.2 Mechanism and regulation of metabolism**

#### *Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease DOI: http://dx.doi.org/10.5772/intechopen.91028*

cornstarch 54%, lard 15%, butterfat 9%, and salts 4% and adequate vitamin A (as cod liver oil), vitamin B (as yeast), and vitamin C (as orange juice) did not reproduce. They observed in females defective placental function, whereas the ovaries, ovulation, and implantation were unimpaired; and in males, there was a complete atrophy of the seminiferous epithelium [24, 25]. The addition of lettuce to the diet prevented embryo resorption during rodent gestation, and healthy pups were born again, thus, leading to the discovery of an anti-sterility factor, then termed as factor X. Wheat germ oil was later found to be a rich source of factor X. It was not until some 10 years later that Evans successfully isolated the components of vitamin E family and named them tocopherols (Greek: *toc* (child), *phero* (to bring forth), and –*ol* because it behaves chemically like an alcohol) [25, 26].

Meanwhile, tocotrienol was named by Bunyan and colleagues, when they identified the unsaturated derivatives of tocols, isolated from the latex of the rubber plant (*Hevea brasiliensis*) [27]. The structure of tocotrienols was further described by Pennock and colleagues, who found that palm oil was a rich source of this "new tocopherol" [28]. Palm oil derived from *Elaeis guineensis* (African oil palm) now represents the richest source of the lesser characterized vitamin E, α-tocotrienol.

α-Tocopherol is currently the only form of vitamin E recognized to meet human requirements, and recommended adequate intake values are established based on α-tocopherol alone. Other forms of vitamin E must fulfill the following to be recognized as vitamin E: (1) converted to α-tocopherol in humans and (2) recognized by the α-tocopherol transfer protein. Plasma α-tocopherol concentrations in humans range from 11 to 37 μmol/L, whereas γ-tocopherol concentrations are roughly 2–5 μmol/L, and tocotrienol concentrations are less than 1 μmol/L in nonsupplemented humans [3].

Tocopherols are widely found in nature, predominantly in plant seeds such as peanuts, sunflower seeds, almonds, walnuts, and sesame seeds. The major dietary source of tocopherol comes from the widespread use of corn and soybean oil [4]. Tocotrienols, which are less ubiquitous, are found in certain cereals and vegetables such as palm oil, rice bran oil, and annatto. Lower levels of tocotrienols can be found in grapefruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flaxseed oil, poppy seed oil, and sunflower oil [3]. A non-food source of tocotrienols is the latex of the rubber plant. While it has been shown that the different vitamin E forms are interconvertible by plants, there has been no convincing evidence that the same is true for animals [29].

While alpha-tocopherol was the first vitamin E isomer to be recognized, there are now eight chemically distinct isomers known, consisting of alpha (α), beta (β), gamma (γ), and delta (δ)-isoforms of tocopherols and tocotrienols [2], as shown in **Figure 1**. The molecular structure of vitamin E is based on a chromanol ring with a side chain at the C2 position. While the lipophilic tail of tocopherols is completely saturated, tocotrienols have three double bonds, at the 3′, 7′, and 11′ positions. Plants synthesize eight different forms of vitamin E, tocopherols and tocotrienols, which include α, β, γ, and δ forms that differ in the number of methyl groups on the chromanol ring [29]. The slight difference in structure between isoforms translates into striking variations in activity. Compared with tocopherols, tocotrienols are more efficiently incorporated into membranes and cultured cells [30], thus giving rise to more potent antioxidant activities.

#### **2.2 Mechanism and regulation of metabolism**

Upon oral administration, vitamin E, a lipid-soluble vitamin, requires biliary and pancreatic secretions in order to form micelles for the subsequent uptake by intestinal epithelial cells [3]. Therefore, the absorption of vitamin E is enhanced if

*Neuroprotection - New Approaches and Prospects*

smooth muscle cell proliferation [8].

feature of CSVD [17–19].

Alzheimer's disease, and full-blown stroke [14, 15].

tive impact on EC-dependent NO signaling [22, 23].

health as we age, and in mitigating disease.

**2. Natural sources of vitamin E**

**2.1 Forms and structure**

involvement is the vascular endothelium, which lines the intraluminal surface of blood vessels and is involved in the regulation of vascular tone, platelet activity, thrombosis, and the overriding pathogenesis of atherosclerosis [5, 6]. Vitamin E engages with the production of nitric oxide (NO) that relaxes the vascular smooth muscle while limiting free radicals to maintain arterial compliance [7]. More recently, vitamin E has been linked with anti-atherogenic effects that decrease low-density lipoprotein (LDL) oxidation and downstream inhibition of protein kinase C (PKC), adhesion molecules, monocyte transmigration, and vascular

Therefore, the foregoing facts on vascular health and vitamin E profiles offer interrelated perspectives for a largely unexplored neurological condition termed cerebral small vessel diseases (CSVD). CSVD variable manifestations inflict small blood vessels or microcirculation at the subcortical and deeper parts of the brain. It has been widely reported to cause cerebral ischemic stroke or lacunar stroke that accounts for nearly a third of all stroke subtypes worldwide [9–12]. The pathological consequences of small vessel disease on the brain parenchyma rather than the underlying diseases of the vessels is frequently viewed as the basis of CSVD [13]. Notably, CSVD lesions can be silent, and the affected individual may not have any apparent clinical symptoms. This silent (subclinical) lesion, with higher numbers (single or multiple), poses as a risk for vascular cognitive impairment, dementia,

Furthermore, aging and chronic hypertension are known to accelerate CSVD, as the two conditions (physiological and pathological, respectively) may result in less efficient ability to self-regulate cerebral blood flow (cBF) from the concurrent varying systemic blood pressure levels and increased arterial stiffness which increases the speed and flow pulsatility in cerebral arterioles [16]. These hemodynamic changes are postulated to cause variable degrees of endothelial damage in the blood-brain barrier (BBB) and alter its permeability through an increase of the shear stress [17]. Hence, the BBB breakdown is an important etiopathogenesis

In addition, there is an elevated production of reactive oxygen species (ROS) in CSVD that ultimately leads to endothelium dysfunctions [20, 21]. This is mainly due to the cumulative reactions and processes (i.e., high blood pressure, very low density of lipoproteins, diabetes mellitus, homocysteinemia, and smoking) that trigger and escalate the inflammatory responses and oxidative stress [20, 21]. This, in turn, heightens the release of adhesion molecules and recruits leukocytes, causing higher leukocyte-endothelial cell (EC) adhesion and reduced cBF. Accordingly, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases intensify the oxidative stress (a major source of ROS in vessel wall) and the consequent destruc-

Collectively, this chapter focuses on highlighting the contemporary evidence on vitamin E, especially α-tocopherol and α-tocotrienol, their neuroprotective potential in relation to the heterogenous spectrum of CSVD manifestations, in promoting

Vitamin E was first discovered in 1922 by Herbert Evans and Katherine Bishop at the University of California in Berkeley when they studied nutritive dependencies in reproduction [1]. They observed that rats fed with a purified diet of casein 18%,

**186**

#### **Figure 1.**

*Chemical structures of (A) tocopherol and (B) tocotrienol. Note the three double bonds in the tocotrienol side chain. Note: Isoforms—α (R′ = CH3, R″ = CH3); β (R′ = CH3, R″ = H); γ (R′ = H, R″ = CH3); δ (R′ = H, R″ = H).*

taken with food which contributes fat, thereby triggering the secretion of enzymes that facilitate the formation of micelles required for absorption. Despite many years since its discovery, there is still a lack of understanding of the mechanism of absorption, liver trafficking, and disposition of vitamin E isoforms [31].

The general understanding of vitamin E absorption and trafficking is that orally administered vitamin E undergoes intestinal luminal processing, where it accumulates in lipid droplets, which then coalesce with nascent chylomicrons [32]. The vitamin E isoforms are not discriminated during the intestinal absorption or incorporation into chylomicrons. Chylomicrons then transport vitamin E from the intestine through circulation to the liver, which metabolizes or resecretes vitamin E back into the plasma for trafficking to tissues via enriched lipoproteins.

After the liver takes up chylomicron remnants, vitamin E isoforms with greater affinity to α-tocopherol transport protein (αTTP) are preferentially bound for transport to tissues, thereby avoiding catabolism. αTTP expressed in the liver is required to facilitate vitamin E transport from the liver to other tissues and organs. The discrimination of vitamin E isoforms occurs in the liver as a result of differing affinity of isoforms to αTTP. αTTP has the ability to bind to both α-tocotrienol and α-tocopherol, but αTTP binds to α-tocotrienol with approximately 10 fold lower affinity than that for α-tocopherol [33]. All lipoproteins are involved in the trafficking of α-tocopherol to the tissues, although very low-density lipoprotein apparently leaves the liver preferentially enriched in α-tocopherol compared with LDL or high-density lipoprotein (HDL) [29]. Discrimination between dietary forms of vitamin E is dependent upon the hepatic αTTP to maintain circulating α-tocopherol [34]. α-tocopherol is also most retained in tissues due to preferential binding by αTT, facilitating secretion into plasma [2] and trafficking to tissues, whereas large portions of other forms of vitamin E are catabolized through general xenobiotic processes [4].

Interestingly, a study using αTTP knockout mice showed that orally administered α-tocotrienol was absorbed and delivered to vital organs, despite being deficient of αTTP [35]. In organs such as adipose tissue, skin, skeletal muscle, and the heart, α-tocotrienol levels were many folds higher than α-tocopherol in supplemented αTTP knockout mice. Oral supplementation of the female mice with α-tocotrienol also restored fertility, suggesting that it can be successfully delivered to the relevant tissues and that α-tocotrienol supported reproductive function under

**189**

**Figure 2.**

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

α-tocopherol secretion from the liver into the circulation [31].

changes reflect long-term vitamin E status [31].

conditions of α-tocopherol deficiency. These findings suggest TTP-independent mechanisms for the tissue delivery of oral α-tocotrienol. While αTTP may contribute to tocotrienol trafficking, αTTP does not represent a major or sole mechanism of

Vitamin E is metabolized by ω-hydroxylation by cytochrome P450 (CYP), followed by β-oxidation and conjugation to generate carboxychromanols and conjugated counterparts [2, 29]. The tail of vitamin E isoforms is ω-hydroxylated by CYP 4F2 and subjected to several rounds of β-oxidation, which ultimately results in the formation of carboxyethyl hydroxy chromanol (CEHC) (**Figure 2**). Thus, the tail-shortened, water-soluble metabolite, CEHC, is synthesized and excreted in the urine [36]. Conjugation such as sulfation and glucuronidation of the phenolic on the chromanol may also take place in parallel with β-oxidation when there is a high intake of vitamin E forms [4]. Although α-tocopherol largely escapes catabolism and ends up in the blood circulation, α-CEHC is synthesized endogenously when the quantity of hepatic α-tocopherol exceeds the capacity of αTTP to facilitate

Traber and colleagues established that urinary α-CEHC might be useful to noninvasively assess α-tocopherol adequacy, especially in populations with metabolic syndrome-associated hepatic dysfunction that likely impairs α-tocopherol trafficking. Their finding also suggests that people with metabolic syndrome may have a higher requirement for vitamin E due to poorer trafficking leading to lower apparent α-tocopherol bioavailability. However, it is still unknown whether urinary α-CEHC excretion reflects α-tocopherol intake from a single meal or whether its

Recently, Traber and colleagues, which lead as one of the most prolific research groups in vitamin E tocopherol, suggested novel approaches to assess α-tocopherol absorption and trafficking in order to establish human vitamin E requirements [32]. Their study observed that the absorption of α-tocopherol is not necessarily limited by the absence of fat or fasting and that the absorption is highly dependent on chylomicron assembly processes. The transport of α-tocopherol across the intestines may be prolonged during fasting and

*Tocol structures. The chromanol head group is identical in the alpha-forms of synthetic (A) all-racemic α-tocopherol [2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl) chroman-6-ol], (B) natural (RRR) α-tocopherols [(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl) chroman-6-ol], (C) α-tocotrienol [2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl) chroman-6-ol], and (D) the metabolite of all three isoforms, α-carboxyethyl hydroxychromanol (CEHC) [3-(6-hydroxy-2,5,7,8 tetramethylchroman-2-yl) propanoic acid]. CEHC results from the ω-hydroxylation, followed by β-oxidation* 

*of the side chain (as well as conjugation with glucuronide, sulfate, or other compounds), yielding a* 

*water-soluble molecule that is largely excreted in urine [34].*

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

α-tocotrienol transport in the body [35].

#### *Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease DOI: http://dx.doi.org/10.5772/intechopen.91028*

conditions of α-tocopherol deficiency. These findings suggest TTP-independent mechanisms for the tissue delivery of oral α-tocotrienol. While αTTP may contribute to tocotrienol trafficking, αTTP does not represent a major or sole mechanism of α-tocotrienol transport in the body [35].

Vitamin E is metabolized by ω-hydroxylation by cytochrome P450 (CYP), followed by β-oxidation and conjugation to generate carboxychromanols and conjugated counterparts [2, 29]. The tail of vitamin E isoforms is ω-hydroxylated by CYP 4F2 and subjected to several rounds of β-oxidation, which ultimately results in the formation of carboxyethyl hydroxy chromanol (CEHC) (**Figure 2**). Thus, the tail-shortened, water-soluble metabolite, CEHC, is synthesized and excreted in the urine [36]. Conjugation such as sulfation and glucuronidation of the phenolic on the chromanol may also take place in parallel with β-oxidation when there is a high intake of vitamin E forms [4]. Although α-tocopherol largely escapes catabolism and ends up in the blood circulation, α-CEHC is synthesized endogenously when the quantity of hepatic α-tocopherol exceeds the capacity of αTTP to facilitate α-tocopherol secretion from the liver into the circulation [31].

Traber and colleagues established that urinary α-CEHC might be useful to noninvasively assess α-tocopherol adequacy, especially in populations with metabolic syndrome-associated hepatic dysfunction that likely impairs α-tocopherol trafficking. Their finding also suggests that people with metabolic syndrome may have a higher requirement for vitamin E due to poorer trafficking leading to lower apparent α-tocopherol bioavailability. However, it is still unknown whether urinary α-CEHC excretion reflects α-tocopherol intake from a single meal or whether its changes reflect long-term vitamin E status [31].

Recently, Traber and colleagues, which lead as one of the most prolific research groups in vitamin E tocopherol, suggested novel approaches to assess α-tocopherol absorption and trafficking in order to establish human vitamin E requirements [32]. Their study observed that the absorption of α-tocopherol is not necessarily limited by the absence of fat or fasting and that the absorption is highly dependent on chylomicron assembly processes. The transport of α-tocopherol across the intestines may be prolonged during fasting and

#### **Figure 2.**

*Neuroprotection - New Approaches and Prospects*

taken with food which contributes fat, thereby triggering the secretion of enzymes that facilitate the formation of micelles required for absorption. Despite many years since its discovery, there is still a lack of understanding of the mechanism of

*Chemical structures of (A) tocopherol and (B) tocotrienol. Note the three double bonds in the tocotrienol side chain. Note: Isoforms—α (R′ = CH3, R″ = CH3); β (R′ = CH3, R″ = H); γ (R′ = H, R″ = CH3); δ (R′ = H,* 

The general understanding of vitamin E absorption and trafficking is that orally administered vitamin E undergoes intestinal luminal processing, where it accumulates in lipid droplets, which then coalesce with nascent chylomicrons [32]. The vitamin E isoforms are not discriminated during the intestinal absorption or incorporation into chylomicrons. Chylomicrons then transport vitamin E from the intestine through circulation to the liver, which metabolizes or resecretes vitamin E

After the liver takes up chylomicron remnants, vitamin E isoforms with greater

affinity to α-tocopherol transport protein (αTTP) are preferentially bound for transport to tissues, thereby avoiding catabolism. αTTP expressed in the liver is required to facilitate vitamin E transport from the liver to other tissues and organs. The discrimination of vitamin E isoforms occurs in the liver as a result of differing affinity of isoforms to αTTP. αTTP has the ability to bind to both α-tocotrienol and α-tocopherol, but αTTP binds to α-tocotrienol with approximately 10 fold lower affinity than that for α-tocopherol [33]. All lipoproteins are involved in the trafficking of α-tocopherol to the tissues, although very low-density lipoprotein apparently leaves the liver preferentially enriched in α-tocopherol compared with LDL or high-density lipoprotein (HDL) [29]. Discrimination between dietary forms of vitamin E is dependent upon the hepatic αTTP to maintain circulating α-tocopherol [34]. α-tocopherol is also most retained in tissues due to preferential binding by αTT, facilitating secretion into plasma [2] and trafficking to tissues, whereas large portions of other forms of vitamin E are catabolized through general xenobiotic

Interestingly, a study using αTTP knockout mice showed that orally administered α-tocotrienol was absorbed and delivered to vital organs, despite being deficient of αTTP [35]. In organs such as adipose tissue, skin, skeletal muscle, and the heart, α-tocotrienol levels were many folds higher than α-tocopherol in supplemented αTTP knockout mice. Oral supplementation of the female mice with α-tocotrienol also restored fertility, suggesting that it can be successfully delivered to the relevant tissues and that α-tocotrienol supported reproductive function under

absorption, liver trafficking, and disposition of vitamin E isoforms [31].

back into the plasma for trafficking to tissues via enriched lipoproteins.

**188**

processes [4].

**Figure 1.**

*R″ = H).*

*Tocol structures. The chromanol head group is identical in the alpha-forms of synthetic (A) all-racemic α-tocopherol [2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl) chroman-6-ol], (B) natural (RRR) α-tocopherols [(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl) chroman-6-ol], (C) α-tocotrienol [2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl) chroman-6-ol], and (D) the metabolite of all three isoforms, α-carboxyethyl hydroxychromanol (CEHC) [3-(6-hydroxy-2,5,7,8 tetramethylchroman-2-yl) propanoic acid]. CEHC results from the ω-hydroxylation, followed by β-oxidation of the side chain (as well as conjugation with glucuronide, sulfate, or other compounds), yielding a water-soluble molecule that is largely excreted in urine [34].*

potentiated by eating. However, the authors recognized the conclusion derived from the study has several limitations, including small sample size, lack of randomization or blinding, and compliance issues, leading to an imbalance with attendant potential for baseline and residual confounding. Nevertheless, if proven in a larger trial, this observation changes the conventional thinking that vitamin E needs to be taken with or immediately after meal to enhance absorption and also reflects that there is still much to learn on the absorption and transport of vitamin E in humans.
