Vitamin E has a fundamental role in the normal metabolism of all cells. Therefore, its deficiency can affect several different organ systems. Its function is related to those of several other nutrients that, collectively, comprise a multicomponent system that provides protection against the potentially damaging effects of reactive species of oxygen formed during metabolism or that are encountered in the environment. This can be affected by nutrients, such as selenium and vitamin C, and by exposure to such pro-oxidant factors as polyunsaturated fatty acids (PUFAs), air pollution, and ultraviolet (UV) light. Recent evidence indicates that vitamin E may also have non-antioxidant functions in regulating gene expression and cell signalling. Unlike other vitamins, vitamin E is not only essentially non-toxic, but also appears to be beneficial at dose levels appreciably greater than those required to prevent clinical signs of deficiency. Most notably, high levels of the vitamin have been useful in reducing the oxidation of low-density lipoproteins (LDLs), and thus reducing the risk of atherosclerosis. Although vitamin E is present in most plants, only plant oils are rich sources, and most people consume less than recommended levels (1). Its low regular intake and the complex nature of its biological function, its demonstrated safety, and its apparent usefulness in combating a variety of oxidative stress disorders have generated enormous interest in this vitamin.
The enteric absorption of vitamin E is dependent on the adequate absorption of lipids; the process requires the presence of fat in the lumen of the gut, as well as the secretion of pancreatic enzymes for the formation of mixed micelles. Individuals unable to produce pancreatic juice or bile (e.g., patients with biliary obstruction, cholestatic liver disease, pancreatitis, cystic fibrosis) show impaired absorption of vitamin E, as well as other fat-soluble nutrients that are dependent on micelle-facilitated diffusion for their uptake. The need for lipid would explain reports of vitamin E in dietary supplements not being well absorbed unless taken with a meal (2,3). Enteric absorption in humans can be impaired by dietary fat levels less than ca. 10% (i.e., 21% of total calories).
Unlike vitamins A and D, vitamin E does not have a specific carrier protein in the plasma. Plasma tocopherols are distributed among three lipoprotein classes, with the more abundant LDL and HDL classes comprising the major carriers of vitamin E. Patients with hypercholesterolemia and/or hypertriglyceridemia show reduced plasma uptake of newly absorbed vitamin E. Transport can also be disrupted by impairments in the expression of apolipoprotein B; patients with apobetalipoproteinemia become vitamin E-deficient due to very low rates of uptake regardless of dietary vitamin E status. The co-transport of vitamin E with other polyunsaturated lipids ensures protection of the latter from free-radical attack, and circulating tocopherol levels tend to correlate with those of total lipids and cholesterol.
While all vitamers E are taken up by the liver, only α-tocopherol is released into the circulation. This is due to the function of a specific tocopherol-binding protein, the α-tocopherol transfer protein (α-TTP). Variants in the gene have been associated with differences in circulating α-tocopherol levels, and cases of more serious genetic defects in the α-TTP gene have been described. These patients have exceedingly low circulating tocopherol concentrations unless maintained on high-level vitamin E supplements (e.g., 1 g/day); if untreated, they experience progressive peripheral neuropathy and ataxia.
Studies indicate that tissues have two pools of the vitamin: a labile, rapidly turning over pool; and a fixed, slowly turning over pool. The labile pools predominate in tissues as plasma and liver, as the tocopherol contents of those tissues are depleted rapidly under conditions of vitamin E deprivation. In most non-adipose cells, vitamin E (mostly as α-tocopherol) is localized almost exclusively in membranes. Some 90% of vitamin E in the body is contained in adipose tissue, where it resides predominantly in the bulk lipid phase. This constitutes a fixed pool from which the vitamin is slowly mobilized, thus having long-term physiological significance. After a change in α-tocopherol intake, adipose tissue tocopherols may not reach a new steady state for 2 or more years. That adipose comprises a sink for vitamin E is indicated by the fact that circulating tocopherols are inversely related to body mass index (BMI), and people on weight-loss programs do not lose vitamin E from their adipose tissues. However, circulating tocopherol levels have been found to rise significantly (10–20%) during intensive exercise.
The primary nutritional role of vitamin E is as a biological antioxidant. In this regard, vitamin E has functional importance in the maintenance of membrane integrity in virtually all cells of the body. Its antioxidant function involves the reduction of free radicals, thus protecting against the potentially deleterious reactions of such highly reactive oxidizing species.
Free radicals are produced in cells under normal circumstances. It has been estimated that as much as 5% of inhaled molecular oxygen (O2) is metabolized to yield the so-called reactive oxygen species. There appear to be three sources of ROS: Normal oxidative metabolism, Microsomal cytochrome P-450 activity; Respiratory burst of stimulated phagocytes.
The PUFAs of biological membranes are particularly susceptible to attack by free radicals. This oxidative degradation of membrane phospholipid PUFAs is believed to result in physicochemical changes resulting in membrane dysfunction within the cell. Vitamin E has antioxidant activity capable of terminating chain reactions among PUFAs in the membranes wherein it resides an action, termed free-radical scavenging. In serving its antioxidant function, tocopherols and tocotrienols are converted from their respective alcohol forms to semi-stable radical intermediates, the tocopheroxyl radical. Unlike the free radicals formed from PUFAs, the tocopheroxyl radical is relatively unreactive, thus stopping the destructive propagative cycle of lipid peroxidation. Because α-tocopherol can compete for peroxyl radicals much faster than PUFAs, small amounts of the vitamin are able to effect the antioxidant protection of relatively large amounts of the latter. Tocotrienols are thought to have more potent antioxidant properties than tocopherols, as their unsaturated side chain facilitate more efficient penetration into tissues containing saturated fatty layers – e.g., brain, liver.
Factors that increase the production of ROS can be expected to increase the metabolic demand for antioxidant protection, including the need for vitamin E and the other nutrients involved in this system. However, the antioxidant function of vitamin E is but one of several factors in an antioxidant defence system that protects the cell from the damaging effects of oxidative stress. This system includes: Membrane antioxidant-. The most important membrane antioxidants are the tocopherols, but the ubiquinones and carotenoids also participate in this function; Soluble antioxidants-Soluble antioxidants include NADPH and NADH, ascorbic acid, and reduced glutathione; Antioxidant enzymes-include the superoxide dismutases, the glutathione peroxidases, thioredoxin reductase, and catalase. In this multicomponent system, vitamin E scavenges radicals within the membrane, where it blocks the initiation and interrupts the propagation of lipid peroxidation, thus preventing the generation of other, more highly reactive oxygen species.
Some components of this system are endogenous (e.g., NADPH, NADH, and, for most species, ascorbic acid), whereas other components must be obtained, at least in part, from the external chemical environment. The diversity of this system implies the ability to benefit from various antioxidants and other key factors obtained from dietary sources in variable amounts. The activities of various components of this system have been found to change markedly during cellular differentiation, corresponding to increased oxidant production under those conditions. Thus, it appears that the antioxidant defence system actually serves to control peroxide tone, such that the beneficial effects of pro-oxidizing conditions are realized and their deleterious effects are minimized.
Studies in both animal models and humans have demonstrated anti-inflammatory effects of tocopherols. α-Tocopherols have been found to modulate T cell function, reduce production of the pro-inflammatory mediator prostaglandin PGE2 by macrophages and other pro-inflammatory cytokines by activated macrophages and monocytes, and reduce plasma levels of the inflammation marker C-reactive protein (CRP) (4).
While some anti-inflammatory actions of vitamin E appear to be unrelated to antioxidant function, the vitamin clearly serves as a biological antioxidant protecting immune cells from ROS produced during the inflammatory process by phagocytic cells attracted to the site of tissue injury. On encountering or ingesting a bacterium or other foreign particle, activated neutrophils and macrophages induce a process referred to as the respiratory burst. These reactions are important in killing pathogens, but they can also be deleterious to immune cells themselves. If not controlled, they can contribute to the pathogenesis of disease. Therefore, it appears that adequate antioxidant status is required to maintain appropriate peroxide tone.
High intakes of vitamin E have been found to stimulate many immune functions, including antibody production. Studies with experimental animals have shown these effects to result in increased resistance to infection (5). A randomized controlled trial found a high level of vitamin E (800 IU/day) to increase T cell-mediated responses. These responses typically decline with aging, and another study found older subjects to show improvements in delayed-type hypersensitivity in response to vitamin E more frequently than younger subjects.
However, α-Tocopherol can promote lipid peroxidation in LDLs in the absence of other antioxidants (e.g., ascorbic acid, coenzyme Q10). Under such conditions, tocopherol converts it to the tocopheroxyl radical, which yields a peroxyl radical. Under such circumstances vitamin E serves as an agent to propagate lipid peroxidation in the lipid core, rather than as a chain-breaking antioxidant to block that process. Therefore, the presence of secondary antioxidants is needed to prevent LDL oxidation. Accordingly, one intervention trial found that a very high dose (1,050 mg/day) of α-tocopherol increased susceptibility to peroxidation (6).
Vitamin E deficiency can result from insufficient dietary intake or impaired absorption of the vitamin. Several other dietary factors affect the need for vitamin E. Two are most important in this regard: selenium and PUFAs. Selenium spares the need for vitamin E; accordingly, animals fed low-selenium diets generally require more vitamin E than animals fed the same diets supplemented with an available source of selenium. In contrast, the dietary intake of PUFAs directly affects the need for vitamin E; animals fed high-PUFA diets require more vitamin E than those fed low-PUFA diets. Other factors that can be expected to increase vitamin E needs are deficiencies of sulphur-containing amino acids; deficiencies of copper, zinc, and/or manganese; and deficiency of riboflavin. Alternatively, vitamin E can be replaced by several lipid-soluble synthetic antioxidants and possibly, by vitamin C.
Conditions involving the malabsorption of lipids can also lead to vitamin E deficiency. Such conditions include those resulting in loss of pancreatic exocrine function (e.g., pancreatitis, pancreatic tumour, nutritional pancreatic atrophy in severe selenium deficiency), those involving a lumenal deficiency of bile. Premature infants, who are typically impaired in their ability to utilize dietary fats, are also at risk of vitamin E deficiency.
The clinical manifestations of vitamin E deficiency vary considerably between species. In general, however, the targets are the neuromuscular, vascular, and reproductive systems. The various signs of vitamin E deficiency are believed to be manifestations of membrane dysfunction resulting from the oxidative degradation of polyunsaturated membrane phospholipids and/or the disruption of other critical cellular processes
Vitamin E has been viewed as one of the least toxic of the vitamins. Both animals and humans appear to be able to tolerate rather high levels. For humans, daily doses as high as 400 IU have been considered to be harmless, and large oral doses, as great as 3,200 IU, have not been found to have consistent ill effects. These views were challenged a few years ago by a meta-analysis (of 19 trials) suggesting that vitamin E supplements (400 IU/day) may increase all-cause mortality. A more recent meta-analysis, which included a larger number of published trial results, concluded that supplemental vitamin E does not affect all-cause mortality at doses up to 5,500 IU/day. It is known that at very high doses vitamin E can antagonize the functions of other fat-soluble vitamins.
SOURCES OF VITAMIN E
Vitamin E is synthesized only by photosynthetic organisms – plants, algae, and some cyanobacteria – where it is thought to function as a protective antioxidant in germination and cold adaptation. All higher plants appear to contain α-tocopherol in their leaves and other green parts. The richest food sources are plant oils. Wheatgerm, sunflower, and safflower oils are rich sources of α-(RRR)-tocopherol, whereas corn and soybean oils contain mostly γ-(RRR)- tocopherol. Some plant tissues, notably bran and germ fractions, can also contain tocotrienols. Animal tissues tend to contain low amounts of α-tocopherol, the highest levels occurring in fatty tissues. These levels vary according to the dietary intake of the vitamin. Because vitamin E occurs naturally in fats and oils, reductions in fat intake can be expected also to reduce vitamin E intake Synthetic preparations of vitamin E are mixtures of all eight stereoisomers. Other forms used commercially include tocopheryl succinate and α-tocopheryl polyethylene glycol-succinate.
Vitamin E activity is shown by several analogues of tocopherol and tocotrienol. An international standard facilitating the referencing of these various sources of vitamin E activity, which relates to differences in their absorption, transport, retention, and/or metabolism is now in place. R,R,R-α-tocopherol is now used as the international standard. Some of the vitamers E common in foods (β- and γ-tocopherol, the tocotrienols) have little biological activity. The most biopotent vitamer, i.e., the vitamer of greatest interest in nutrition, is α-tocopherol, which occurs naturally as the RRR stereoisomer [(RRR)-α-tocopherol].
The important sources of vitamin E in human diets and animal feeds are vegetable oils and, to lesser extents, seeds and cereal grains. The dominant dietary form is γ-tocopherol. Wheatgerm oil is the richest natural source of α-tocopherol. The seeds and grains from which these oils are derived also contain appreciable amounts of vitamin E. Plants also synthesize tocotrienols and the richest food sources are rice-bran oil, in which tocotrienols comprise most of the vitamers E, and palm oil. Cereals contain small amounts of tocotrienols. Accordingly, cereals in general and wheatgerm in particular are good sources of the vitamin. Foods that are formulated with vegetable oils (e.g., margarine, baked products) tend to vary greatly in vitamin E content owing to differences in the types of oils used, and to the thermal stabilities of the vitamers E present. α-Tocopherol is used in dietary supplements. Regardless of the form consumed, α-tocopherol is the main form found in tissues.
The processing of foods and feedstuffs can remove substantial amounts of vitamin E. Vitamin E losses can occur as a result of exposure to peroxidizing lipids formed during the development of oxidative rancidity of fats, and to other oxidizing conditions such as drying in the presence of sunlight and air, the addition of organic acids, irradiation, and canning. Milling and refining can reduce vitamin E content by removal of tocopherol-rich bran and germ fractions as well as through the use of bleaching agents to improve the baking characteristics of flour. Some foods (e.g., milk and milk products) also show marked seasonal fluctuations in vitamin E content related to variations in vitamin E intake of the host (e.g., vitamin E intake is greatest when fresh forage is consumed).
VITAMIN E IN HEALTH AND DISEASE
The efficacy of vitamin E as a biological antioxidant appears to be dependent on the amount of the vitamin present at critical cellular loci, and the ability of the organism to maintain its supply and/or recycle it. Therefore, in the presence of other components of the cellular antioxidant defence system, antioxidant protection would be expected to increase with increasing intake of vitamin E. High levels of vitamin E may therefore be appropriate in situations in which oxidative stress is increased.
Because most ROS are produced by mitochondria, which process 99% of the oxygen utilized by the cell, factors such as exercise that increase normal oxidative metabolism also increase the need for vitamin E. Thus, it is thought that exercise-induced injuries to muscle membranes may be due to the enhancement of oxidative reactions. Tissue vitamin E levels do drop as a result of exercise and studies with humans have found that vitamin E supplementation can reduce the oxidative stress and lipid peroxidative damage induced by exhaustive exercise. Metabolically produced ROS also appear to have essential metabolic functions as signalling molecules for the adaptation of skeletal muscle to accommodate the stresses presented by exercise training or periods of disuse. This signalling affects the rate of mitochondrial biogenesis, as well as the induction of genes related to insulin sensitivity. This system of adaptive responses to oxidative stress facilitates the ultimate development of long-term resistance to that stress. That this system, which has been called mitochondrial hormesis, can be impaired by high-level antioxidant treatment was demonstrated by the finding that supplements of vitamins E and C (400 IU α-tocopheryl acetate plus two doses of 500 mg ascorbic acid per day) blocked the upregulation of muscle glucose uptake that is otherwise induced by exercise (7). This finding raises several questions: Is this effect due to vitamin E, vitamin C, or the combination? What antioxidant dose is required for such effects? What level of “peroxide tone” is beneficial?
ROS are also thought to have causative roles in aging, which involves the accumulation of a wide array of oxidative lesions and chronic, low-grade inflammation. This includes oxidative damage to mitochondrial DNA and proteins, and lipid-soluble pigments collectively called lipofuscin in several tissues (e.g., retinal pigment epithelium, heart muscle, brain). That these changes are related causally to aging is suggested by interspecies observations that mammalian life-span potentials tend to correlate inversely with metabolic rate and directly with tissue concentrations of tocopherols and other antioxidants. According to the free-radical theory of aging, it is proposed that cumulative damage by ROS is accompanied by gradual decreases in repair capacity likely due to changes in gene expression, diminished immune function, and enhanced programmed cell death induced by increases in “peroxide tone” (i.e., the net amount of ROS within the cell). Vitamin E supplements have been found to promote immune responsiveness, which is of particular benefit in older people. Doses as low as 50 mg/day have been associated with reduced incidence of the common cold. Trials evaluating effects of vitamin E on acute respiratory infection in older subjects have yielded inconsistent results (8,9).
Individuals living in smog-filled urban areas can be exposed to relatively high levels of ozone (O3) and nitrogen dioxide (NO2), strong oxidants that provoke inflammatory responses of the airway. These include the activation of neutrophils and a respiratory burst resulting in overproduction of ROS leading to peroxidative damage. Vitamin E deprivation has been found to increase the susceptibility of experimental animals to the pathological effects of O3 and NO2. It has been suggested that supplements of the vitamin may protect humans against chronic exposure to smog.
Individuals living at high altitudes can also be exposed to relatively high levels of ozone (O3). One study found that a daily supplement of 400 IU vitamin E prevented decreases in anaerobic thresholds of high-altitude mountain climbers. Collectively, these findings support the hypothesis that exercise at altitude increases the need for vitamin E (10).
Smoking constitutes an oxidative burden on the lungs and other tissues owing to the sustained exposure to free radicals from the tar and gas phases of tobacco smoke. This is characterized by increased levels of peroxidation products in the circulation (e.g., malonyldialdehyde) and breath (e.g., ethane, pentane), with decreased levels of ascorbic acid in plasma and leukocytes, and of vitamin E in plasma and erythrocytes. One intervention trial found supranutritional doses of vitamin E (up to 560 mg of α-tocopherol per day) to reduce the peroxidation potential of erythrocyte lipids from smokers, although a very high level (1,050 mg/day) increased susceptibility to peroxidation for non-smokers (11).
Neural tissues conserve vitamin E, apparently by maintaining a relatively larger portion in the less labile cellular pool (12). In fact, vitamin E appears to be redistributed to neural tissues under conditions of nutritional deficiency. There is no question that vitamin E is essential for neurologic function. Epidemiological studies have found estimated vitamin E intake to be inversely associated with risks of Alzheimer’s disease and Parkinson’s disease, both of which are thought to involve oxidative stress etiologically. Nevertheless, randomized clinical trials of vitamin E supplementation have yielded inconsistent results with respect to both diseases.
In comparison with controls, diabetic erythrocytes have significantly more lipid peroxidation which, by altering membrane fluidity, is thought to render erythrocytes hypercoagulable and more ready to adhere to endothelial cells (13). Membrane lipid peroxidation correlates with erythrocyte contents of glycated haemoglobin (HbA1c), and supplementation of non-insulin-dependent (type 2) diabetics with high levels of vitamin E has been found to reduce haemoglobin damage (14).
Studies have found diabetics to have low plasma tocopherols, and high-level vitamin E supplements (e.g., 900 mg α-tocopherol per day) to improve insulin responsiveness in both normal and diabetic individuals. One randomized clinical trial reported protection by vitamin E against the development of type 2 diabetes among subjects with impaired glucose tolerance (15). Vitamin E has been considered as a factor in protecting against diabetic complications (e.g., retinopathy, cardiac dysfunction), the aetiologies of which are thought to involve oxidative stress. However, clinical trials have not found vitamin E supplementation to be beneficial in this regard.
Cataracts result from the accumulation in the lens of damaged proteins that aggregate and precipitate, resulting in opacification of the lens. Several epidemiological studies have found circulating α-tocopherol level or vitamin E intake to be inversely associated with cataract risk. Vitamin E has been shown in animal models to reduce or delay cataracts induced by galactose or aminotriazol treatment, and to reduce the photoperoxidation of lens lipids. These effects are thought to involve its direct action as an antioxidant or its indirect antioxidant effect in maintaining lens glutathione in the reduced state. Nevertheless, large scale, randomized controlled trials have not found α-tocopherol supplementation at supranutritional levels (50–500 mg/day) to reduce risk of cataracts.
The lungs are continuously exposed to relatively high concentrations of O2 as well as environmental oxidants and irritants. The first line of defence is the respiratory tract lining fluid, which contains a variety of antioxidants, including vitamin E. Nevertheless, a meta-analysis of observational studies found no relationship of estimated dietary intake of vitamins E, C or β-carotene on risk of asthma.
A key role of vitamin E in pregnancy is suggested by the fact that circulating α-tocopherol levels correlate positively with foetal growth rate, particularly during the last trimester when oxygen utilization is increased. That the resulting oxidative stress may increase risk of pre-eclampsia is indicated by the fact that increases in lipid peroxides of placental origin in the maternal circulation correlate with the severity of pre-eclampsia. Nevertheless, a systematic review of clinical intervention trials conducted with vitamin E concluded that there was no evidence that supplemental vitamin E reduced pre-eclampsia risk (16).
The skin is subject to the oxidizing effects resulting from exposure to ultraviolet light, which is known to generate ROS from the photolysis of intracellular water. Studies with animal models have shown that the tocopherol content of dermal tissues decreases with UV irradiation, presumably as a result of that oxidative stress. Vitamin E in skin is found in greatest concentrations in the lower levels of the strateum corneum, where it is released by sebum. One study reported that regular topical application of vitamin E reduced wrinkle amplitude and skin roughness in about half of cases. For these reasons, α-tocopherol and α-tocopheryl acetate are widely used in skin creams and cosmetics
Rheumatoid arthritis is thought to be caused by antigenic triggering, in the articular joints, of an inappropriate immune response that leads to chronic inflammation. Indirect evidence suggests that the inflammatory production of ROS leads to the oxidation of lipids in the synovial fluid, which increases the viscosity of that fluid. Studies with animal models have found that vitamin E supplementation can reduce joint swelling, and randomized controlled trials have shown high-level supplementation with the vitamin (100–600 IU/day) to relieve pain and be anti-inflammatory; however, α-tocopherol supplements have not been found effective in reducing rheumatoid arthritis risk (17).
Observational epidemiologic studies have consistently demonstrated benefits of vitamin E on cardiovascular disease risk (18). Seven of the nine major cohort studies conducted to date (and involving nearly a quarter of a million subjects) found inverse associations of vitamin E intake and cardiovascular disease incidence or associated mortality. Two large cohort studies found beneficial effects of vitamin E only for high vitamin E intakes achieved through the use of dietary supplements for at least two years’ duration (19,20). The results of case–control and cohort studies have, however, been mixed. This is not surprising, given the many sources of variation in such studies: inherent errors in estimating vitamin E intake, variability in cardiovascular risk factors, variability in vitamin E utilization and baseline status, oxidative degradation of tocopherols during sample handling and storage, etc.
That vitamin E may protect against cardiovascular disease would appear likely, because it can function as a protective antioxidant in LDLs, as oxidative damage to LDLs appears to be a factor in the etiology of atherosclerosis. Being rich in both cholesterol and PUFAs, LDLs are susceptible to peroxidation by ROS. Research has shown that oxidized LDLs stimulate the recruitment, in the subendothelial space of the vessel wall, of monocyte-macrophages that can take up the oxidized particles via scavenger receptors to form the lipid-containing foam cells found in the early stages of atherogenesis. Studies in vitro have shown that the peroxidation of LDL PUFAs occurs only after the lag phase caused by the loss of LDL antioxidants. Enrichment of LDLs with vitamin E, the predominant antioxidant occurring naturally in those particles, increases the lag phase, thus indicating increased resistance to oxidation. This has been demonstrated for oral supplements of the vitamin.
Protection of LDLs by vitamin E appears to depend on the presence of multiple antioxidants, as high tocopherol concentrations can act as pro-oxidants in the absence of water-soluble antioxidants (e.g., ascorbate, urate). Under such conditions the tocopheroxyl radical formed on the LDL surface moves into the particle’s core, where it can abstract hydrogen from a cholesteryl-PUFA ester to yield a peroxyl radical, thus serving propagating lipid peroxidation in the lipid core.
Evidence indicates that vitamin E can also affect the adherence and aggregation of platelets, reductions of which would prevent the progression of a fatty streak and cell proliferation to advanced lesions. Studies have shown that vitamin E supplementation at levels of about 200 IU/day reduced the adhesion of human platelets to a variety of adhesive proteins. In light of the above view of vitamin E functions, it has been surprising that the majority of randomized clinical trials have not found vitamin E supplementation to reduce cardiovascular risk. Meta-analyses of those trials have detected no beneficial effects. As the intervention agent in most studies has been α-tocopheryl acetate, some have asked whether non-α vitamers, particularly γ-tocopherol and the tocotrienols, may be effective. It is possible that beneficial effects of vitamin E may have been missed because of failure to consider disease subtypes, or sensitive sub-groups. Preventive effects of vitamin E may occur for individuals with polymorphisms with specific genes involved in cellular antioxidant protection. A recent randomized controlled trial found that adults with type 2 diabetes showed reduced cardiovascular disease risk in subjects with the Hp2-2 genotype. It is likely that such genetic polymorphisms also determine responsiveness to vitamin E. Candidates include proteins involved in vitamin E transport/ retention, vitamin E-mediated gene expression, vitamin E metabolism, and antioxidant metabolism. Polymorphisms of each have been found to affect circulating α-tocopherol levels.
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Keywords-vitamin E, antioxidants, exercise, aging, air pollution, altitude, smoking, alzheimers disease, diabetes, cataracts, lungs, pre-eclampsia, skin, cardiovascular disease (heart, atherosclerosis).