VITAMIN E

Synonyms:
VITAMIN E; alpha-Tocopherol; D-alpha-Tocopherol; 59-02-9; 5,7,8; Trimethyltocol; (+)-alpha-Tocopherol; alpha-Vitamin E; Aquasol E; (R,R,R)-alpha-Tocopherol; TOCOPHEROL; Eprolin; a-Tocopherol; (2R,4'R,8'R)-alpha-Tocopherol; dl-a-Tocopherol; Tocopherol alpha; 2074-53-5; Phytogermine
(2R)-2,5,7,8-TETRAMETHYL-2-[(4R,8R)-4,8,12-TRIMETHYLTRIDECYL]CHROMAN-6-OL; alpha Tocopherol; Vitamin Ea; Mixed tocopherols; D-alpha tocopherol; Syntopherol; Denamone; Viteolin; Esorb; Tocopherol (R,S); UNII-N9PR3490H9; CHEBI:18145; 2,5,7,8-Tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanol; Evitaminum; Profecundin; Waynecomycin; Almefrol; Emipherol; Ephanyl; Epsilan; Etamican; Tokopharm; Vascuals; Viprimol; Vitayonon; Etavit; Ilitia; E Prolin; Spavit E; ido-E; Endo E; N9PR3490H9; Vita E; EINECS 215-798-8; Lan-E; Med-E; Antisterility vitamin; alpha-Tocopherol acid; Tenox GT 1 2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-, (2R)-; Rhenogran; Ronotec 50; Vi-E; Covitol F 1000; E307; E 307 (tocopherol);VITAMIN E; E Vitamini; Vitamin e; vitamin; E; VİTAMİNE E
 

VITAMIN E

Alpha-Tocopherol is the orally bioavailable alpha form of the naturally-occurring fat-soluble vitamin E, with potent antioxidant and cytoprotective activities. Upon administration, alpha-tocopherol neutralizes free radicals, thereby protecting tissues and organs from oxidative damage. Alpha-tocopherol gets incorporated into biological membranes, prevents protein oxidation and inhibits lipid peroxidation, thereby maintaining cell membrane integrity and protecting the cell against damage. In addition, alpha-tocopherol inhibits the activity of protein kinase C (PKC) and PKC-mediated pathways. Alpha-tocopherol also modulates the expression of various genes, plays a key role in neurological function, inhibits platelet aggregation and enhances vasodilation. Compared with other forms of tocopherol, alpha-tocopherol is the most biologically active form and is the form that is preferentially absorbed and retained in the body.

NCI Thesaurus (NCIt)
d-Alpha-Tocopherol is a naturally-occurring form of vitamin E, a fat-soluble vitamin with potent antioxidant properties. Considered essential for the stabilization of biological membranes (especially those with high amounts of polyunsaturated fatty acids), d-alpha-Tocopherol is a potent peroxyl radical scavenger and inhibits noncompetitively cyclooxygenase activity in many tissues, resulting in a decrease in prostaglandin production. Vitamin E also inhibits angiogenesis and tumor dormancy through suppressing vascular endothelial growth factor (VEGF) gene transcription. (NCI04)

NCI Thesaurus (NCIt)
Vitamin E (alpha tocopherol) is a fat soluble vitamin and potent antioxidant that is believed to be important in protecting cells from oxidative stress, regulating immune function, maintaining endothelial cell integrity and balancing normal coagulation. There is no evidence that vitamin E, in physiologic or even super-physiologic, high doses, causes liver injury or jaundice.

Introduction
Vitamin E is found naturally in some foods, added to others, and available as a dietary supplement. “Vitamin E” is the collective name for a group of fat-soluble compounds with distinctive antioxidant activities [1].

Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity [1]. Alpha- (or α-) tocopherol is the only form that is recognized to meet human requirements.

Serum concentrations of vitamin E (alpha-tocopherol) depend on the liver, which takes up the nutrient after the various forms are absorbed from the small intestine. The liver preferentially resecretes only alpha-tocopherol via the hepatic alpha-tocopherol transfer protein [1]; the liver metabolizes and excretes the other vitamin E forms [2]. As a result, blood and cellular concentrations of other forms of vitamin E are lower than those of alpha-tocopherol and have been the subjects of less research [3,4].

Antioxidants protect cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer [5]. Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species (ROS). The body forms ROS endogenously when it converts food to energy, and antioxidants might protect cells from the damaging effects of ROS. The body is also exposed to free radicals from environmental exposures, such as cigarette smoke, air pollution, and ultraviolet radiation from the sun. ROS are part of signaling mechanisms among cells.

Vitamin E is a fat-soluble antioxidant that stops the production of ROS formed when fat undergoes oxidation. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

In addition to its activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and other metabolic processes [1]. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes [6]. Vitamin-E–replete endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation [6].

Recommended Intakes
Intake recommendations for vitamin E and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences) [6]. DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:

Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.
The FNB’s vitamin E recommendations are for alpha-tocopherol alone, the only form maintained in plasma. The FNB based these recommendations primarily on serum levels of the nutrient that provide adequate protection in a test measuring the survival of erythrocytes when exposed to hydrogen peroxide, a free radical [6]. Acknowledging “great uncertainties” in these data, the FNB has called for research to identify other biomarkers for assessing vitamin E requirements.

Naturally sourced vitamin E is called RRR-alpha-tocopherol (commonly labeled as d-alpha-tocopherol); the synthetically produced form is all rac-alpha-tocopherol (commonly labeled as dl-alpha-tocopherol).

RDAs for vitamin E are provided in milligrams (mg) and are listed in Table 1. One mg vitamin E (alpha-tocopherol) is equivalent to 1 mg RRR-alpha-tocopherol or 2 mg all rac-alpha-tocopherol. Because insufficient data are available to develop RDAs for infants, AIs were developed based on the amount of vitamin E consumed by healthy breastfed babies.

Table 1: Recommended Dietary Allowances (RDAs) for Vitamin E (Alpha-Tocopherol) [6]
Age    Males    Females    Pregnancy    Lactation
0–6 months*    4 mg    4 mg        
7–12 months*    5 mg    5 mg        
1–3 years    6 mg    6 mg        
4–8 years    7 mg    7 mg        
9–13 years    11 mg    11 mg        
14+ years    15 mg    15 mg    15 mg    19 mg
*Adequate Intake (AI)

International Units and Milligrams

Vitamin E is listed on the new Nutrition Facts and Supplement Facts labels in mg [7]. The U.S. Food and Drug Administration (FDA) required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list vitamin E in international units (IUs) until January 2021 [8]. Conversion rules are as follows:

To convert from mg to IU:
1 mg of alpha-tocopherol is equivalent to 1.49 IU of the natural form or 2.22 IU of the synthetic form.
To convert from IU to mg:
1 IU of the natural form is equivalent to 0.67 mg of alpha-tocopherol.
1 IU of the synthetic form is equivalent to 0.45 mg of alpha-tocopherol.
For example, 15 mg of natural alpha-tocopherol would equal 22.4 IU (15 mg x 1.49 IU/mg = 22.4 IU). The corresponding value for synthetic alpha-tocopherol would be 33.3 IU (15 mg x 2.22 IU/mg).

Sources of Vitamin E
Food
Numerous foods provide vitamin E. Nuts, seeds, and vegetable oils are among the best sources of alpha-tocopherol, and significant amounts are available in green leafy vegetables and fortified cereals (see Table 2 for a more detailed list) [9]. Most vitamin E in American diets is in the form of gamma-tocopherol from soybean, canola, corn, and other vegetable oils and food products [4].

Table 2: Selected Food Sources of Vitamin E (Alpha-Tocopherol) [9]
Food    Milligrams (mg)
per serving    Percent DV*
Wheat germ oil, 1 tablespoon    20.3    135
Sunflower seeds, dry roasted, 1 ounce    7.4    49
Almonds, dry roasted, 1 ounce    6.8    45
Sunflower oil, 1 tablespoon    5.6    37
Safflower oil, 1 tablespoon    4.6    31
Hazelnuts, dry roasted, 1 ounce    4.3    29
Peanut butter, 2 tablespoons    2.9    19
Peanuts, dry roasted, 1 ounce    2.2    15
Corn oil, 1 tablespoon    1.9    13
Spinach, boiled, ½ cup    1.9    13
Broccoli, chopped, boiled, ½ cup    1.2    8
Soybean oil, 1 tablespoon    1.1    7
Kiwifruit, 1 medium    1.1    7
Mango, sliced, ½ cup    0.7    5
Tomato, raw, 1 medium    0.7    5
Spinach, raw, 1 cup    0.6    4
*DV = Daily Value. FDA developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin E on the new Nutrition Facts and Supplement Facts labels and used for the values in Table 2 is 15 mg for adults and children age 4 years and older [7]. 1 mg vitamin E = 1 mg RRR-alpha-tocopherol = 2 mg all rac-alpha-tocopherol. FDA required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list a vitamin E DV of 30 IU (approximately 20 mg of natural alpha-tocopherol) until January 2021 [8,10]. FDA does not require food labels to list vitamin E content unless vitamin E has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s (USDA’s) FoodData Centralexternal link disclaimer website lists the nutrient content of many foods, including, in some cases, the amounts of alpha-, beta-, gamma-, and delta-tocopherol. The USDA also provides a comprehensive list of foods containing vitamin E arranged by nutrient content and by food name.

Dietary supplements
Supplements of vitamin E typically provide only alpha-tocopherol, although “mixed” products containing other tocopherols and even tocotrienols are available. Naturally occurring alpha-tocopherol exists in one stereoisomeric form. In contrast, synthetically produced alpha-tocopherol contains equal amounts of its eight possible stereoisomers; serum and tissues maintain only four of these stereoisomers [6]. A given amount of synthetic alpha-tocopherol (all rac-alpha-tocopherol; commonly labeled as “DL” or “dl”) is therefore only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol; commonly labeled as “D” or “d”).

Most vitamin-E-only supplements provide ≥67 mg (100 IU of natural vitamin E) of the nutrient. These amounts are substantially higher than the RDAs.

Alpha-tocopherol in dietary supplements and fortified foods is often esterified to prolong its shelf life while protecting its antioxidant properties. The body hydrolyzes and absorbs these esters (alpha-tocopheryl acetate and succinate) as efficiently as alpha-tocopherol [6].

Vitamin E Intakes and Status
Three national surveys—the 2001–2002 National Health and Nutrition Examination Survey (NHANES) [12], NHANES III (1988–1994) [12], and the Continuing Survey of Food Intakes by Individuals (1994–1996) [13]—have found that the diets of most Americans provide less than the RDA levels of vitamin E. These intake estimates might be low, however, because the amounts and types of fat added during cooking are often unknown and not accounted for [6].

The FNB suggests that mean intakes of vitamin E among healthy adults are probably higher than the RDA but cautions that low-fat diets might provide insufficient amounts unless people make their food choices carefully by, for example, increasing their intakes of nuts, seeds, fruits, and vegetables [6,12]. The 1999–2000 NHANES found that 11.3% of adults took vitamin E supplements containing at least 400 IU [11].

Vitamin E Deficiency
Frank vitamin E deficiency is rare and overt deficiency symptoms have not been found in healthy people who obtain little vitamin E from their diets [6]. Premature babies of very low birth weight (<1,500 grams) might be deficient in vitamin E. Vitamin E supplementation in these infants might reduce the risk of some complications, such as those affecting the retina, but they can also increase the risk of infections [14].

Because the digestive tract requires fat to absorb vitamin E, people with fat-malabsorption disorders are more likely to become deficient than people without such disorders. Deficiency symptoms include peripheral neuropathy, ataxia, skeletal myopathy, retinopathy, and impairment of the immune response [6,15]. People with Crohn’s disease, cystic fibrosis, or an inability to secrete bile from the liver into the digestive tract, for example, often pass greasy stools or have chronic diarrhea; as a result, they sometimes require water-soluble forms of vitamin E, such as tocopheryl polyethylene glycol-1000 succinate [1].

Some people with abetalipoproteinemia, a rare inherited disorder resulting in poor absorption of dietary fat, require enormous doses of supplemental vitamin E (approximately 100 mg/kg or 5–10 g/day) [1]. Vitamin E deficiency secondary to abetalipoproteinemia causes such problems as poor transmission of nerve impulses, muscle weakness, and retinal degeneration that leads to blindness [16]. Ataxia and vitamin E deficiency (AVED) is another rare, inherited disorder in which the liver’s alpha-tocopherol transfer protein is defective or absent. People with AVED have such severe vitamin E deficiency that they develop nerve damage and lose the ability to walk unless they take large doses of supplemental vitamin E [17].

Vitamin E and Health
Many claims have been made about vitamin E’s potential to promote health and prevent and treat disease. The mechanisms by which vitamin E might provide this protection include its function as an antioxidant and its roles in anti-inflammatory processes, inhibition of platelet aggregation, and immune enhancement.

A primary barrier to characterizing the roles of vitamin E in health is the lack of validated biomarkers for vitamin E intake and status to help relate intakes to valid predictors of clinical outcomes [6]. This section focuses on four diseases and disorders in which vitamin E might be involved: heart disease, cancer, eye disorders, and cognitive decline.

Coronary heart disease
Evidence that vitamin E could help prevent or delay coronary heart disease (CHD) comes from several sources. In vitro studies have found that the nutrient inhibits oxidation of low-density lipoprotein (LDL) cholesterol, thought to be a crucial initiating step for atherosclerosis [6]. Vitamin E might also help prevent the formation of blood clots that could lead to a heart attack or venous thromboembolism [18].

Several observational studies have associated lower rates of heart disease with higher vitamin E intakes. One study of approximately 90,000 nurses found that the incidence of heart disease was 30% to 40% lower in those with the highest intakes of vitamin E, primarily from supplements [19]. Among a group of 5,133 Finnish men and women followed for a mean of 14 years, higher vitamin E intakes from food were associated with decreased mortality from CHD [20].

However, randomized clinical trials cast doubt on the efficacy of vitamin E supplements to prevent CHD [21]. For example, the Heart Outcomes Prevention Evaluation (HOPE) study, which followed almost 10,000 patients at high risk of heart attack or stroke for 4.5 years [22], found that participants taking 400 IU/day of natural vitamin E (268 mg) experienced no fewer cardiovascular events or hospitalizations for heart failure or chest pain than participants taking a placebo. In the HOPE-TOO followup study, almost 4,000 of the original participants continued to take vitamin E or placebo for an additional 2.5 years [23]. HOPE-TOO found that vitamin E provided no significant protection against heart attacks, strokes, unstable angina, or deaths from cardiovascular disease or other causes after 7 years of treatment. Participants taking vitamin E, however, were 13% more likely to experience, and 21% more likely to be hospitalized for, heart failure, a statistically significant but unexpected finding not reported in other large studies.

The HOPE and HOPE-TOO trials provide compelling evidence that moderately high doses of vitamin E supplements do not reduce the risk of serious cardiovascular events among men and women >50 years of age with established heart disease or diabetes [24]. These findings are supported by evidence from the Women’s Angiographic Vitamin and Estrogen study, in which 423 postmenopausal women with some degree of coronary stenosis took supplements with 400 IU vitamin E (form not specified) and 500 mg vitamin C twice a day or placebo for >4 years [25]. Not only did the supplements provide no cardiovascular benefits, but all-cause mortality was significantly higher in the women taking the supplements.

The latest published clinical trial of vitamin E’s effects on the heart and blood vessels of women included almost 40,000 healthy women ≥45 years of age who were randomly assigned to receive either 600 IU of natural vitamin E (402 mg) on alternate days or placebo and who were followed for an average of 10 years [26]. The investigators found no significant differences in rates of overall cardiovascular events (combined nonfatal heart attacks, strokes, and cardiovascular deaths) or all-cause mortality between the groups. However, the study did find two positive and significant results for women taking vitamin E: they had a 24% reduction in cardiovascular death rates, and those ≥65 years of age had a 26% decrease in nonfatal heart attack and a 49% decrease in cardiovascular death rates.

The most recent published clinical trial of vitamin E and men’s cardiovascular health included almost 15,000 healthy physicians ≥50 years of age who were randomly assigned to receive 400 IU synthetic alpha-tocopherol (180 mg) every other day, 500 mg vitamin C daily, both vitamins, or placebo [27]. During a mean follow-up period of 8 years, intake of vitamin E (and/or vitamin C) had no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, or cardiovascular morality. Furthermore, use of vitamin E was associated with a significantly increased risk of hemorrhagic stroke.

In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. However, participants in these studies have been largely middle-aged or elderly individuals with demonstrated heart disease or risk factors for heart disease. Some researchers have suggested that understanding the potential utility of vitamin E in preventing CHD might require longer studies in younger participants taking higher doses of the supplement [28]. Further research is needed to determine whether supplemental vitamin E has any protective value for younger, healthier people at no obvious risk of CHD.

Cancer
Antioxidant nutrients like vitamin E protect cell constituents from the damaging effects of free radicals that, if unchecked, might contribute to cancer development [9]. Vitamin E might also block the formation of carcinogenic nitrosamines formed in the stomach from nitrites in foods and protect against cancer by enhancing immune function [29]. Unfortunately, human trials and surveys that have attempted to associate vitamin E intake with cancer incidence have found that vitamin E is not beneficial in most cases.

Both the HOPE-TOO Trial and Women’s Health Study evaluated whether vitamin E supplements might protect people from cancer. HOPE-TOO, which followed men and women ≥55 years of age with heart disease or diabetes for 7 years, found no significant differences in the number of new cancers or cancer deaths between individuals randomly assigned to take 400 IU/day of natural vitamin E (268 mg) or a placebo [23]. In the Women’s Health Study, in which healthy women ≥45 years of age received either 600 IU of natural vitamin E (402 mg) every other day or a placebo for 10 years, the supplement did not reduce the risk of developing any form of cancer [26].

Several studies have examined whether vitamin E intake and/or supplemental vitamin E affects the risk of developing prostate cancer. A prospective cohort study of >29,000 men found no association between dietary or supplemental vitamin E intake and prostate cancer risk [30]. However, among current smokers and men who had quit, vitamin E intakes of more than 400 IU/day (form not specified) were associated with a statistically significant 71% reduction in the risk of advanced prostate cancer. In a clinical trial involving 29,133 male smokers, men randomly assigned to take daily supplements of 111 IU of synthetic vitamin E (50 mg, as dl-alpha-tocopheryl acetate) for 5–8 years had 32% fewer prostate cancers compared to subjects who did not take the supplements [31]. Based in part on the promising results of this study, a large randomized clinical trial, called the SELECT trial, began in 2001 to determine whether 7–12 years of daily supplementation with 400 IU of synthetic vitamin E (180 mg, as dl-alpha-tocopheryl acetate), with or without selenium (200 mcg, as L-selenomethionine), reduced the number of new prostate cancers in 35,533 healthy men age 50 and older. The trial was discontinued in October 2008 when an analysis found that the supplements, taken alone or together for about 5.5 years, did not prevent prostate cancer [32]. Results from an additional 1.5 years of follow-up from this trial (during which the subjects no longer received vitamin E or selenium), showed that the men who had taken the vitamin E had a 17 percent increased risk of prostate cancer compared to men only taking placebos, a statistically significant difference [33]. The risk of developing prostate cancer was also slightly increased in subjects taking vitamin E plus selenium or selenium alone, but the differences were not statistically significant. No differences were found among groups in the incidence of lung or colorectal cancers or all cancers combined. Study staff members will continue to monitor participants’ health for up to 5 more years. The National Cancer Institute website provides additional information on the SELECT trialexternal link disclaimer.

One study of women in Iowa provides evidence that higher intakes of vitamin E from foods and supplements could decrease the risk of colon cancer, especially in women <65 years of age [34]. The overall relative risk for the highest quintile of intake (>35.7 IU/day, form not specified) compared to the lowest quintile (<5.7 IU/day, form not specified) was 0.32. However, prospective cohort studies of 87,998 women in the Nurses’ Health Study and 47,344 men in the Health Professionals Follow-up Study failed to replicate these results [35]. Although some research links higher intakes of vitamin E with decreased incidence of breast cancer, an examination of the impact of dietary factors, including vitamin E, on the incidence of postmenopausal breast cancer in >18,000 women found no benefit from the vitamin [36].

The American Cancer Society conducted an epidemiologic study examining the association between use of vitamin C and vitamin E supplements and bladder cancer mortality. Of the almost one million adults followed between 1982 and 1998, adults who took supplemental vitamin E for 10 years or longer had a reduced risk of death from bladder cancer [37]; vitamin C supplementation provided no protection.

Evidence to date is insufficient to support taking vitamin E to prevent cancer. In fact, daily use of large-dose vitamin E supplements (400 IU of synthetic vitamin E [180 mg]) may increase the risk of prostate cancer.

Eye disorders
Age-related macular degeneration (AMD) and cataracts are among the most common causes of significant vision loss in older people. Their etiologies are usually unknown, but the cumulative effects of oxidative stress have been postulated to play a role. If so, nutrients with antioxidant functions, such as vitamin E, could be used to prevent or treat these conditions.

Prospective cohort studies have found that people with relatively high dietary intakes of vitamin E (e.g., 20 mg/day [30 IU]) have an approximately 20% lower risk of developing AMD than people with low intakes (e.g., <10 mg/day [<15 IU]) [38,39]. However, two randomized controlled trials in which participants took supplements of vitamin E (500 IU/day [335 mg] d-alpha-tocopherol in one study [40] and 111 IU/day (50 mg) dl-alpha-tocopheryl acetate combined with 20 mg/day beta-carotene in the other [41]) or a placebo failed to show a protective effect for vitamin E on AMD. The Age-Related Eye Disease Study (AREDS), a large randomized clinical trial, found that participants at high risk of developing advanced AMD (i.e., those with intermediate AMD or those with advanced AMD in one eye) reduced their risk of developing advanced AMD by 25% by taking a daily supplement containing vitamin E (400 IU [180 mg] dl-alpha-tocopheryl acetate), beta-carotene (15 mg), vitamin C (500 mg), zinc (80 mg), and copper (2 mg) compared to participants taking a placebo over 5 years [42]. A follow-up AREDS2 study confirmed the value of this and similar supplement formulations in reducing the progression of AMD over a median follow-up period of 5 years” [43].

Several observational studies have revealed a potential relationship between vitamin E supplements and the risk of cataract formation. One prospective cohort study found that lens clarity was superior in participants who took vitamin E supplements and those with higher blood levels of the vitamin [44]. In another study, long-term use of vitamin E supplements was associated with slower progression of age-related lens opacification [45]. However, in the AREDS trial, the use of a vitamin E-containing (as dl-alpha-tocopheryl acetate) formulation had no apparent effect on the development or progression of cataracts over an average of 6.3 years [46]. The AREDS2 study, which also tested formulations containing 400 IU (180 mg) vitamin E, confirmed these findings” [47].

Overall, the available evidence is inconsistent with respect to whether vitamin E supplements, taken alone or in combination with other antioxidants, can reduce the risk of developing AMD or cataracts. However, the formulations of vitamin E, other antioxidants, zinc, and copper used in AREDS hold promise for slowing the progression of AMD in people at high risk of developing advanced AMD.

Cognitive decline
The brain has a high oxygen consumption rate and abundant polyunsaturated fatty acids in the neuronal cell membranes. Researchers hypothesize that if cumulative free-radical damage to neurons over time contributes to cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, then ingestion of sufficient or supplemental antioxidants (such as vitamin E) might provide some protection [48]. This hypothesis was supported by the results of a clinical trial in 341 patients with Alzheimer’s disease of moderate severity who were randomly assigned to receive a placebo, vitamin E (2,000 IU/day dl-alpha-tocopherol), a monoamine oxidase inhibitor (selegiline), or vitamin E and selegiline [48]. Over 2 years, treatment with vitamin E and selegiline, separately or together, significantly delayed functional deterioration and the need for institutionalization compared to placebo. However, participants taking vitamin E experienced significantly more falls.

Vitamin E consumption from foods or supplements was associated with less cognitive decline over 3 years in a prospective cohort study of elderly, free-living individuals aged 65–102 years [49]. However, a clinical trial in primarily healthy older women who were randomly assigned to receive 600 IU (402 mg) d-alpha-tocopherol every other day or a placebo for ≤4 years found that the supplements provided no apparent cognitive benefits [50]. Another trial in which 769 men and women with mild cognitive impairment were randomly assigned to receive 2,000 IU/day vitamin E (form not specified), a cholinesterase inhibitor (donepezil), or placebo found no significant differences in the progression rate of Alzheimer’s disease between the vitamin E and placebo groups [51]

In summary, most research results do not support the use of vitamin E supplements by healthy or mildly impaired individuals to maintain cognitive performance or slow its decline with normal aging [52]. More research is needed to identify the role of vitamin E, if any, in the management of cognitive impairment [53].

Health Risks from Excessive Vitamin E
Research has not found any adverse effects from consuming vitamin E in food [6]. However, high doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation. Two clinical trials have found an increased risk of hemorrhagic stroke in participants taking alpha-tocopherol; one trial included Finnish male smokers who consumed 50 mg/day for an average of 6 years [54] and the other trial involved a large group of male physicians in the United States who consumed 400 IU (180 mg) of synthetic vitamin E every other day for 8 years [27]. Because the majority of physicians in the latter study were also taking aspirin, this finding could indicate that vitamin E has a tendency to cause bleeding.

The FNB has established ULs for vitamin E based on the potential for hemorrhagic effects (see Table 3). The ULs apply to all forms of supplemental alpha-tocopherol, including the eight stereoisomers present in synthetic vitamin E. Doses of up to 1,000 mg/day (1,500 IU/day of the natural form or 1,100 IU/day of the synthetic form) in adults appear to be safe, although the data are limited and based on small groups of people taking up to 3,200 mg/day of alpha-tocopherol for only a few weeks or months. Long-term intakes above the UL increase the risk of adverse health effects [6]. Vitamin E ULs for infants have not been established.

Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin E [6]
Age    Male    Female    Pregnancy    Lactation
1–3 years    200 mg    200 mg        
4–8 years    300 mg    300 mg            
9–13 years    600 mg    600 mg        
14–18 years    800 mg    800 mg    800 mg    800 mg
19+ years    1,000 mg    1,000 mg    1,000 mg    1,000 mg
Two meta-analyses of randomized trials have also raised questions about the safety of large doses of vitamin E, including doses lower than the UL. These meta-analyses linked supplementation to small but statistically significant increases in all-cause mortality. One analysis found an increased risk of death at doses of 400 IU/day (form not specified), although the risk began to increase at 150 IU [55]. In the other analysis of studies of antioxidant supplements for disease prevention, the highest quality trials revealed that vitamin E, administered singly (dose range 10 IU–5,000 IU/day; mean 569 IU [form not specified]) or combined with up to four other antioxidants, significantly increased mortality risk [56].

The implications of these analyses for the potential adverse effects of high-dose vitamin E supplements are unclear [57-60]. Participants in the studies included in these analyses were typically middle-aged or older and had chronic diseases or related risk factors. These participants often consumed other supplements in addition to vitamin E. Some of the studies analyzed took place in developing countries in which nutritional deficiencies are common. A review of the subset of studies in which vitamin E supplements were given to healthy individuals for the primary prevention of chronic disease found no convincing evidence that the supplements increased mortality [61].

However, results from the recently published, large SELECT trial show that vitamin E supplements (400 IU/day [180 mg] as dl-alpha-tocopheryl acetate) may harm adult men in the general population by increasing their risk of prostate cancer [33]. Follow-up studies are assessing whether the cancer risk was associated with baseline blood levels of vitamin E and selenium prior to supplementation as well as whether changes in one or more genes might increase a man’s risk of developing prostate cancer while taking vitamin E.

Interactions with Medications
Vitamin E supplements have the potential to interact with several types of medications. A few examples are provided below. People taking these and other medications on a regular basis should discuss their vitamin E intakes with their healthcare providers.

Anticoagulant and antiplatelet medications
Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. As a result, taking large doses with anticoagulant or antiplatelet medications, such as warfarin (Coumadin®), can increase the risk of bleeding, especially in conjunction with low vitamin K intake. The amounts of supplemental vitamin E needed to produce clinically significant effects are unknown but probably exceed 400 IU/day [62].

Simvastatin and niacin
Some people take vitamin E supplements with other antioxidants, such as vitamin C, selenium, and beta-carotene. This collection of antioxidant ingredients blunted the rise in high-density lipoprotein (HDL) cholesterol levels, especially levels of HDL2, the most cardioprotective HDL component, among people treated with a combination of simvastatin (brand name Zocor®) and niacin [63,64].

Chemotherapy and radiotherapy
Oncologists generally advise against the use of antioxidant supplements during cancer chemotherapy or radiotherapy because they might reduce the effectiveness of these therapies by inhibiting cellular oxidative damage in cancerous cells [65,66]. Although a systematic review of randomized controlled trials has called this concern into question [67], further research is needed to evaluate the potential risks and benefits of concurrent antioxidant supplementation with conventional therapies for cancer.

Vitamin E and Healthful Diets
The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”

For more information about building a healthy diet, refer to the Dietary Guidelines for Americansexternal link disclaimer and the U.S. Department of Agriculture’s MyPlateexternal link disclaimer.

The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.
Vitamin E is found in green leafy vegetables, whole grains, fortified cereals, and vegetable oils.
Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.
Nuts are good sources of vitamin E.
Limits saturated and trans fats, added sugars, and sodium.
Stays within your daily calorie needs.

Vitamin E
Foods rich in vitamin E such as wheat germ oil, dried wheat germ, dried apricots, hazelnuts, almonds, parsley leaves, avocado, walnuts, pumpkin seeds, sunflower seeds, spinach and bell pepper
Vitamin E is a fat-soluble vitamin with several forms, but alpha-tocopherol is the only one used by the human body. Its main role is to act as an antioxidant, scavenging loose electrons—so-called “free radicals”—that can damage cells. [1] It also enhances immune function and prevents clots from forming in heart arteries. Antioxidant vitamins, including vitamin E, came to public attention in the 1980s when scientists began to understand that free radical damage was involved in the early stages of artery-clogging atherosclerosis, and might also contribute to cancer, vision loss, and a host of other chronic conditions. Vitamin E has the ability to protect cells from free radical damage as well as stop the production of free radical cells entirely. However, conflicting study results have dimmed some of the promise of using high dose vitamin E to prevent chronic diseases.

Recommended Amounts
The Recommended Dietary Allowance (RDA) for vitamin E for males and females ages 14 years and older is 15 mg daily (or 22 international units, IU), including women who are pregnant. Lactating women need slightly more at 19 mg (28 IU) daily.

Signs of Deficiency
Because vitamin E is found in a variety of foods and supplements, a deficiency in the U.S. is rare. People who have digestive disorders or do not absorb fat properly (e.g., pancreatitis, cystic fibrosis, celiac disease) can develop a vitamin E deficiency. The following are common signs of a deficiency:

Retinopathy (damage to the retina of the eyes that can impair vision)
Peripheral neuropathy (damage to the peripheral nerves, usually in the hands or feet, causing weakness or pain)
Ataxia (loss of control of body movements)
Decreased immune function
Toxicity
There is no evidence of toxic effects from vitamin E found naturally in foods. Most adults who obtain more than the RDA of 22 IU daily are using multivitamins or separate vitamin E supplements that contain anywhere from 400-1000 IU daily. There have not been reports of harmful side effects of supplement use in healthy people. However, there is a risk of excess bleeding, particularly with doses greater than 1000 mg daily or if an individual is also using a blood thinning medication such as warfarin. For this reason, an upper limit for vitamin E has been set for adults 19 years and older of 1000 mg daily (1465 IU) of any form of tocopherol supplement. [1]

Did You Know?
Due to occasional reports of negative health effects of vitamin E supplements, scientists have debated whether these supplements could be harmful and even increase the risk of death.

Researchers have tried to answer this question by combining the results of multiple studies. In one such analysis, the authors gathered and re-analyzed data from 19 clinical trials of vitamin E, including the GISSI and HOPE studies [48]; they found a higher rate of death in trials where patients took more than 400 IU of supplements a day. While this meta-analysis drew headlines when it was released, there are limitations to the conclusions that can be drawn from it. Some of the findings were based on very small studies. In some of these trials, vitamin E was combined with high doses of beta-carotene, which itself has been related to excess mortality.  Furthermore, many of the high-dose vitamin E trials included in the analysis included people who had advanced heart disease or Alzheimer’s disease. Other meta-analyses have come to different conclusions. So it is not clear that these findings would apply to healthy people. The Physicians’ Health Study II, for example, did not find any difference in death rates between the study participants who took vitamin E and those who took a placebo. [12]

Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols.[1][2] Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitamin E,[3] can cause nerve problems.[4] Vitamin E is a fat-soluble antioxidant protecting cell membranes from reactive oxygen species.[2][4]

Worldwide, government organizations recommend adults consume in the range of 7 to 15 mg per day. As of 2016, consumption was below recommendations according to a worldwide summary of more than one hundred studies that reported a median dietary intake of 6.2 mg per day for alpha-tocopherol.[5] Research with alpha-tocopherol as a dietary supplement, with daily amounts as high as 2000 mg per day, has had mixed results.[6] Population studies suggested that people who consumed foods with more vitamin E, or who chose on their own to consume a vitamin E dietary supplement, had lower incidence of cardiovascular diseases, cancer, dementia, and other diseases, but placebo-controlled clinical trials could not always replicate these findings.[2] As of 2017, vitamin E continues to be a topic of active clinical research.[7] There is no clinical evidence that use of vitamin E skincare products are effective.[8] Both natural and synthetic tocopherols are subject to oxidation, and so in dietary supplements are esterified, creating tocopheryl acetate for stability purposes.[2][9]

Both the tocopherols and tocotrienols occur in α (alpha), β (beta), γ (gamma) and δ (delta) forms, as determined by the number and position of methyl groups on the chromanol ring.[4][10] All eight of these vitamers feature a chromane double ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals, and a hydrophobic side chain which allows for penetration into biological membranes. Of the many different forms of vitamin E, gamma-tocopherol (γ-tocopherol) is the most common form found in the North American diet, but alpha-tocopherol (α-tocopherol) is the most biologically active.[2][11] Palm oil is a source of tocotrienols.

Vitamin E was discovered in 1922, isolated in 1935 and first synthesized in 1938. Because the vitamin activity was first identified as essential for fertilized eggs to result in live births (in rats), it was given the name "tocopherol" from Greek words meaning birth and to bear or carry.[12][13][14] Alpha-tocopherol, either naturally extracted from plant oils or, most commonly, as the synthetic tocopheryl acetate, is sold as a popular dietary supplement, either by itself or incorporated into a multivitamin product, and in oils or lotions for use on skin.

Functions

Tocopherols function by donating H atoms to radicals (X).
Vitamin E may have various roles as a vitamin.[4] Many biological functions have been postulated, including a role as a fat-soluble antioxidant.[4] In this role, vitamin E acts as a radical scavenger, delivering a hydrogen (H) atom to free radicals. At 323 kJ/mol, the O-H bond in tocopherols is about 10% weaker than in most other phenols.[15] This weak bond allows the vitamin to donate a hydrogen atom to the peroxyl radical and other free radicals, minimizing their damaging effect. The thus-generated tocopheryl radical is recycled to tocopherol by a redox reaction with a hydrogen donor, such as vitamin C.[16] As it is fat-soluble, vitamin E is incorporated into cell membranes, which are therefore protected from oxidative damage.

Vitamin E affects gene expression[17] and is an enzyme activity regulator, such as for protein kinase C (PKC) – which plays a role in smooth muscle growth – with vitamin E participating in deactivation of PKC to inhibit smooth muscle growth.[18]

Deficiency
Main article: Vitamin E deficiency
Vitamin E deficiency is rare in humans, occurring as a consequence of abnormalities in dietary fat absorption or metabolism rather than from a diet low in vitamin E.[3] One example of a genetic abnormality in metabolism is mutations of genes coding for alpha-tocopherol transfer protein (α-TTP). Humans with this genetic defect exhibit a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED) despite consuming normal amounts of vitamin E. Large amounts of alpha-tocopherol as a dietary supplement are needed to compensate for the lack of α-TTP[19][20] Vitamin E deficiency due to either malabsorption or metabolic anomaly can cause nerve problems due to poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function. In addition to ataxia, vitamin E deficiency can cause peripheral neuropathy, myopathies, retinopathy and impairment of immune responses.[3][4]

Declining supplement use
In the United States vitamin E supplement use by female health professionals was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but decreased to 19.8% in 2006. Similarly, for male health professionals, rates for same years were 18.9%, 52.0%, 49.4% and 24.5%. The authors theorized that declining use in these populations may have been due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements.[21] Within the US military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%.[22] A report on vitamin E sales volume in the US documented a 50% decrease between 2000 and 2006,[23] with a potential reason being a meta-analysis that concluded high-dosage (≥400 IU/d for at least 1 year) vitamin E was associated with an increase in all-cause mortality.[24]

Side effects
The U.S. Food and Nutrition Board set a Tolerable upper intake level (UL) at 1,000 mg (1,500 IU) per day derived from animal models that demonstrated bleeding at high doses.[3] The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day.[25] A meta-analysis of long-term clinical trials reported a non-significant 2% increase in all-cause mortality when alpha-tocopherol was the only supplement used. The same meta-analysis reported a statistically significant 3% increase for results when alpha-tocopherol was used by itself or in combination with other nutrients (vitamin A, vitamin C, beta-carotene, selenium).[6] Another meta-analysis reported a non-significant 1% increase in all-cause mortality when alpha-tocopherol was the only supplement. Subset analysis reported no difference between natural (plant extracted) or synthetic alpha-tocopherol, or whether the amount used was less than or more than 400 IU/day.[26] There are reports of vitamin E-induced allergic contact dermatitis from use of vitamin-E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products. Incidence is low despite widespread use.[27]

Drug interactions
The amounts of alpha-tocopherol, other tocopherols and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of alpha-tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with aspirin, warfarin, tamoxifen and cyclosporine A in ways that alter function. For aspirin and warfarin, high amounts of vitamin E may potentiate anti-blood clotting action.[4][28] One small trial demonstrated that vitamin E at 400 mg/day reduced blood concentration of the anti-breast cancer drug tamoxifen. In multiple clinical trials, vitamin E lowered blood concentration of the immunosuppressant medication, cyclosporine A.[28] The US National Institutes of Health, Office of Dietary Supplements, raises a concern that co-administration of vitamin E could counter the mechanisms of anti-cancer radiation therapy and some types of chemotherapy, and so advises against its use in these patient populations. The references it cited reported instances of reduced treatment adverse effects, but also poorer cancer survival, raising the possibility of tumor protection from the intended oxidative damage by the treatments.[4]

Diet
Dietary recommendations
US vitamin E recommendations (mg per day)[3]
AI (children ages 0–6 months)    4
AI (children ages 7–12 months)    5
RDA (children ages 1–3 years)    6
RDA (children ages 4–8 years)    7
RDA (children ages 9–13 years)    11
RDA (children ages 14–18 years)    15
RDA (adults ages 19+)    15
RDA (pregnancy)    15
RDA (lactation)    19
UL (adults)    1,000
The US National Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin E in 2000. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. Adequate intakes (AIs) are identified when there is not sufficient information to set EARs and RDAs. The EAR for vitamin E for women and men ages 14 and up is 12 mg/day. The RDA is 15 mg/day.[3] As for safety, tolerable upper intake levels ("upper limits" or ULs) are set for vitamins and minerals when evidence is sufficient. Hemorrhagic effects in rats were selected as the critical endpoint to calculate the upper limit via starting with the lowest-observed-adverse-effect-level. The end result was a human upper limit set at 1000 mg/day.[3] Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.[3]

The European Food Safety Authority (EFSA) refers to the collective set of information as dietary reference values, with population reference intakes (PRIs) instead of RDAs, and average requirements instead of EARs. AIs and ULs are defined the same as in US. For women and men ages 10 and older the PRIs are set at 11 and 13 mg/day, respectively. PRI for pregnancy is 11 mg/day, for lactation 11 mg/day. For children ages 1–9 years the PRIs increase with age from 6 to 9 mg/day.[29] The EFSA used an effect on blood clotting as a safety-critical effect. It identified that no adverse effects were observed in a human trial as 540 mg/day, used an uncertainty factor of 2 to get to a suggest an upper limit of half of that, then rounded to 300 mg/day.[25]

The Japan National Institute of Health and Nutrition set adult AIs at 6.5 mg/day (females) and 7.0 mg/day (males), and 650–700 mg/day (females), and 750-900 mg/day (males) for upper limits, amounts depending on age.[30] India recommends an intake of 8–10 mg/day and does not set an upper limit.[31] The World Health Organization recommends that adults consume 10 mg/day.[5]

Consumption is below these government recommendations. Government survey results in the US reported average consumption for adult females at 8.4 mg/d and adult males 10.4 mg/d.[32] Both are below the RDA of 15 mg/day.A worldwide summary of more than one hundred studies reported a median dietary intake of 6.2 mg/d for alpha-tocopherol.[5]

Food labeling
For US food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of daily value. For vitamin E labeling purposes 100% of the daily value was 30 international units, but as of 27 May 2016 it was revised to 15 mg to bring it into agreement with the RDA.[33][34] Companies had several years to comply with the label change.[35][36] A table of the old and new adult daily values is provided at Reference Daily Intake. European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of daily values, amounts are shown as percent of reference intakes (RIs). For vitamin E, 100% RI was set at 12 mg in 2011.[37]

The international unit measurement was used by the United States in 1968–2016. 1 IU is the biological equivalent of about 0.667 mg d (RRR)-alpha-tocopherol (2/3 mg exactly), or of 0.90 mg of dl-alpha-tocopherol, corresponding to the then-measured relative potency of stereoisomers. In May 2016, the measurements have been revised, such that 1 mg of "Vitamin E" is 1 mg of d-alpha-tocopherol or 2 mg of dl-alpha-tocopherol.[38] The change was originally started in 2000, when forms of Vitamin E other than alpha-tocopherol was dropped from dietary calculations by the IOM. The UL amount disregards any conversion.[39] The EFSA has never used an IU unit, and their measurement only considers RRR-alpha-tocopherol.[40]

Sources
The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015. In addition to the naturally occurring sources shown in the table,[41] certain ready-to-eat cereals, infant formulas, liquid nutrition products and other foods are fortified with alpha-tocopherol.[citation needed]

Plant source[41]    Amount
(mg / 100 g)
Wheat germ oil    150
Hazelnut oil    47
Canola/rapeseed oil    44
Sunflower oil    41.1
Almond oil    39.2
Safflower oil    34.1
Grapeseed oil    28.8
Sunflower seed kernels    26.1
Almonds    25.6
Almond butter    24.2
Wheat germ    19
Plant source[41]    Amount
(mg / 100 g)
Canola oil    17.5
Palm oil    15.9
Peanut oil    15.7
Margarine, tub    15.4
Hazelnuts    15.3
Corn oil    14.8
Olive oil    14.3
Soybean oil    12.1
Pine nuts    9.3
Peanut butter    9.0
Peanuts    8.3
Plant source[41]    Amount
(mg / 100 g)
Popcorn    5.0
Pistachio nuts    2.8
Avocados    2.6
Spinach, raw    2.0
Asparagus    1.5
Broccoli    1.4
Cashew nuts    0.9
Bread    0.2-0.3
Rice, brown    0.2
Potato, Pasta    <0.1
Animal source[41]    Amount
(mg / 100 g)
Fish    1.0-2.8
Oysters    1.7
Butter    1.6
Cheese    0.6-0.7
Eggs    1.1
Chicken    0.3
Beef    0.1
Pork    0.1
Milk, whole    0.1
Milk, skim    0.01
Supplements

Softgel capsules used for large amounts of vitamin E
Vitamin E is fat soluble, so dietary supplement products are usually in the form of the vitamin, esterified with acetic acid to generate tocopheryl acetate, and dissolved in vegetable oil in a softgel capsule.[2] For alpha-tocopherol, amounts range from 100 to 1000 IU per serving. Smaller amounts are incorporated into multi-vitamin/mineral tablets. Gamma-tocopherol and tocotrienol supplements are also available from dietary supplement companies. The latter are extracts from palm or annatto oils.

Fortification
The World Health Organization does not have any recommendations for food fortification with vitamin E.[42] The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E.[43] Infant formulas have alpha-tocopherol as an ingredient. In some countries, certain brands of ready-to-eat cereals, liquid nutrition products and other foods have alpha-tocopherol as an added ingredient.[41]

Food additives
Various forms of vitamin E are common food additive in oily food, used to deter rancidity caused by peroxidation. Those with an E number include:[44]

E306 Tocopherol-rich extract (mixed, natural, can include tocotrienol)
E307 Alpha-tocopherol (synthetic)
E308 Gamma-tocopherol (synthetic)
E309 Delta-tocopherol (synthetic)
These E numbers include all racemic forms and acetate esters thereof.[44] Commonly found on food labels in Europe and some other countries, their safety assessment and approval are the responsibility of the European Food Safety Authority.[45]

Chemistry

General chemical structure of tocopherols

RRR alpha-tocopherol; chiral points are where the three dashed lines connect to the side chain
The nutritional content of vitamin E is defined by equivalency to 100% RRR-configuration α-tocopherol activity. The molecules that contribute α-tocopherol activity are four tocopherols and four tocotrienols, within each group of four identified by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-). For alpha(α)-tocopherol each of the three "R" sites has a methyl group (CH3) attached. For beta(β)-tocopherol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocopherol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocopherol: R1 = H, R2 = H, R3 = methyl group. The same configurations exist for the tocotrienols, except that the hydrophobic side chain has three carbon-carbon double bonds whereas the tocopherols have a saturated side chain.[46]

Stereoisomers
In addition to distinguishing tocopherols and tocotrienols by position of methyl groups, the tocopherols have a phytyl tail with three chiral points or centers that can have a right or left orientation. The naturally occurring plant form of alpha-tocopherol is RRR-α-tocopherol, also referred to as d-tocopherol, whereas the synthetic form (all-racemic or all-rac vitamin E, also dl-tocopherol) is equal parts of eight stereoisomers RRR, RRS, RSS, SSS, RSR, SRS, SRR and SSR with progressively decreasing biological equivalency, so that 1.36 mg of dl-tocopherol is considered equivalent to 1.0 mg of d-tocopherol, the natural form. Rephrased, the synthetic has 73.5% of the potency of the natural.[46]

Form    Structure
alpha-Tocopherol    Tocopherol, alpha-.svg
beta-Tocopherol    Beta-tocopherol.png
gamma-Tocopherol    Gamma-tocopherol.png
delta-Tocopherol    Delta-tocopherol.png
Tocopheryl acetate    Tocopheryl acetate.png
Tocopherols

General chemical structure of tocotrienols.
Alpha-tocopherol is a lipid-soluble antioxidant functioning within the glutathione peroxidase pathway,[47] and protecting cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.[2][48] This removes the free radical intermediates and prevents the oxidation reaction from continuing. The oxidized α-tocopheroxyl radicals produced in this process may be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol.[49] Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.[10]

Tocotrienols
The four tocotrienols (alpha, beta, gamma, delta) are similar in structure to the four tocopherols, with the main difference being that the former have hydrophobic side chains with three carbon-carbon double bonds, whereas the tocopherols have saturated side chains. For alpha(α)-tocotrienol each of the three "R" sites has a methyl group (CH3) attached. For beta(β)-tocotrienol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocotrienol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocotrienol: R1 = H, R2 = H, R3 = methyl group. Palm oil is a good source of alpha and gamma tocotrienols.[50]

Tocotrienols have only a single chiral center, which exists at the 2' chromanol ring carbon, at the point where the isoprenoid tail joins the ring. The other two corresponding centers in the phytyl tail of the corresponding tocopherols do not exist as chiral centers for tocotrienols due to unsatu