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Vitamin E
Vitamin E
Vitamin E
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Vitamin E
Drug class
The RRR alpha-tocopherol form of vitamin E
Class identifiers
UseVitamin E deficiency, antioxidant
ATC codeA11HA03
Biological targetReactive oxygen species
Clinical data
Drugs.comMedFacts Natural Products
External links
MeSHD014810
Legal status
In Wikidata

Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols.[1][2] The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen species.[1][2]

Vitamin E is classified as an essential nutrient for humans.[1][2][3] Various government organizations recommend that adults consume between 3 and 15 mg per day, while a 2016 worldwide review reported a median dietary intake of 6.2 mg per day.[4] Sources rich in vitamin E include seeds, nuts, seed oils, peanut butter, vitamin E–fortified foods, and dietary supplements.[2][1] Symptomatic vitamin E deficiency is rare, usually caused by an underlying problem with digesting dietary fat rather than from a diet low in vitamin E.[5] Deficiency can cause neurological disorders.[1]

Tocopherols and tocotrienols both 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.[1][6] 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 that allows for penetration into biological membranes. Both natural and synthetic tocopherols are subject to oxidation, so dietary supplements are esterified, creating tocopheryl acetate, (or other forms such as succinate or palmitate) for stability purposes.[2][7]

Population studies have 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. However, placebo-controlled clinical trials using alpha-tocopherol as a supplement, with daily amounts as high as 2,000 mg per day, could not always replicate these findings.[2] In the United States, vitamin E supplement use peaked around 2002, but had declined by over 50% by 2006. Declining use was theorized to be due to publications of meta-analyses that showed either no benefits[8][9][10] or actual negative consequences from high-dose vitamin E.[8][11][12]

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.[13] 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.

Chemistry

[edit]
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 unsaturated side chain has three carbon-carbon double bonds whereas the tocopherols have a saturated side chain.[14]

Stereoisomers

[edit]

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.[14]

Form Structure
alpha-Tocopherol
beta-Tocopherol
gamma-Tocopherol
delta-Tocopherol
Tocopheryl acetate

Tocopherols

[edit]

Alpha-tocopherol is a fat-soluble antioxidant functioning within the glutathione peroxidase pathway,[15] and protecting cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.[2][16] 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.[17] Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.[6]

Tocotrienols

[edit]

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. 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 unsaturation (C-C double bonds) at these sites. Tocotrienols extracted from plants are always dextrorotatory stereoisomers, signified as d-tocotrienols. In theory, levorotatory forms of tocotrienols (l-tocotrienols) could exist as well, which would have a 2S rather than 2R configuration at the molecules' single chiral center, but unlike synthetic dl-alpha-tocopherol, the marketed tocotrienol dietary supplements are extracted from palm oil or rice bran oil.[18]

Tocotrienols are not essential nutrients; government organizations have not specified an estimated average requirement or recommended dietary allowance. A number of health benefits of tocotrienols have been proposed, including decreased risk of age-associated cognitive impairment, heart disease and cancer. Reviews of human research linked tocotrienol treatment to improved biomarkers for inflammation and cardiovascular disease, although those reviews did not report any information on clinically significant disease outcomes.[19][20][21] Biomarkers for other diseases were not affected by tocotrienol supplementation.[22]

Functions

[edit]
Tocopherols function by donating H atoms to radicals (X).

Vitamin E may have various roles as a vitamin.[1] Many biological functions have been postulated, including a role as a lipid-soluble antioxidant.[1] 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.[23] 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.[24]

Vitamin E affects gene expression[25] 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.[26]

Synthesis

[edit]

Biosynthesis

[edit]
Synthesis of tocopheryl acetate

Photosynthesizing plants, algae, and cyanobacteria synthesize tocochromanols, the chemical family of compounds made up of four tocopherols and four tocotrienols; in a nutrition context this family is referred to as Vitamin E. Biosynthesis starts with formation of the closed-ring part of the molecule as homogentisic acid (HGA). The side chain is attached (saturated for tocopherols, polyunsaturated for tocotrienols). The pathway for both is the same, so that gamma- is created and from that alpha-, or delta- is created and from that the beta- compounds.[27][28] Biosynthesis takes place in the plastids.[28]

The main reason plants synthesize tocochromanols appears to be for antioxidant activity. Different parts of plants, and different species, are dominated by different tocochromanols. The predominant form in leaves, and hence leafy green vegetables, is α-tocopherol.[27] Located in chloroplast membranes in close proximity to the photosynthetic process,[28] they protect against damage from the ultraviolet radiation of sunlight. Under normal growing conditions, the presence of α-tocopherol does not appear to be essential, as there are other photo-protective compounds; plants that, through mutations, have lost the ability to synthesize α-tocopherol demonstrate normal growth. However, under stressed growing conditions such as drought, elevated temperature, or salt-induced oxidative stress, the plants' physiological status is superior if it has the normal synthesis capacity.[29]

Seeds are lipid-rich to provide energy for germination and early growth. Tocochromanols protect the seed lipids from oxidizing and becoming rancid.[27][28] The presence of tocochromanols extends seed longevity and promotes successful germination and seedling growth.[29] Gamma-tocopherol dominates in seeds of most plant species, but there are exceptions. For canola, corn and soy bean oils, there is more γ-tocopherol than α-tocopherol, but for safflower, sunflower and olive oils the reverse is true.[27][28][30] Of the commonly used food oils, palm oil is unique in that tocotrienol content is higher than tocopherol content.[30] Seed tocochromanols content is also dependent on environmental stressors. In almonds, for example, drought or elevated temperature increase α-tocopherol and γ-tocopherol content of the nuts. Drought increases the tocopherol content of olives, and heat likewise for soybeans.[31]

Vitamin E biosynthesis occurs in the plastid and goes through two different pathways: the Shikimate pathway and the Methylerythritol Phosphate pathway (MEP pathway).[27] The Shikimate pathway generates the chromanol ring from the Homogentisic Acid (HGA), and the MEP pathway produces the hydrophobic tail which differs between tocopherol and tocotrienol. The synthesis of the specific tail is dependent on which molecule it originates from. In a tocopherol, its prenyl tail emerges from the geranylgeranyl diphosphate (GGDP) group, while the phytyl tail of a tocotrienol stems from a phytyl diphosphate.[27]

Industrial synthesis

[edit]

The synthetic product is all-rac-alpha-tocopherol,[32] also referred to as dl-alpha tocopherol. It consists of eight stereoisomers (RRR, RRS, RSS, RSR, SRR, SSR, SRS and SSS) in equal quantities. "It is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-alpha-tocopherol, using iron in the presence of hydrogen chloride gas as catalyst. The reaction mixture obtained is filtered and extracted with aqueous caustic soda. Toluene is removed by evaporation and the residue (all rac-alpha-tocopherol) is purified by vacuum distillation."[32] The natural alpha tocopherol extracted from plants is RRR-alpha tocopherol, referred to as d-alpha-tocopherol.[6] The synthetic has 73.5% of the potency of the natural.[33] Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to an ester using either acetic acid or succinic acid because the esters are more chemically stable, providing for a longer shelf-life.[2][34]

Deficiency

[edit]
Main article: Vitamin E deficiency

A worldwide summary of more than one hundred human studies reported a median of 22.1 μmol/L for serum α-tocopherol and defined α-tocopherol deficiency as less than 12 μmol/L. It cited a recommendation that serum α-tocopherol concentration be ≥30 μmol/L to optimize health benefits.[4] In contrast, the U.S. Dietary Reference Intake text for vitamin E concluded that a plasma concentration of 12 μmol/L was sufficient to achieve normal ex vivo hydrogen peroxide-induced hemolysis.[5] A 2014 review defined less than 9 μmol/L as deficient, 9-12 μmol/L as marginal, and greater than 12 μmol/L as adequate.[35]

Regardless of which definition is used, 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.[5] Cystic fibrosis and other fat malabsorption conditions can result in low serum vitamin E.[1] 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.[36][37]

Bariatric surgery as a treatment for obesity can lead to vitamin deficiencies. Long-term follow-up reported a 16.5% prevalence of vitamin E deficiency.[38] There are guidelines for multivitamin supplementation, but adherence rates are reported to be less than 20%.[39]

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.[5][1]

Drug interactions

[edit]

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.[40] For aspirin and warfarin, high amounts of vitamin E may potentiate anti-blood clotting action.[1][40] In multiple clinical trials, vitamin E lowered blood concentration of the immunosuppressant medication cyclosporine A.[40] 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 cites report 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.[1]

Dietary recommendations

[edit]
US vitamin E recommendations (mg per day)[5]
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 U.S. 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.[5] 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 result was a human upper limit set at 1000 mg/day.[5] Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.[5]

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 the United States. 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.[41] 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 derive an upper limit of half of that, then rounded to 300 mg/day.[42]

The People's Republic of China publishes dietary guidelines without specifics for individual vitamins or minerals.[43] The United Kingdom recommends 4 mg/day for adult men and 3 mg/day for adult women.[44] 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).[45] India recommends an adult intake of 7.5–10 mg/day and does not set an upper limit.[46] The World Health Organization recommends that adults consume 10 mg/day.[4]

Consumption tends to be below these recommendations. A worldwide summary reported a median dietary intake of 6.2 mg/d for alpha-tocopherol.[4]

Food labeling

[edit]

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 (IUs), but as of May 2016, it was revised to 15 mg to bring it into agreement with the RDA.[47] 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.[48]

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 were revised, such that 1 mg of "Vitamin E" is 1 mg of d-alpha-tocopherol or 2 mg of dl-alpha-tocopherol.[49] The change was originally started in 2000, when forms of vitamin E other than alpha-tocopherol were dropped from dietary calculations by the IOM. The UL amount disregards any conversion.[50] The EFSA has never used an IU unit, and their measurement only considers RRR-alpha-tocopherol.[51]

Sources

[edit]

Of the 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][52]

The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015. Common naturally occurring vitamin E sources are shown in the table,[53] as are some alpha-tocopherol fortified sources such as ready-to-eat cereals, infant formulas, and liquid nutrition products.[53]

Plant source[53] 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
Plant source[53] Amount
(mg / 100 g)
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
Plant source[53] Amount
(mg / 100 g)
Pistachio nuts 2 .8  
Avocados 2 .6
Spinach, raw 2
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[53] Amount
(mg / 100 g)
Fish 1.0–2.8
Oysters   1 .7
Butter 1 .6
Eggs 1 .1
Cheese 0.6–0.7
Chicken 0 .3
Beef, Pork 0 .1
Milk, whole 0 .1
Milk, skim 0 .01

Tocotrienols occur in some food sources, the richest being palm oil, and to a lesser extent rice bran oil, barley, oats, and certain seeds, nuts and grains, and the oils derived from them.[54][55]

Supplements

[edit]
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 oil.[18]

Fortification

[edit]

The World Health Organization does not have any recommendations for food fortification with vitamin E.[56] The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E.[57] 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.[53]

Non-nutrient food additives

[edit]

Various forms of vitamin E are common food additives in oily food, used to deter rancidity caused by peroxidation. Those with an E number include:[58]

  1. E306 Tocopherol-rich extract (mixed, natural, can include tocotrienol)
  2. E307 Alpha-tocopherol (synthetic)
  3. E308 Gamma-tocopherol (synthetic)
  4. E309 Delta-tocopherol (synthetic)

These E numbers include all racemic forms and acetate esters thereof.[58] 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.[59]

Absorption, metabolism, and excretion

[edit]

Tocotrienols and tocopherols, the latter including the stereoisomers of synthetic alpha-tocopherol, are absorbed from the intestinal lumen, incorporated into chylomicrons, and secreted into the portal vein, leading to the liver. Absorption efficiency is estimated at 51% to 86%,[5] and that applies to all of the vitamin E family – there is no discrimination among the vitamin E vitamers during absorption. Bile is necessary for chylomicron formation, so disease conditions such as cystic fibrosis result in biliary insufficiency and vitamin E malabsorption.[3] When consumed as an alpha-tocopheryl acetate dietary supplement, absorption is promoted when consumed with a fat-containing meal.[3] Unabsorbed vitamin E is excreted via feces. Additionally, vitamin E is excreted by the liver via bile into the intestinal lumen, where it will either be reabsorbed or excreted via feces, and all of the vitamin E vitamers are metabolized and then excreted via urine.[5][14]

Upon reaching the liver, RRR-alpha-tocopherol is preferentially taken up by alpha-tocopherol transfer protein (α-TTP). All other forms are degraded to 2'-carboxethyl-6-hydroxychromane (CEHC), a process that involves truncating the phytic tail of the molecule, then either sulfated or glucuronidated. This renders the molecules water-soluble and leads to excretion via urine. Alpha-tocopherol is also degraded by the same process, to 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychromane (α-CEHC), but more slowly because it is partially protected by α-TTP. Large intakes of α-tocopherol result in increased urinary α-CEHC, so this appears to be a means of disposing of excess vitamin E.[5][14]

Alpha-tocopherol transfer protein is coded by the TTPA gene on chromosome 8. The binding site for RRR-α-tocopherol is a hydrophobic pocket with a lower affinity for beta-, gamma-, or delta-tocopherols, or for the stereoisomers with an S configuration at the chiral 2 site. Tocotrienols are also a poor fit because the double bonds in the phytic tail create a rigid configuration that is a mismatch with the α-TTP pocket.[14] A rare genetic defect of the TTPA gene results in people exhibiting 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.[36] The role of α-TTP is to move α-tocopherol to the plasma membrane of hepatocytes (liver cells), where it can be incorporated into newly created very low density lipoprotein (VLDL) molecules. These convey α-tocopherol to cells in the rest of the body. As an example of a result of the preferential treatment, the US diet delivers approximately 70 mg/d of γ-tocopherol, and plasma concentrations are on the order of 2–5 μmol/L; meanwhile, dietary α-tocopherol is about 7 mg/d, but plasma concentrations are in the range of 11–37 μmol/L.[14]

Affinity of α-TTP for vitamin E vitamers[14]

Vitamin E compound Affinity
RRR-alpha-tocopherol 100%
beta-tocopherol 38%
gamma-tocopherol 9%
delta-tocopherol 2%
SSR-alpha-tocopherol 11%
alpha-tocotrienol 12%

Medical applications

[edit]

Vitamin E has been suggested as a supplement for helping many health conditions, mostly due to its antioxidant activity and potential to protect cells from oxidative damage. In the US, the vitamin is widely available as an over-the-counter supplement; however, medical evidence supporting its effectiveness and safety for treating or preventing a variety of health conditions is mixed. Vitamin E can also interact with some medications and other supplements.[1] Vitamin E has been studied as a treatment for skin health and skin ageing, immune function,[60] and managing conditions like cardiovascular disease[61] or Alzheimer's disease (AD),[62] or certain types of cancer.[61] Most studies have found limited or inconclusive benefits and the potential for some risks. It is most often recommended to obtain vitamin E through a balanced diet because high-dose supplementation may have health risks.[1] There is evidence that the sale of dietary supplement vitamin E has decreased by up to 33% following a report showing little or no effect of vitamin E in preventing cancer or cardiovascular disease.[11]

In 2023, it was the 290th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.[63][64]

All-cause mortality

[edit]

Two meta-analyses concluded that as a dietary supplement, vitamin E neither improved nor impaired all-cause mortality.[9][10] 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 journal article reported a statistically significant 3% increase for results when alpha-tocopherol was used in combination with other nutrients (vitamin A, vitamin C, beta-carotene, selenium).[12]

[edit]

A Cochrane review concluded that there were no changes seen for risk of developing age-related macular degeneration (AMD) from long-term vitamin E supplementation and that supplementation may slightly increase the chances of developing late AMD.[65]

Cognitive impairment and Alzheimer's disease

[edit]

Two meta-analyses reported lower vitamin E blood levels in AD people compared to healthy, age-matched people.[66][67] However, a review of vitamin E supplementation trials concluded that there was insufficient evidence to state that supplementation reduced the risk of developing AD or slowed the progression of AD.[62]

Cancer

[edit]

In a 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.[61]

As for literature on different types of cancer, an inverse relationship between dietary vitamin E and kidney cancer and bladder cancer is seen in observational studies.[68][69] A large clinical trial reported no difference in bladder cancer cases between treatment and placebo.[70]

An inverse relationship between dietary vitamin E and lung cancer was reported in observational studies,[71] but a large clinical trial in male tobacco smokers reported no impact on lung cancer between treatment and placebo,[72] and a trial which tracked people who chose to consume a vitamin E dietary supplement reported an increased risk of lung cancer for those consuming more than 215 mg/day.[73]

For prostate cancer, there are also conflicting results. A meta-analysis based on serum alpha-tocopherol content reported an inverse correlation in relative risk,[74] but a second meta-analysis of observational studies reported no such relationship.[75] A large clinical trial with male tobacco smokers and reported a 32% decrease in the incidence of prostate cancer,[76] but the SELECT trial of selenium or vitamin E for prostate cancer enrolled men ages 55 or older and reported relative risk 17% higher for the vitamin group.[77]

For colorectal cancer, a systematic review of randomized clinical trials and the large SELECT trial reported no statistically significant change in relative risk.[78][79] The Women's Health Study reported no significant differences for incidences of all types of cancer, cancer deaths, or specifically for breast, lung or colon cancers.[80]

Potential confounding factors are the form of vitamin E used in prospective studies and the amounts. Synthetic, racemic mixtures of vitamin E isomers are not bioequivalent to natural, non-racemic mixtures, yet are widely used in clinical trials and as dietary supplement ingredients.[81] One review reported a modest increase in cancer risk with vitamin E supplementation while stating that more than 90% of the cited clinical trials used the synthetic, racemic form dl-alpha-tocopherol.[73]

Cancer health claims

[edit]

The U.S. Food and Drug Administration initiated a process of reviewing and approving food and dietary supplement health claims in 1993. Reviews of petitions results in proposed claims being rejected or approved. If approved, specific wording is allowed on package labels. In 1999, a second process for claims review was created. If there is not a scientific consensus on the totality of the evidence, a Qualified Health Claim (QHC) may be established. The FDA does not "approve" qualified health claim petitions. Instead, it issues a Letter of Enforcement Discretion that includes very specific claim language and the restrictions on using that wording.[82] The first QHCs relevant to vitamin E were issued in 2003: "Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer." In 2009, the claims became more specific, allowing that vitamin E might reduce the risk of renal, bladder and colorectal cancers, but with required mention that the evidence was deemed weak and the claimed benefits highly unlikely. A petition to add brain, cervical, gastric and lung cancers was rejected. A further revision, May 2012, allowed that vitamin E may reduce risk of renal, bladder and colorectal cancers, with a more concise qualifier sentence added: "FDA has concluded that there is very little scientific evidence for this claim." Any company product label making the cancer claims has to include a qualifier sentence.[83]

Cataracts

[edit]

A review measured serum tocopherol and reported higher serum concentration was associated with a 23% reduction in relative risk of age-related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract.[84] In contrast, meta-analyses reporting on clinical trials of alpha-tocopherol supplementation reported no statistically significant change to risk of ARC compared to placebo.[84][85]

Cardiovascular diseases

[edit]

In a 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.[61]

Research on the effects of vitamin E on cardiovascular disease has produced conflicting results. In theory, oxidative modification of LDL-cholesterol promotes blockages in coronary arteries that lead to atherosclerosis and heart attacks, so vitamin E functioning as an antioxidant would reduce oxidized cholesterol and lower risk of cardiovascular disease. Vitamin E status has also been implicated in the maintenance of normal endothelial cell function of cells lining the inner surface of arteries, anti-inflammatory activity and inhibition of platelet adhesion and aggregation.[86] An inverse relation has been observed between coronary heart disease and the consumption of foods high in vitamin E, and also higher serum concentration of alpha-tocopherol.[86][87] The problem with observational studies is that these cannot confirm a relation between the lower risk of coronary heart disease and vitamin E consumption diets higher in vitamin E may also be higher in other, unidentified components that promote heart health, or lower in diet components detrimental to heart health, or people choosing such diets may be making other healthy lifestyle choices.[86]

A meta-analysis of randomized clinical trials (RCTs) reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%.[88] However, two large trials that were incorporated into the meta-analysis either did not show any benefit for heart attack, stroke, coronary mortality or all-cause mortality,[89] or else a higher risk of heart failure in the alpha-tocopherol group.[90]

Vitamin E supplementation does not reduce the incidence of ischemic or hemorrhagic stroke.[91][92] However, supplementation of vitamin E with other antioxidants reduced risk of ischemic stroke by 9% while increased the risk for hemorrhagic stroke by 22%.[92]

Denial of cardiovascular health claims

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In 2001, the U.S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health.[93] The U.S. National Institutes of Health reviewed literature published up to 2008 and concluded "In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality."[1] The European Food Safety Authority (EFSA) reviews proposed health claims for the European Union countries. In 2010, the EFSA reviewed and rejected claims that a cause and effect relationship has been established between the dietary intake of vitamin E and maintenance of normal cardiac function or of normal blood circulation.[94]

Nonalcoholic fatty liver disease

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Supplemental vitamin E significantly reduced elevated liver enzymes, steatosis, inflammation and fibrosis, suggesting that the vitamin may be useful for treatment of nonalcoholic fatty liver disease (NAFLD) and the more extreme subset known as nonalcoholic steatohepatitis (NASH) in adults,[95][96][97] but not in children.[98][99]

Exercise recovery

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In healthy adults, after exercise, vitamin E was shown to not have any benefits for post-exercise recovery, as measured by muscle soreness and muscle strength, or measured by indicators for inflammation or muscle damage, such as interleukin-6 and creatine kinase.[100]

Parkinson's disease

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For Parkinson's disease, there is an observed inverse correlation seen with dietary vitamin E, but no confirming evidence from placebo-controlled clinical trials.[101][102]

Pregnancy

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Supplementation with a combination of vitamins E and C during pregnancy is not recommended by the World Health Organization.[103] A Cochrane review concluded there was no support for the combination reducing risk of stillbirth, neonatal death, preterm birth, preeclampsia, or any other maternal or infant outcomes, either in healthy women or those considered at risk for pregnancy complications.[104]

Topical applications

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There is widespread use of tocopheryl acetate in some skincare and wound-treatment products as a topical medication, with claims for improved wound healing and reduced scar tissue,[105] but reviews have repeatedly concluded that there is insufficient evidence to support these claims.[106][107] There are also reports of allergic contact dermatitis from use of vitamin-E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products.[108]

Vaping-associated lung injury

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Main article: Vaping-associated pulmonary injury

The US Centers for Disease Control and Prevention (CDC) stated in February 2020 that previous research suggested inhaled vitamin E acetate (α-tocopheryl acetate) may interfere with normal lung functioning.[109] In September 2019, the US Food and Drug Administration had announced that vape liquids linked to recent vaping related lung disease outbreak in the United States, tested positive for vitamin E acetate[110] which had been used as a thickening agent by illicit THC vape cartridge manufacturers.[111] By November 2019, the CDC had identified vitamin E acetate as a very strong culprit of concern in the vaping-related illnesses, but has not ruled out other chemicals or toxicants as possible causes. These findings were based on fluid samples from the lungs of people with vaping-associated pulmonary injury.[112][113] Pyrolysis of vitamin E acetate produces exceptionally toxic ketene gas, along with carcinogenic alkenes and benzene.[114]

History

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Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop[115] and first isolated in a pure form by Evans and Gladys Anderson Emerson in 1935 at the University of California, Berkeley.[116] Because the vitamin activity was first identified as a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words "τόκος" [tókos, birth], and "φέρειν", [phérein, to bear or carry] meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol.[13] George M. Calhoun, Professor of Greek at the University of California, was credited with helping with the naming process.[13] Erhard Fernholz elucidated its structure in 1938 and shortly afterward the same year, Paul Karrer and his team first synthesized it.[117]

Nearly 50 years after the discovery of vitamin E, an editorial in the Journal of the American Medical Association titled "Vitamin in search of a disease" read in part "...research revealed many of the vitamin's secrets, but no certain therapeutic use and no definite deficiency disease in man." The animal discovery experiments had been a requirement for successful pregnancy, but no benefits were observed for women prone to miscarriage. Evidence for vascular health was characterized as unconvincing. The editorial closed with mention of some preliminary human evidence for protection against hemolytic anemia in young children.[118]

A role for vitamin E in coronary heart disease was first proposed in 1946 by Evan Shute and colleagues.[119][120] More cardiovascular work from the same research group followed,[121] including a proposal that megadoses of vitamin E could slow down and even reverse the development of atherosclerosis.[122] Subsequent research showed no association between vitamin E supplementation and cardiovascular events such as nonfatal stroke or myocardial infarction, or cardiovascular mortality.[123]

There is a long history of belief that topical application of vitamin E containing oil benefits burn and wound healing.[105] This belief persists even though scientific reviews refuted this claim.[106][107]

The role of vitamin E in infant nutrition has a long research history. From 1949 onward there were trials with premature infants suggesting that oral alpha-tocopherol was protective against edema, intracranial hemorrhage, hemolytic anemia and retrolental fibroplasia.[124] A more recent review concluded that vitamin E supplementation in preterm infants reduced the risk of intracranial hemorrhage and retinopathy, but noted an increased risk of sepsis.[125]

References

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Vitamin E

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Vitamin E is a fat-soluble vitamin essential for human health, functioning primarily as an to protect cells from damage caused by free radicals and generated during lipid oxidation. It comprises eight naturally occurring compounds—four tocopherols (alpha, beta, gamma, delta) and four —but alpha-tocopherol is the most biologically active form in the and the primary metric used to assess vitamin E status. In addition to its antioxidant properties, vitamin E supports immune function by enhancing T-cell activation and proliferation, and it may play roles in , , and maintaining the integrity of cell membranes. Dietary sources of vitamin E are abundant in plant-based foods, including vegetable oils (such as sunflower and oil), nuts (like almonds and ), seeds, green leafy vegetables (such as ), and fortified cereals; animal products provide smaller amounts. The recommended dietary allowance (RDA) for adults is 15 mg (22 IU) per day of alpha-tocopherol, the same during , and 19 mg (28 IU) during . Deficiency in vitamin E is uncommon in healthy individuals but can occur in conditions impairing fat absorption, such as , , or , leading to symptoms like , , and . Conversely, excessive intake from supplements—particularly above the tolerable upper intake level of 1,000 mg (1,500 IU) per day—may increase risks of bleeding, hemorrhagic stroke, and, in some studies, ; for instance, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found that 400 IU/day of synthetic alpha-tocopherol raised incidence by 17% in healthy men. While vitamin E supplements are sometimes used to slow the progression of age-related in combination with other antioxidants, evidence for benefits in preventing or cognitive decline remains inconclusive.

Chemistry

Forms and Structures

Vitamin E encompasses a group of eight fat-soluble compounds, consisting of four tocopherols (α-, β-, γ-, and δ-tocopherol) and four (α-, β-, γ-, and δ-tocotrienol), all featuring a phenolic hydroxyl group attached to a chromane ring structure that contributes to their capabilities. These compounds are naturally occurring and essential for various biological processes, with the phenolic group enabling them to donate atoms to neutralize free radicals. The primary structural distinction between tocopherols and tocotrienols lies in their side chains attached at the 2-position of the chromane ring: tocopherols have a saturated 16-carbon phytyl chain, while tocotrienols possess an unsaturated 15-carbon farnesyl chain with three double bonds, conferring differences in and membrane interactions. The α-, β-, γ-, and δ- forms are differentiated by the number and positioning of methyl groups on the chromane ring (three for α, two for β, two for γ in a different , and one for δ). Representative molecular formulas include (C29_{29}H50_{50}O2_{2}), β-tocopherol and γ-tocopherol (both C28_{28}H48_{48}O2_{2}), δ-tocopherol (C27_{27}H46_{46}O2_{2}), and α-tocotrienol (C29_{29}H44_{44}O2_{2}), reflecting the impact of side-chain saturation and ring substitutions on overall molecular weight. In terms of biological potency, is the most active form in humans, defined as the standard for vitamin E activity, with 1 mg of natural (RRR-) equivalent to 1.49 international units (IU). The other forms exhibit lower relative biological potencies in humans, such as β-tocopherol at 38%, γ-tocopherol at 9%, and δ-tocopherol at 2% of 's activity based on affinity to the α-tocopherol transfer protein (α-TTP), though their antioxidant activities are comparable; only fully satisfies human nutritional requirements. Physically, vitamin E compounds are lipophilic, exhibiting high in fats, oils, and nonpolar solvents but negligible in , which influences their absorption and storage in adipose tissues. They demonstrate moderate stability under neutral conditions but are susceptible to oxidation, particularly when exposed to , , or oxygen, yielding products like α-tocopherylquinone and epoxy-α-tocopherylquinones through one-electron oxidation mechanisms. Esters such as enhance stability for commercial applications without altering core .

Stereoisomers

, the most biologically active form of vitamin E, features three chiral centers located at carbon atoms 2, 4' (in the phytyl side chain), and 8', which give rise to eight distinct stereoisomers. The naturally occurring form, derived from plant sources and retained in animal tissues, is specifically the (2R,4'R,8'R)-, commonly denoted as RRR- or d-. In contrast, synthetic vitamin E, known as all-rac-α-tocopherol or dl-α-tocopherol, is produced as a comprising equal amounts of all eight stereoisomers: RRR, RRS, RSR, , SRR, SRS, SSR, and SSS. These stereoisomers exhibit varying biopotencies, with only the four 2R configurations (, RRS, RSR, ) demonstrating significant retention in human plasma and tissues due to selective binding by the hepatic α-tocopherol transfer protein (α-TTP); the 2S forms are rapidly catabolized and excreted. Overall, the 2R stereoisomers possess approximately 1.49 times the biopotency of the all-rac mixture when assessed via the rat fetal resorption , the historical standard for vitamin E activity. This stereochemical variation directly influences measurement and standardization. One milligram of RRR-α-tocopherol equates to 1.49 International Units (IU) of vitamin E activity, while one milligram of all-rac-α-tocopherol corresponds to 1 IU, reflecting the lower average potency of the synthetic blend. These IU conversions, rooted in results, facilitate comparisons between natural and synthetic forms in nutritional contexts. The differences in stereochemistry also affect bioavailability, as the natural RRR form is more efficiently absorbed, transported, and utilized than the synthetic isomers, leading to higher plasma concentrations and tissue retention for equivalent doses. Regulatory bodies like the U.S. (FDA) address this in supplement labeling by requiring declarations in milligrams of α-tocopherol equivalents, where 1 mg label claim represents the activity of 1 mg RRR-α-tocopherol or 2 mg all-rac-α-tocopherol, ensuring consumers receive accurate potency information without relying solely on outdated IU values.

Tocopherols and Tocotrienols

Vitamin E comprises two primary subclasses: tocopherols and , each consisting of four homologues (α, β, γ, and δ) that differ in the number and position of methyl groups on the chromane ring, along with variations in at the C2 position of the ring and the chiral centers in the for tocopherols. The structural distinction between tocopherols and lies in their isoprenoid side chains attached to the chromane ring: tocopherols feature a saturated phytyl tail, while possess an unsaturated tail with three trans double bonds, conferring greater flexibility and mobility. This unsaturation in enhances their integration into cell membranes compared to the more rigid tocopherols, potentially improving distribution within lipid bilayers. Tocotrienols were first identified in the as the unsaturated counterparts to tocopherols, initially isolated from sources like and later recognized in other plant materials. In terms of prevalence, tocopherols predominate in animal tissues and blood, where α-tocopherol is the primary form retained for vitamin E activity. In contrast, tocotrienols are mainly found in specific plant sources, such as (where they constitute about 70% of total vitamin E) and . Tocotrienols exhibit unique attributes relative to tocopherols, including faster metabolism in humans, leading to more extensive breakdown and excretion of metabolites. This results in lower plasma levels of tocotrienols compared to tocopherols following supplementation.

Biological Roles

Antioxidant Functions

Vitamin E functions primarily as a lipid-soluble antioxidant, scavenging free radicals and reactive oxygen species to protect cellular components from oxidative damage. Its antioxidant activity is centered on the phenolic hydroxyl group in the chromanol ring, which donates a hydrogen atom to neutralize peroxyl radicals (ROO•), forming a relatively stable tocopheroxyl radical (TO•). This radical can be reduced back to its active form by other antioxidants, such as ascorbic acid (vitamin C) or reduced glutathione, preventing the propagation of oxidative chains. A key role of vitamin E is to inhibit in biological membranes, where polyunsaturated fatty acids (PUFAs) are particularly susceptible to oxidative attack. By interrupting the chain reaction of —initiated by free radicals abstracting hydrogen from PUFA methylene groups—vitamin E terminates the formation of harmful lipid hydroperoxides and secondary products like , thereby maintaining membrane integrity and fluidity. This protective effect is especially critical in environments rich in oxidizable lipids, such as cell membranes and circulating lipoproteins. In vivo, vitamin E is predominantly distributed in lipoproteins and cellular membranes, with α-tocopherol serving as the primary circulating form in human plasma due to its selective retention by the α-tocopherol transfer protein. This localization positions it optimally to shield low-density lipoproteins (LDL) from oxidation during transport and to embed within phospholipid bilayers for direct membrane defense. The synergy between vitamin E and hydrophilic antioxidants like vitamin C enhances overall efficacy; for instance, vitamin C reduces the tocopheroxyl radical in aqueous phases, recycling vitamin E and amplifying protection against oxidative stress in both lipophilic and hydrophilic compartments.

Non-Antioxidant Functions

Vitamin E exhibits several non-antioxidant functions that contribute to cellular signaling and physiological processes. One key role involves gene regulation, where modulates the expression of genes associated with and . Specifically, it binds to and activates peroxisome proliferator-activated receptors (PPARs), such as PPARγ, which in turn regulate the transcription of target genes like the scavenger receptor, influencing cellular uptake of oxidized . Additionally, vitamin E inhibits the activation of nuclear factor-κB (), a that promotes pro-inflammatory gene expression, thereby reducing the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in various cell types. In reproduction, vitamin E is essential for maintaining and preventing in animal models. Discovered in the early through studies in rats, its deficiency leads to impaired , with fetuses resorbed around day 9 of due to failure in sustaining the . This role is linked to support of progesterone production, as vitamin E supplementation restores luteal function and progesterone levels, ensuring implantation and early embryonic development without reliance on its oxidative protective effects. Vitamin E also modulates immune responses through direct effects on immune cell signaling and function, particularly evident in deficiency states. It enhances T-cell proliferation and differentiation by stabilizing integrity and facilitating pathways, such as those involving LAT and , which improve naïve T-cell activation and interleukin-2 (IL-2) production in aged or deficient models. In deficiency, such as in preterm infants, and bactericidal activity are impaired, leading to increased susceptibility; supplementation restores phagocytic capacity while modulating generation. Neurologically, vitamin E influences signaling cascades critical for neuronal integrity and protection. It inhibits protein kinase C (PKC) activity by activating protein phosphatase 2A (PP2A), which dephosphorylates PKC and reduces its role in promoting and . This PKC modulation supports neuronal protection by altering downstream pathways involved in and preventing aberrant signaling that could lead to neurodegeneration, as observed in cellular models of oxidative insult. Emerging research as of 2024 suggests additional non-antioxidant roles for vitamin E in , potentially mediating signaling through bioactive to support muscle function.

Production

Biosynthesis in

Vitamin E, encompassing tocopherols and , is synthesized in through a pathway localized primarily in plastids, where precursors from the (, HGA) and the methylerythritol phosphate (MEP) pathway converge. The initial and committed step involves the of HGA by homogentisate prenyltransferase (HPT, also known as VTE2), which catalyzes the formation of the chromanol ring precursor by condensing HGA with phytyl diphosphate (PDP) to produce 2-methyl-6-phytyl-1,4-benzoquinol (MPBQ) for tocopherols, or with geranylgeranyl diphosphate (GGDP) via homogentisate geranylgeranyltransferase (HGGT) for . This step is crucial for directing the synthesis toward either saturated (tocopherols) or unsaturated () forms, with HPT predominant in most and HGGT more active in monocots like cereals. Subsequent steps refine the structure: MPBQ (or its geranylgeranyl analog) is methylated at the 2-position by 2-methyl-6-phytyl-1,4-benzoquinol methyltransferase (MPBQ MT, VTE3) to form 2,3-dimethyl-5-phytyl-1,4-benzoquinol (DMPBQ), followed by cyclization by tocopherol cyclase (TC, VTE1) to yield δ- and γ-tocopherols (or tocotrienols). The final modification occurs via γ-tocopherol methyltransferase (γ-TMT, VTE4), which adds a methyl group at the 5-position using S-adenosyl-L-methionine as the donor, converting γ-tocopherol to the biologically most active α-tocopherol (or β- to α-tocotrienol). These enzymatic reactions ensure the production of eight vitamin E homologs, with α-tocopherol often accumulating as the dominant form in leaves for photosynthetic protection. The pathway is tightly regulated, particularly under abiotic stresses such as oxidative damage, high , , or , where genes encoding key enzymes like VTE2 and VTE4 are upregulated to enhance tocochromanol levels and mitigate (ROS) accumulation in plastids. Transcriptional control involves factors like WRINKLED1 in seeds, while post-translational mechanisms, such as by ABC1K kinases, stabilize enzymes like VTE1 in plastoglobules and membranes. Although HGA is synthesized in the from , its transport into plastids relies on unidentified transporters, highlighting the pathway's compartmentalization. Evolutionarily, the vitamin E biosynthetic pathway originated in ancient photosynthetic organisms, including and , as an to protect photosystems from photooxidative stress during oxygenic , with core enzymes like VTE1 and VTE2 conserved across green lineages but diversified in land plants for stress resilience.

Industrial Synthesis

The industrial synthesis of vitamin E primarily produces all-rac-α-tocopherol (DL-α-tocopherol), a synthetic mixture of eight stereoisomers, which is the most common form used in supplements, , and . This process relies on feedstocks and has dominated commercial production since the mid-20th century, accounting for approximately 80% of global supply. The core synthetic route involves the acid-catalyzed of trimethylhydroquinone (TMHQ) with isophytol to form DL-α-tocopherol. TMHQ is typically synthesized from petrochemical-derived such as 2,3,6-trimethylphenol via oxidation and reduction steps, while isophytol is produced through a multi-step process starting from acetone, , and , involving , dehydrations, and selective hydrogenations. The , often conducted in solvents like with catalysts such as , yields the chromanol ring structure characteristic of , followed by purification through and molecular sieving to achieve purities exceeding 97% for pharmaceutical-grade material. To enhance stability, the is frequently esterified with to produce DL-α-tocopheryl , involving under mild conditions with yields typically above 90%. Traditional routes can encompass up to 20 individual steps, requiring stringent protocols due to the handling of flammable and intermediates. Global production of synthetic vitamin E operates at a scale of approximately 112,000 metric tons annually as of 2024, driven by demand in the feed and sectors, with major producers including and DSM achieving capacities that support this volume through large-scale reactors and continuous processing. The process is cost-effective for high-volume applications, with raw material costs fluctuating based on prices, but it has faced environmental scrutiny due to reliance on non-renewable resources. Post-2020, there has been a shift toward sustainable bio-based methods, such as microbial of isophytol from sugars or using engineered strains, which reduces carbon footprints and aligns with principles, though these remain a minority of production. Quality control in industrial synthesis emphasizes distinguishing synthetic vitamin E from forms to meet regulatory standards for labeling and claims. Synthetic products lack isotopes present in plant-derived tocopherols, as petrochemical feedstocks originate from ancient sources without recent biogenic carbon; this difference is quantified via , enabling unambiguous authentication with detection limits below 1% content. Additionally, chromatographic analysis confirms the racemic stereoisomer profile of synthetic material versus the RRR-form dominant in extracts, ensuring compliance with pharmacopeial specifications like USP and EP.

Sources and Intake

Dietary Sources

Vitamin E, primarily in the form of and other tocopherols and , is abundant in various plant-based foods, with vegetable oils serving as the richest sources due to their high fat content, which enhances of the fat-soluble . These natural forms are generally well-absorbed when consumed with dietary fats, contributing significantly to meeting the recommended daily intake of 15 mg for adults. Plant oils are among the most concentrated dietary sources of vitamin E, particularly . For instance, contains approximately 149 mg of per 100 g, while provides about 41 mg per 100 g. Other notable oils include safflower oil (around 34 mg per 100 g) and (about 17 mg per 100 g). These values can vary slightly based on extraction methods and crop conditions. Nuts and seeds offer substantial amounts of vitamin E, often in forms that are readily bioavailable due to their natural oil matrices. Almonds, for example, contain roughly 25 mg per 100 g, and sunflower seeds provide up to 35 mg per 100 g. Green leafy vegetables contribute smaller but valuable quantities; boiled spinach delivers about 2 mg per 100 g, supporting overall intake when consumed regularly. Certain foods are particularly rich in tocotrienols, the less common but biologically active forms of vitamin E with potentially distinct bioavailability profiles. Palm oil is dominated by γ-tocotrienol, containing approximately 50 mg (range 40-70 mg) of total tocotrienols per 100 g, with γ-tocotrienol comprising about 40-50% of total vitamin E. In palm oil, tocotrienols typically include α-T3 (15-20%), γ-T3 (40-50%), and δ-T3 (10-15%), alongside ~21% α-tocopherol. Annatto seeds stand out as an exceptional source, with δ-tocotrienol levels reaching 140-147 mg per 100 g of dry seeds. The vitamin E content in foods can be influenced by processing and environmental factors, potentially reducing bioavailability. High-temperature methods like frying may cause up to 50% degradation of tocopherols due to oxidation, while regional variations in soil quality and climate can lead to differences of 20-30% in crop concentrations.
Food SourceVitamin E FormApproximate Content (mg/100 g)
149
41
Almonds25
Sunflower seeds35
(boiled)2
γ-tocotrienol (dominant)50 (40-70) total
Annatto seeds (dry)δ-tocotrienol140-147

Supplements and Fortification

Vitamin E supplements are available in various forms, primarily as , with distinctions between natural and synthetic variants. The natural form, d- (also known as RRR-), is derived from plant sources and typically provided as the free alcohol or esters like d-. In contrast, the synthetic form, dl- (all-rac-), is a racemic mixture produced chemically and often esterified as dl-. Esters such as or succinate are commonly used in both natural and synthetic supplements to enhance stability and prevent oxidation during storage and processing. Bioavailability differs significantly between these forms, with natural d- exhibiting approximately twice the absorption and retention in tissues compared to synthetic dl- due to preferential binding by the hepatic . Esterified versions, whether natural or synthetic, are efficiently hydrolyzed in the intestine to the free form prior to absorption, yielding similar to the non-esterified alcohol once processed. Combination supplements pairing vitamin E with vitamin C are available, offering basic synergistic antioxidant protection through vitamin C's regeneration of oxidized vitamin E, aiding against oxidative stress. Common dosages in vitamin E supplements range from 15 IU (the approximate adult RDA equivalent) to 400 IU per day, with many products providing 100–200 IU in single servings; higher doses up to 1,000 IU are available but exceed typical recommendations. The global vitamin E market, encompassing supplements and other uses, was projected to reach $2.99 billion in 2025, driven by increasing consumer preference for natural forms amid demand for clean-label products. Fortification involves adding vitamin E to foods to enhance nutritional content, commonly in cereals and spreads where is used for its stability. In the , vitamin E is mandated in infant formulas at specified minimum levels under Commission Delegated Regulation (EU) 2016/127 to ensure adequate intake for . In the United States, of general foods like cereals is voluntary under FDA policy, though infant formulas require minimum vitamin E levels as part of the 27 essential nutrients regulated by the agency. This contrasts with dietary sources, where vitamin E occurs naturally in foods like nuts and oils without added .

Physiology

Absorption and Transport

Vitamin E, a fat-soluble vitamin, is primarily absorbed in the proximal following emulsification of dietary . Upon ingestion, tocopherols and are released from food matrices and incorporated into mixed micelles composed of salts, fatty acids, and monoglycerides, which facilitate their across the unstirred water layer and uptake by enterocytes via passive and possibly facilitated involving proteins like NPC1L1 and SR-BII. Absorption efficiency varies but is generally estimated at 20-50%, influenced by factors such as the presence of dietary fat, which enhances micelle formation, and is preferential for over other vitamers due to its higher affinity for intestinal uptake mechanisms. Conditions impairing salt secretion or fat digestion, such as or pancreatic insufficiency, significantly reduce this efficiency. Once inside enterocytes, absorbed vitamin E is esterified and packaged into chylomicrons, which are secreted into the and transported to the liver via the . In the liver, α-tocopherol is selectively retained and transferred to very low-density lipoproteins (VLDL) for secretion into the bloodstream, primarily through the action of the α-tocopherol transfer protein (α-TTP), a liver-specific chaperone that exhibits high affinity for the natural RRR-α-tocopherol stereoisomer (also known as 2R,4'R,8'R-α-tocopherol) over other isomers and non-α forms. These VLDL particles are metabolized into intermediate-density and low-density lipoproteins (LDL), which distribute α-tocopherol to peripheral tissues, while high-density lipoproteins (HDL) carry smaller amounts; overall, about 75% of plasma vitamin E is associated with LDL. Cellular uptake from lipoproteins occurs via (e.g., LDL receptors) or scavenger receptor class B type I (SR-BI)-facilitated selective transfer. Normal plasma α-tocopherol concentrations range from 5 to 20 μg/mL in healthy individuals, correlating with adequate nutritional status and influenced by dietary fat intake, which can increase by up to twofold when vitamin E is consumed with . Levels are also modulated by plasma concentrations, as vitamin E circulates bound to lipoproteins. Genetic variations, particularly in the TTPA gene encoding α-TTP, impair hepatic secretion of α-tocopherol, leading to with (AVED), an autosomal recessive disorder characterized by low plasma levels despite normal intake and treatable with high-dose supplementation.

Metabolism and Excretion

Vitamin E undergoes hepatic metabolism primarily through P450-mediated oxidation, where the CYP4F2 catalyzes ω-hydroxylation of the side chain, forming long-chain metabolites such as 13'-hydroxychromanols and 13'-carboxychromanols. These intermediates then undergo successive cycles of β-oxidation in the peroxisomes and mitochondria, ultimately yielding short-chain metabolites known as carboxyethyl hydroxychromans (CEHCs), which serve as the primary end products of vitamin E . Non-α forms of vitamin E, including γ- and δ- and , are metabolized more extensively than α- via this pathway. The excretion of vitamin E metabolites occurs mainly through the biliary route into the , accounting for approximately 80% of total elimination, while the remaining portion is excreted in urine as conjugated CEHCs, which act as reliable biomarkers of vitamin E status and intake. The plasma of , the most biologically active form, is about 48 hours in humans, reflecting a balance between hepatic retention and catabolic clearance. Regulation of vitamin E catabolism involves transcriptional control, where induction of peroxisome proliferator-activated receptor α (PPARα) upregulates enzymes involved in ω-hydroxylation and β-oxidation, enhancing metabolite formation and excretion. In cases of excess intake, this regulatory mechanism promotes rapid clearance to prevent accumulation, primarily through increased biliary secretion of long-chain metabolites. Interspecies differences in vitamin E metabolism highlight variations in efficiency; humans exhibit less efficient catabolism compared to , excreting higher proportions of unconjugated CEHCs in urine, whereas produce more sulfated metabolites and demonstrate faster overall turnover.

Nutritional Guidelines

The Recommended Dietary Allowance (RDA) for vitamin E, expressed as , is 15 mg (22 international units, IU) per day for adults aged 14 years and older, sufficient to meet the needs of nearly all healthy individuals. For children, the RDA varies by age: 6 mg/day for ages 1–3 years, 7 mg/day for ages 4–8 years, and 11 mg/day for ages 9–13 years. During , the RDA remains 15 mg/day, while for it increases to 19 mg/day to account for additional demands on maternal stores. The Tolerable Upper Intake Level (UL) for vitamin E from all sources, derived from the 2000 Institute of Medicine report, is 600 mg/day for children aged 9–13 years, 800 mg/day for those aged 14–18 years, and 1,000 mg/day for adults aged 19 years and older, established to prevent adverse effects such as increased of due to interference with vitamin K-dependent clotting factors. Lower ULs apply to younger children: 200 mg/day for ages 1–3 years and 300 mg/day for ages 4–8 years. This UL has been retained in subsequent reviews. In contrast, the (EFSA) in 2024 reaffirmed a lower UL of 300 mg/day for adults (including pregnant and lactating women). International guidelines from the (WHO) and (FAO) align closely with these RDAs, recommending 10 mg/day for adults as an estimated average requirement, and note low toxicity without a specific upper limit. For premature infants, who are at high risk of deficiency due to low birth stores and , intravenous supplementation of 7–10 mg/kg/day is recommended initially to achieve adequate plasma levels and prevent complications like . Vitamin E status is assessed primarily through plasma α-tocopherol concentration, where levels below 5 μg/mL (11.6 μmol/L) indicate deficiency, often associated with fat or genetic disorders, while levels of 5–20 μg/mL are considered normal for healthy individuals. These thresholds guide clinical monitoring and adjustment of intakes in at-risk populations.

Labeling and Regulations

In the United States, the (FDA) mandates that vitamin E content on Facts and Supplement Facts labels be declared in milligrams (mg) of alpha-tocopherol, with the Daily Value (%DV) set at 15 mg for adults and children aged 4 years and older. This standardization aims to provide clearer information on nutrient intake relative to recommended levels. Labels must specify whether the vitamin E is in the natural form (d-alpha-tocopherol) or synthetic form (dl-alpha-tocopherol), as their biopotencies differ: 1 mg of natural alpha-tocopherol equates to 1.49 International Units (IU), while 1 mg of synthetic form equates to 2.22 IU. The FDA completed the transition from IU to mg labeling for foods by January 2020 and for dietary supplements by January 2021, eliminating IU declarations to reduce consumer confusion over potency equivalencies. In the , the (EFSA) regulates vitamin E labeling through authorized health claims, permitting statements such as "Vitamin E contributes to the protection of cells from " on products that deliver at least 12 mg of alpha-tocopherol equivalents per daily portion. This claim is substantiated by evidence showing vitamin E's role in protecting DNA, proteins, and lipids from oxidative damage across all age groups, including infants and young children. EFSA's guidelines ensure claims are evidence-based and tied to specific intake thresholds to prevent misleading representations. Internationally, the Commission provides guidelines for the addition of vitamins to foods, including vitamin E primarily as alpha-tocopherol, with recommended levels designed to meet nutritional needs without exceeding safe upper limits—typically up to 20 mg per 100 g in select fortified products like formulas. These standards promote harmonized practices for labeling and to facilitate global trade while prioritizing consumer safety. Recent discussions within Codex working groups have explored the inclusion of as contributing forms of vitamin E activity in equivalency calculations, though no formal updates were adopted by 2024. Prior to the widespread adoption of mg-based labeling, mislabeling issues plagued vitamin E supplements, particularly those overstating content in IU, which led to discrepancies between claimed and actual amounts. Independent testing in revealed that some products contained as little as 1% or 88% of the labeled vitamin E, prompting FDA warnings for misbranding and voluntary recalls to address adulteration and inaccurate potency claims. These incidents underscored the risks of IU labeling in fostering confusion and non-compliance with regulatory standards.

Deficiency and Toxicity

Deficiency Symptoms and Risks

Vitamin E deficiency is rare in developed countries due to adequate dietary intake and efficient absorption mechanisms in healthy individuals. Clinical manifestations primarily affect the nervous system, with common symptoms including peripheral neuropathy, ataxia, hyporeflexia, and loss of proprioception and vibratory sense. Other signs may involve muscle weakness, dysarthria, ophthalmoplegia, and, in severe cases, retinopathy or blindness. Hemolytic anemia can occur, particularly in children and preterm infants, due to increased red blood cell fragility. The primary causes of vitamin E deficiency stem from impaired absorption or transport of this fat-soluble vitamin, rather than isolated dietary inadequacy. Fat malabsorption syndromes, such as those associated with , cholestatic liver disease, , or short-bowel syndrome, prevent proper uptake of vitamin E from the diet. Genetic disorders also contribute significantly; with vitamin E deficiency (AVED) results from mutations in the TTPA gene, leading to defective intracellular transport of alpha-tocopherol and subsequent low tissue levels. Similarly, , caused by MTTP gene variants, impairs lipoprotein formation and fat-soluble vitamin absorption, resulting in progressive neurological deficits if untreated. At-risk populations include premature infants weighing less than 1500 grams, who have limited placental transfer of vitamin E and low hepatic stores. Individuals with chronic fat malabsorption disorders, such as those with or post-bariatric surgery (especially malabsorptive procedures like ), face elevated risks. Diagnosis typically involves measuring plasma alpha-tocopherol levels, with concentrations below 5 μg/mL indicating deficiency in adults; an alpha-tocopherol-to-total ratio less than 0.8 mg/g provides additional context, particularly in cases of altered profiles. Clinical evaluation, including and assessment of risk factors, supports , often supplemented by a positive response to vitamin E supplementation.

Toxicity and Adverse Effects

Vitamin E is generally considered safe when consumed through dietary sources, but high-dose supplementation can lead to , primarily manifesting as hemorrhagic complications due to its interference with blood mechanisms. Unlike many nutrients, vitamin E does not have an established 50 (LD50) in humans, but chronic intake exceeding 1,000 mg (approximately 1,500 IU) per day has been associated with an elevated risk of events, including , through antagonism of -dependent clotting factors. This antagonism disrupts the synthesis of prothrombin and other proteins, potentially exacerbating tendencies in susceptible individuals. The tolerable upper intake level (UL) for adults, confirmed by the as of 2023, remains 1,000 mg/day based on risk. Drug interactions represent a significant concern with high-dose vitamin E, particularly in patients on or antiplatelet therapies. Supplementation can potentiate the effects of by enhancing antagonism, leading to prolonged prothrombin times and increased risk, as evidenced by case reports of and ecchymoses in concurrent users. Similarly, vitamin E may interact with statins, such as simvastatin or , by contributing to hepatobiliary dysfunction or altered , though clinical impacts vary. Recent analyses highlight broader adverse outcomes from excess vitamin E, including an approximately 4% increased risk of all-cause mortality ( 1.04) at high supplemental doses (>400 IU/day), potentially linked to hemorrhagic and other cardiovascular events, as detailed in a 2025 review of clinical trials. Follow-up data from the Selenium and Vitamin E Trial (SELECT) indicate that long-term supplementation promotes incidence, with a of 1.17 for vitamin E alone. For individuals using high-dose vitamin E, monitoring is essential, with regular coagulation tests such as (PT) and international normalized ratio (INR) recommended to detect early signs of impaired . These measures help prevent severe complications, especially in those with concurrent use or underlying coagulopathies.

Health Applications

Scientific evidence on the effects of vitamin E supplementation is mixed: it helps maintain cell health and may reduce oxidative stress or inflammation in certain contexts. Some studies show benefits for eye health or venous thromboembolism risk reduction. Large trials often find no significant prevention of heart disease, cancer, or overall mortality in healthy people.

Cardiovascular and Mortality Risks

on vitamin E supplementation and (CVD) has largely failed to demonstrate protective effects, with several large randomized controlled trials showing no reduction in major cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) trial, involving over 9,000 high-risk patients, found that daily supplementation with 400 IU of natural-source vitamin E for a median of 4.5 years had no significant impact on the composite outcome of , , or cardiovascular death compared to . The extension of this study, HOPE-TOO, followed participants for an additional 2.5 years and similarly reported no benefits for cancer or major cardiovascular events, though it noted a modest increase in the risk of (relative risk [RR] 1.13, 95% [CI] 1.01-1.26) and related hospitalizations among those receiving vitamin E. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which included over 35,000 men and assessed 400 IU/day of vitamin E as a secondary endpoint, also showed no reduction in major cardiovascular events after approximately 5.5 years of follow-up. Regarding overall mortality, a 2005 of 19 randomized trials involving 135,967 participants indicated that high-dosage vitamin E supplementation (≥400 IU/day) was associated with a small but statistically significant increase in all-cause mortality (RR 1.04, 95% CI 1.01-1.06), prompting recommendations to avoid such doses. More recent analyses, including a 2023 of observational and interventional studies, have confirmed no beneficial effect of vitamin E supplementation on , with relative risks for all-cause mortality hovering near 1.0 across various doses and populations, thus providing no evidence for mortality reduction. The initial hypothesis that vitamin E's antioxidant properties could prevent CVD by inhibiting low-density lipoprotein oxidation and atherosclerosis progression has not been supported by clinical outcomes, as multiple trials failed to translate and observational benefits into reduced event rates. At high doses, vitamin E may exhibit pro-oxidant effects, potentially exacerbating and contributing to adverse outcomes like increased risk, as observed and in some human studies. In light of this evidence, the U.S. Food and Drug Administration (FDA) has consistently rejected qualified health claims linking vitamin E supplementation to reduced risk of coronary heart disease or CVD prevention, with denials upheld from initial evaluations in 2000 through subsequent reviews, including a 2009 assessment finding no credible supporting data.

Neurological Disorders

Research on vitamin E's role in neurological disorders has primarily focused on its potential neuroprotective effects against in conditions like , , and cognitive decline, as well as its established therapeutic use in ataxia with vitamin E deficiency (AVED). Clinical trials have yielded mixed results, highlighting benefits in specific contexts while showing limited efficacy in others. In , evidence from a large indicated that high-dose supplementation at 2,000 IU per day slowed functional decline in patients with mild to moderate stages by approximately 19% per year, potentially delaying progression by about 6 months. However, subsequent analyses and updates from authoritative sources confirm that vitamin E does not prevent the onset of , with other studies failing to replicate benefits in broader populations or advanced stages. For , the landmark DATATOP trial, involving early-stage patients, found no significant delay in disability progression with 2,000 IU per day of supplementation over two years, unlike the deprenyl. Nonetheless, preclinical and mechanistic studies suggest potential through transfer protein (), which facilitates vitamin E delivery to and may mitigate dopaminergic neuron loss in models of the disease, though this has not translated to clinical benefits in human trials. Regarding cognitive decline, multiple cohort studies have linked low dietary vitamin E intake to an increased risk of incident , with participants in the lowest intake quartiles showing up to a 2-3 times higher compared to those with adequate levels, independent of other antioxidants. In contrast, supplementation trials in healthy elderly individuals have generally been neutral, showing no consistent prevention of age-related or progression, possibly due to sufficient baseline levels in many participants. Vitamin E supplementation is highly effective for treating AVED, a rare genetic disorder caused by mutations in the α-TTP leading to severe neurological symptoms including and neuropathy. High doses of 800 mg per day have been shown to stabilize or reverse early symptoms, prevent further progression, and normalize serum levels when initiated promptly, underscoring the vitamin's critical role in maintaining neuronal integrity beyond its antioxidant properties.

Eye Health

Vitamin E has been investigated for its potential role in preventing age-related (), a leading cause of vision loss in older adults. The Age-Related Eye Disease Study (AREDS), a multicenter conducted from 1992 to 1998, evaluated high-dose supplements including 400 IU of vitamin E combined with , beta-carotene, and in participants with intermediate AMD or advanced AMD in one eye. The results showed that this combination reduced the risk of progression to advanced AMD by approximately 25% over five years, with benefits primarily attributed to the synergistic effects of the antioxidants and minerals rather than vitamin E alone. The follow-up Age-Related Eye Disease Study 2 (AREDS2), initiated in 2006 and reporting primary results in 2013, tested modifications to the original formula, including replacing beta-carotene with and while maintaining 400 IU of vitamin E. This updated formulation confirmed a similar 25% risk reduction for progression to advanced in high-risk individuals, with no additional benefit from vitamin E supplementation in isolation and no evidence of harm from the vitamin E component. Regarding cataracts, epidemiological evidence from the Eye Study, a population-based cohort initiated in the early 1990s, linked lower dietary intake of antioxidants, including vitamin E, to an increased incidence of nuclear cataracts over a five-year follow-up period among adults aged 43-84 years. Participants with higher vitamin E consumption from food sources exhibited a reduced of cataract development, suggesting a protective association. A subsequent analysis from the same study indicated that long-term use of vitamin supplements, including those containing vitamin E, was associated with a lower incidence of s compared to non-users. Recent meta-analyses support a modest preventive effect of vitamin E against s. A 2024 analyzing data from over 200,000 participants found that higher dietary intakes of vitamin E were inversely associated with risk, with an of 0.96 (95% CI 0.94-0.99) per 1 mg/day increase, though benefits were more pronounced in combination with other nutrients like vitamins B6 and niacin. These findings align with earlier evidence but emphasize that vitamin E's standalone impact remains limited without complementary antioxidants. The protective mechanisms of vitamin E in eye health primarily involve its role as a lipid-soluble that safeguards retinal from photo-oxidation damage caused by light and . By interrupting chains in photoreceptor membranes and the , vitamin E helps maintain cellular integrity and prevents oxidative injury that contributes to and formation. Emerging research reinforces the value of combination therapies over vitamin E monotherapy for eye conditions. A review of clinical trials highlighted that formulations integrating vitamin E with , , and other micronutrients continue to demonstrate superior outcomes in slowing progression and opacity compared to vitamin E alone, with no new evidence of isolated efficacy from recent interventional studies.

Cancer and Other Diseases

The role of vitamin E in cancer prevention and treatment remains controversial, with large-scale clinical trials yielding mixed and often null or adverse results. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a randomized controlled trial involving 29,133 male smokers supplemented with 50 mg/day of alpha-tocopherol for 5-8 years, subsequent analyses confirmed no statistically significant benefit overall for lung cancer (relative risk 0.98; 95% CI 0.86-1.12). Later interpretations retracted any broad claims of lung cancer prevention in smokers due to the lack of overall efficacy and subgroup variability. In contrast, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which followed 35,533 healthy men taking 400 IU/day of alpha-tocopherol for an average of 5.5 years, found no preventive effect on prostate cancer and, upon extended follow-up, reported a 17% increased risk (relative risk 1.17; 99% CI 1.004-1.36). Recent reviews, including those published in 2025, emphasize that high-dose vitamin E supplementation does not support general cancer prevention and may elevate risks for specific cancers like prostate in healthy populations. Beyond cancer, vitamin E has shown promise in managing non-alcoholic fatty liver disease (NAFLD), particularly through its effects. Clinical trials from 2023, building on earlier evidence, demonstrated that 800 IU/day of vitamin E supplementation for 24-96 weeks improved liver , including reductions in and lobular , in non-diabetic patients with biopsy-proven non-alcoholic steatohepatitis (), a severe form of NAFLD. These benefits were attributed to vitamin E's ability to mitigate and hepatic without significant adverse effects in this subgroup, though improvements in were inconsistent. In the context of exercise recovery, a 2024 of randomized controlled trials indicated that vitamin E supplementation (doses ranging from 300-1,000 IU/day) reduces post-exercise markers of muscle damage, such as levels, by inhibiting in . This effect was more pronounced in athletes undergoing eccentric exercise, supporting its role in attenuating and soreness, though it did not consistently enhance overall or strength recovery. For pregnancy-related conditions, vitamin E in combination therapies has demonstrated preventive potential against , a hypertensive disorder. A 2010 randomized trial in women with found that combined supplementation with 750 mg/day and 400 IU/day vitamin E from 9 weeks gestation reduced incidence by 65% compared to (4% vs. 22%; 0.35; 95% CI 0.17-0.70), likely due to synergistic protection against . However, solo vitamin E supplementation shows no independent benefit for prevention in general pregnant populations, as confirmed by multiple trials and guidelines. Tocotrienols, lesser-known forms of vitamin E, may inhibit cancer cell growth by disrupting of oncogenic proteins like Ras, though clinical evidence remains preliminary.

Emerging Uses

Recent research has explored the potential of , a primary form of vitamin E, in preventing allergies through maternal supplementation during pregnancy. A 2025 study from the using a model demonstrated that administering to pregnant and nursing females significantly reduced the development of allergies and in their offspring by modulating neonatal immune responses and increasing plasma levels in neonates. This effect was linked to decreased allergic sensitization to common allergens like , with implications for human applications pending further clinical validation. In metabolic health, low serum levels of vitamin E have been associated with heightened in obesity-related conditions. A 2025 population-based study found an inverse relationship between vitamin E concentrations and inflammatory biomarkers such as in overweight and obese adults, suggesting that exacerbates low-grade characteristic of . Supplementation with vitamin E has shown promise in improving insulin sensitivity. Emerging evidence highlights the role of , unsaturated forms of vitamin E, in supporting reproductive health, particularly sperm quality and epididymal function. A 2024 study in obesity-induced male rats revealed that tocotrienol supplementation improved , reduced abnormal counts, and preserved testicular tissue integrity, including enhanced epididymal architecture against oxidative damage. This protective mechanism is attributed to tocotrienols' potent properties, which mitigate in reproductive tissues, though human trials are needed to confirm these benefits. For healthy aging, vitamin E may contribute to lifespan extension by safeguarding mitochondrial function. A 2023 review synthesized evidence showing that protects mitochondria from age-related oxidative damage, preserving bioenergetic efficiency and reducing in various tissues. Preliminary human data from a 2025 trial on tocotrienol supplementation in older adults reported improvements in quality-of-life metrics over six months, potentially linked to enhanced mitochondrial protection, though direct lifespan effects remain unproven in humans. Combinations of vitamins C and E as antioxidant supplements provide synergistic protection against oxidative stress, with vitamin C regenerating oxidized vitamin E to enhance overall antioxidant capacity. However, high-dose combinations lack evidence for preventing chronic diseases and may interfere with certain medical treatments, such as chemotherapy.

Skin Health

Topical application of vitamin E is generally more effective than oral supplementation for improving skin glow, as it delivers direct moisturizing effects, antioxidant protection at the skin surface, and support to the skin barrier function, resulting in enhanced hydration and radiance. Oral vitamin E provides systemic antioxidant benefits but exhibits limited evidence for significant improvements in skin appearance or glow in healthy individuals without a deficiency. The evidence for benefits from both routes remains mixed, and topical vitamin E can cause irritation or allergic contact dermatitis in some individuals.

Historical Development

Discovery and Isolation

In 1922, researchers Herbert McLean Evans and Katharine Scott Bishop at the , identified a previously unrecognized dietary factor essential for reproduction in rats. While studying the effects of controlled diets on female rats, they observed that pregnant animals fed a diet deficient in certain fats experienced , leading to unsuccessful pregnancies, whereas supplementation with or prevented this condition. They termed this unknown substance "" and demonstrated its fat-soluble nature, distinguishing it from previously known vitamins. By 1936, Evans and his collaborators, including Oliver H. Emerson and Erhard Fernholz, succeeded in isolating the active compound from , naming it . This pale yellow, viscous alcohol was purified through molecular distillation and vacuum processes, yielding a substance that cured in deficient rats when administered in microgram quantities. The name "tocopherol" derives from the Greek words "tokos" () and "pherein" (to bear), reflecting its role in supporting , with the "α" prefix indicating its highest biological potency among related compounds isolated at the time. In 1938, Swiss chemist Paul Karrer and his team at the achieved the first of , confirming its structure as a substituted chromanol with a phytyl side chain. This synthesis involved trimethylhydroquinone with isophytol under acidic conditions, producing a compound identical in properties and activity to the natural isolate. Although Karrer had received the in 1937 for his work on and vitamins A and B2, his vitamin E synthesis was not part of that recognition. Early measurement of vitamin E activity relied on bioassays using the fetal resorption-gestation test established by Evans and . In this method, female s were depleted of the factor through a deficient diet until signs of reproductive failure appeared, then dosed with test substances; the minimum effective dose to prevent resorption in at least 80% of litters defined biological potency, allowing quantification of equivalents in extracts.

Research Milestones

In the , researchers identified as distinct isomers of vitamin E, expanding the understanding of its chemical family beyond tocopherols; these unsaturated compounds were first isolated from natural sources like and rice bran, with key structural elucidation occurring around 1964. Concurrently, experimental studies solidified vitamin E's role as a potent lipid-soluble , demonstrating its ability to inhibit free radical chain reactions in cellular membranes and prevent oxidative damage in animal models. The 1990s marked a surge in clinical interest, driven by large-scale trials that initially fueled optimism about vitamin E's cardioprotective potential. The Cambridge Heart Antioxidant Study (CHAOS), published in 1996, reported that high-dose supplementation reduced nonfatal myocardial infarctions in patients with coronary disease, sparking widespread enthusiasm for its use in cardiovascular prevention. Similarly, the GISSI-Prevenzione trial in 1999 suggested benefits from combined n-3 fatty acids and vitamin E in post-myocardial infarction patients, further amplifying hype around antioxidant therapies despite mixed results on vitamin E alone. A pivotal molecular advance came in 1997 with the of the transfer protein () gene, which encodes the protein responsible for vitamin E transport and , linking genetic defects to disorders like ataxia with vitamin E deficiency (AVED). By the 2000s, enthusiasm waned as several major randomized controlled trials revealed no overall benefits—or even potential harms—from high-dose vitamin E supplementation. The Heart Outcomes Prevention Evaluation (HOPE) study in 2000, involving over 9,000 high-risk participants, found no reduction in cardiovascular events with 400 IU daily , challenging prior positive findings. Subsequent trials, such as the Women's Health Study (2005) and SELECT (2008), reinforced this backlash by showing neutral or adverse effects on mortality and cancer incidence, prompting reevaluation of broad supplementation recommendations. Amid this shift, research pivoted toward , highlighting their unique bioactivities; studies demonstrated superior neuroprotective and anticancer properties compared to tocopherols, with δ- and γ-tocotrienols showing potent inhibition of tumor growth and synthesis in preclinical models. Entering the 2020s, precision medicine approaches have transformed vitamin E research, emphasizing individualized applications. Advances in for AVED, including next-generation sequencing of the TTPA gene, have enabled earlier diagnosis and high-dose supplementation to halt neurological progression, as detailed in the GeneReviews article updated in 2023. Emerging studies on allergies, particularly from 2023 to 2025, have explored α-tocopherol's role in preventing food allergies; maternal supplementation in animal models reduced risk in offspring by modulating immune responses, suggesting potential preventive strategies for at-risk populations. Parallel efforts address market sustainability, with research promoting plant-based production of natural vitamin E to reduce reliance on resource-intensive crop sourcing, aligning with environmental goals and projected market growth for natural sources to USD 2.27 billion by 2035.

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