Forms
Vitamin E exists in eight different forms, four tocopherols and fourα-Tocopherol
α-Tocopherol is the form of vitamin E that is preferentially absorbed and accumulated in humans. The measurement of "vitamin E" activity inTocotrienols
Function and dietary recommendations
Mechanism of action
Tocopherols are radical scavengers, delivering an H atom to quench free radicals. At 323 kJ/mol, the O-H bond in tocopherols is approximately 10% weaker than in most other phenols. 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 relatively unreactive, but reverts to tocopherol by aDietary considerations
The U.S. Recommended Dietary Allowance (RDA) for adults is 15 mg/day. The RDA is based on the α-tocopherol form because it is the most active form as originally tested. Vitamin E supplements are absorbed best when taken with meals. The U.S. Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) per day. The European Food Safety Authority sets UL at 300 mg α-tocopherol equivalents /day.α-Tocopherol equivalents
For dietary purposes, vitamin E activity of vitamin ESources
The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015. In general, food sources with the highest concentrations of vitamin E are vegetable oils, followed by nuts andDeficiency
Vitamin E deficiency is rare, and in almost all instances caused by an underlying disease rather than a diet low in vitamin E. Vitamin E deficiency causes neurological problems due to poor nerve conduction. These include neuromuscular problems such as spinocerebellar ataxia and myopathies. Deficiency also may cause anemia, due to oxidative damage to red blood cells.Supplements
Commercial vitamin E supplements may be classified into several distinct categories: * Fully synthetic vitamin E, "dl-α-tocopherol", the most inexpensive, most commonly sold supplement form usually as the acetate ester * Semi-synthetic "natural source" vitamin E esters, the "natural source" forms used in tablets and multiple vitamins; these are highly fractionated d-α-tocopherol or its esters, often made by synthetic methylation of gamma and beta vitamers extracted from plant oils. * Less fractionated "natural mixed tocopherols" and high d-γ-tocopherol fraction supplementsSynthetic all-racemic
Synthetic vitamin E derived from petroleum products is manufactured as all- racemic α-tocopheryl acetate with a mixture of eight stereoisomers. In this mixture, one α-tocopherol molecule in eight molecules are in the form of ''RRR''-α-tocopherol (12.5% of the total). The 8-isomer ''all-rac'' vitamin E is always marked on labels simply as dl-tocopherol or dl-tocopheryl acetate, even though it is (if fully written out) . The present largest manufacturers of this type are DSM and BASF. Natural α-tocopherol is the RRR-α (or ddd-α) form. The synthetic ("dl-α") form is not so active as the natural ddd-α ("d-α") tocopherol form. This is mainly due to reduced vitamin activity of the four possible stereoisomers that are represented by the ''l'' or ''S'' enantiomer at the first stereocenter (an S or l configuration between the chromanol ring and the tail, i.e., the SRR, SRS, SSR, and SSS stereoisomers). The three unnatural "2R" stereoisomers with natural R configuration at this 2' stereocenter, but S at one of the other centers in the tail (i.e., RSR, RRS, RSS), appear to retain substantial RRR vitamin activity, because they are recognized by the alpha-tocopherol transport protein, and thus maintained in the plasma, where the other four stereoisomers (SRR, SRS, SSR, and SSS) are not. Thus, the synthetic all-rac-α-tocopherol, in theory, would have approximately half the vitamin activity of RRR-α-tocopherol in humans. Experimentally, the ratio of activities of the 8 stereoisomer racemic mixture to the natural vitamin, is 1 to 1.36 in the rat pregnancy model (suggesting a measured activity ratio of 1/1.36 = 74% of natural, for the 8-isomer racemic mix). Although it is clear that mixtures of stereoisomers are not so active as the natural ''RRR''-α-tocopherol form, in the ratios discussed above, specific information on any side effects of the seven synthetic vitamin E stereoisomers is not readily available.Esters
Manufacturers also commonly convert the phenol form of the vitamins (with a free hydroxyl group) toMixed tocopherols
"Mixed tocopherols" in the USA contain at least 20% w/w other natural R, R,R- tocopherols, i.e. R, R,R-α-tocopherol content plus at least 25% R, R,R-β-, R, R,R-γ-, R, R,R-δ-tocopherols. Some brands may contain 20.0% w/w or more of the other tocopherols and measurable tocotrienols. Some mixed tocopherols with higher γ-tocopherol content are marketed as "High Gamma-Tocopherol". The label should report each component in milligrams, except R, R,R-α-tocopherol may still be reported in IU. Mixed tocopherols also may be found in other nutritional supplements.Uses
Observational studies that measure dietary intake and/or serum concentration, and experimental studies that ideally are randomized clinical trials (RCTs), are two means of examining the effects or lack thereof of a proposed intervention on human health. Healthcare outcomes may be expected to be in accord between reviews of observational and experimental studies. If there is a lack of agreement, then factors other than design need to be considered. In observational studies on vitamin E, an inverse correlation between dietary intake and risk of a disease, or serum concentration and risk of a disease, may be considered suggestive, but any conclusions also should rest on randomized clinical trials of sufficient size and duration to measure clinically significant results. One concern with correlations is that other nutrients and non-nutrient compounds (such as polyphenols) may be higher in the same diets that are higher in vitamin E. Another concern for the relevance of RCTs described below is that while observational studies are comparing disease risk between low and high dietary intake of naturally occurring vitamin E from food (when worldwide, the adult median dietary intake is 6.2 mg/d for d-α-tocopherol; 10.2 mg/day when all of the tocopherol and tocotrienol isomers are included), the prospective RCTs often used 400 IU/day of synthetic dl-α-tocopherol as the test product, equivalent to 268 mg of α-tocopherol equivalents.Supplement popularity over time
In the US, the popularity for vitamin E as a dietary supplement may have peaked around 2000. The Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) tracked dietary supplement use by people over the age of 40 during years 1986–2006. For women, user prevalence was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but had decreased to 19.8% in 2006. Similarly, for men, prevalence for same years was 18.9%, 52.0%, 49.4%, and 24.5%. The authors theorized that declining use in these health science aware populations may have due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements. There is other evidence for declining use of vitamin E. Within the U.S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%. A report on vitamin E sales volume in the USA documented a 50% decrease between 2000 and 2006, with a significant cause attributed to a well-publicized meta-analysis that had concluded that high-dosage vitamin E increased all-cause mortality.Age-related macular degeneration
A Cochrane review published in 2017 on antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration (AMD) identified only one vitamin E clinical trial. That trial compared 500 IU/day of α-tocopherol to placebo for four years and reported no effect on the progression of AMD in people already diagnosed with the condition. Another Cochrane review, same year, same authors, reviewed the literature on α-tocopherol preventing the development of AMD. This review identified four trials, duration 4–10 years, and reported no change to risk of developing AMD. A large clinical trial known as AREDS compared β-carotene (15 mg), vitamin C (500 mg), and α-tocopherol (400 IU) to placebo for up to ten years, with a conclusion that the anti-oxidant combination significantly slowed progression. However, because there was no group in the trial receiving only vitamin E, no conclusions could be drawn as to the contribution of the vitamin to the effect.Complementary and alternative medicine
Proponents of megavitamin therapy and orthomolecular medicine advocate ''natural tocopherols.'' Meanwhile, clinical trials have largely concentrated on use of either a synthetic, all-racemic d-α-tocopheryl acetate or synthetic dl-α-tocopheryl acetate.Antioxidant theory
Tocopherol is described as functioning as an antioxidant. A dose-ranging trial was conducted in people with chronic oxidative stress attributed to elevated serum cholesterol. Plasma F2-isoprostane concentration was selected as a biomarker of free radical-mediated lipid peroxidation. Only the two highest doses - 1600 and 3200 IU/day - significantly lowered F2-isoprostane.Alzheimer's disease
Alzheimer's disease (AD) and vascular dementia are common causes of decline of brain functions that occur with age. AD is a chronic neurodegenerative disease that worsens over time. The disease process is associated with plaques and tangles in the brain. Vascular dementia may be caused by ischemic or hemorrhagic infarcts affecting multiple brain areas, including theCancer
From reviews of observational studies, diets higher in vitamin E content were associated with a lower relative risk of kidney cancer, bladder cancer, andCataracts
A meta-analysis from 2015 reported that for studies that reported serum tocopherol, 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 - the three major classifications of age-related cataracts. However, this article and a second meta-analysis reporting on clinical trials of α-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.Cardiovascular diseases
Research on the effects of vitamin E on cardiovascular disease has produced conflicting results. 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 α-tocopherol. In one of the largest observational studies, almost 90,000 healthy nurses were tracked for eight years. Compared to those in the lowest fifth for reported vitamin E consumption (from food and dietary supplements), those in the highest fifth were at a 34% lower risk of major coronary disease. Diet higher in vitamin E also may be higher in other, unidentified components that promote heart health, or people choosing such diets may be making other healthy lifestyle choices. There is some supporting evidence from randomized clinical trials (RCTs). A meta-analysis on the effects of α-tocopherol supplementation in RCTs on aspects of cardiovascular health reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%. The results were not consistent for all of the individual trials incorporated into the meta-analysis. For example, the Physicians' Health Study II did not show any benefit after 400 IU every other day for eight years, for heart attack, stroke, coronary mortality, or all-cause mortality. The effects of vitamin E supplementation on incidence of stroke were summarized in 2011. There were no significant benefits for vitamin E versus placebo for risk of stroke, or for subset analysis for ischaemic stroke, haemorrhagic stroke, fatal stroke, or non-fatal stroke. In 2001 the U.S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health. The U.S. National Institutes of Health also reviewed the literature and concluded there was not sufficient evidence to support the idea that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. In 2010 the European Food Safety Authority 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.Pregnancy
Antioxidant vitamins as dietary supplements have been proposed as having benefits if consumed during pregnancy. For the combination of vitamin E with vitamin C supplemented to pregnant women, a Cochrane review of 21 clinical trials concluded that the data do not support vitamin E supplementation - majority of trials α-tocopherol at 400 IU/day plus vitamin C at 1000 mg/day - as being efficacious for 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. The review identified only three small trials in which vitamin E was supplemented without co-supplementation with vitamin C. None of these trials reported any clinically meaningful information.Topical
Although there is widespread use of vitamin E as a topical medication, with claims for improved wound healing and reducedSide effects
The U.S. Food and Nutrition Board set a Tolerable upper intake level (UL) at 1,000 mg (1,500 IU) per day derived from animal models that demonstrated bleeding at high doses. The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day. A meta-analysis of long-term clinical trials reported a non-significant 2% increase in all-cause mortality when α-tocopherol was the only supplement used. Another meta-analysis reported a non-significant 1% increase in all-cause mortality when α-tocopherol was the only supplement. Subset analysis reported no difference between natural (plant extracted) or synthetic α-tocopherol, or whether the amount used was less than or more than 400 IU/day. There are reports of vitamin E-induced allergic contact dermatitis from use of vitamin-E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products. Incidence is low despite widespread use.Drug interactions
The amounts of α-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 α-tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with aspirin, warfarin, tamoxifen, andSynthesis
Naturally sourced d-α-tocopherol can be extracted and purified from seed oils, or γ-tocopherol can be extracted, purified, and methylated to create d-alpha-tocopherol. In contrast to α-tocopherol extracted from plants, which also is called d-α-tocopherol, industrial synthesis creates dl-α-tocopherol. "It is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-α-tocopherol, using iron in the presence of hydrogen chloride gas as a catalyst. The reaction mixture obtained is filtered and extracted with aqueous caustic soda. Toluene is removed by evaporation and the residue (all rac-α-tocopherol) is purified by vacuum distillation." Specification for the ingredient is >97% pure. This synthetic dl-α-tocopherol has approximately 50% of the potency of d-α-tocopherol. Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to anHistory
During feeding experiments with rats Herbert McLean Evans concluded in 1922 that besides vitamins B and C, an unknown vitamin existed. Although every other nutrition was present, the rats were not fertile. This condition could be changed by additional feeding with wheat germ. It took several years until 1936 when the substance was isolated from wheat germ and the formula C29H50O2 was determined. Evans also found that the compound reacted like an alcohol and concluded that one of the oxygen atoms was part of an OH (hydroxyl) group. As noted in the introduction, the vitamin was given its name by Evans from Greek words meaning "to bear young" with the addition of the -ol as an alcohol. The structure was determined shortly thereafter in 1938.See also
*References
External links