The α-tocopherol form of vitamin E
|Use||Vitamin E deficiency, antioxidant|
|Biological target||Reactive oxygen species|
|Drugs.com||MedFacts Natural Products|
Vitamin E refers to a group of compounds that include both tocopherols and tocotrienols. Of the many different forms of vitamin E, γ-tocopherol is the most common form found in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine, and dressings. α-tocopherol, the most biologically active form of vitamin E, is the second-most common form of vitamin E in the diet. This variant can be found most abundantly in wheat germ oil, sunflower, and safflower oils. As a fat-soluble antioxidant, it interrupts the propagation of reactive oxygen species that spread through biological membranes or through a fat when its lipid content undergoes oxidation by reacting with more-reactive lipid radicals to form more stable products. U.S. and European Union recommendations are to consume, respectively, 15 mg/day or 11 mg/day (female) and 13 mg/day (male).
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. Vitamin E is sold as a dietary supplement, either by itself or incorporated into a multi-vitamin product. It is also sold in topical products, although evidence for any benefits is questionable.
- As an antioxidant, vitamin E acts as a peroxyl radical scavenger, disabling the production of damaging free radicals in tissues, by reacting with them to form a tocopheryl radical, which will then be reduced by a hydrogen donor (such as vitamin C) and thus return to its reduced state. As it is fat-soluble, it is incorporated into cell membranes, which protects them from oxidative damage.
- Vitamin E has also found use as a commercial antioxidant and biocompatible modifier of biomaterials and medical devices, for example in ultra high molecular weight polyethylene (UHMWPE) used in hip and knee implants by resisting oxidation  and in hollow-fiber membrane cartridges used in extracorporeal hemodialysis therapy.
- As an enzymatic activity regulator, for instance, protein kinase C (PKC), which plays a role in smooth muscle growth, can be inhibited by α-tocopherol. α-Tocopherol has a stimulatory effect on the dephosphorylation enzyme, protein phosphatase 2A, which in turn, cleaves phosphate groups from PKC, leading to its deactivation, bringing the smooth muscle growth to a halt.
- Vitamin E also has an effect on gene expression. Macrophages rich in cholesterol are found in atherosclerotic tissue. Scavenger receptor CD36 is a class B scavenger receptor found to be up-regulated by oxidized low density lipoprotein (LDL) and binds it. Treatment with α-tocopherol was found to downregulate the expression of the CD36 scavenger receptor gene and the scavenger receptor class A (SR-A) and modulates expression of the connective tissue growth factor (CTGF). The CTGF gene, when expressed, is responsible for the repair of wounds and regeneration of the extracellular tissue lost or damaged during atherosclerosis.
- Vitamin E also plays a role in eye and neurological functions, and inhibition of platelet coagulation.
- Vitamin E also protects lipids and prevents the oxidation of polyunsaturated fatty acids.
Although most vitamin E supplementation studies used α-tocopherol individually, this design of studying only one isoform of vitamin E may introduce errors in interpreting overall vitamin E effects; for example, using only α-tocopherol in studies of inflammation can reduce serum γ- and δ-tocopherol concentrations. Moreover, a 2013 review involving single long-term supplementation with α-tocopherol showed that many clinical studies revealed an inverse relationship between supplementation and cardiovascular disease risk or mortality, but other studies showed no effect.
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. It can cause nerve problems due to poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function. Vitamin E deficiency can cause: peripheral neuropathy, myopathies, ataxia, retinopathy, impairment of immune responses and red blood cell destruction.
Vitamin E supplementation has not been shown to have significant benefit for people who are healthy, and appears to be harmful. It does not improve blood sugar control in an unselected group of people with diabetes mellitus or decrease the risk of stroke. Daily supplementation of vitamin E does not decrease the risk of prostate cancer, and may increase it. Studies on its role in age-related macular degeneration are ongoing, though if it is of a combination of dietary antioxidants used to treat the condition it may increase the risk. Routine supplementation with vitamin E during pregnancy has been shown to offer no benefit to the mother or the child. Vitamin E has been reported to cause more side effects, such as abdominal pain in pregnant women, and also the increased risk of having early rupture of membranes at term. Supplementary Vitamin E, along with β-carotene and vitamin C, has shown no protective effect on reducing the risk of cataract, cataract extraction, progression of cataract, and slowing the loss of visual acuity. A meta-analysis showed no association between vitamin E supplementation and cardiovascular mortality. A 2015 systematic review found that it may improve endothelial function as determined by measurements of forearm blood flow, but when combined with vitamin C supplementation, it did not.
Although there is widespread use of vitamin E as a topical medication, with claims for improved wound healing and reduced scar tissue, reviews have repeatedly concluded that there is insufficient evidence to support these claims.
The US Food and Nutrition Board has set a Tolerable upper intake level (UL) at 1,000 mg (1,500 IU) per day. The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day. Vitamin E can act as an anticoagulant, increasing the risk of bleeding, specifically acting synergistically with the blood-thinner, warfarin, which acts as a vitamin K antagonist. From a 1982 review, vitamin E was reported as not having an anti-coagulation effect in humans who were vitamin K status sufficient.
Although functioning as an antioxidant when consumed in amounts available from foods, in high doses possible with dietary supplement products, vitamin E can have prooxidant properties, possibly causing oxidation which may damage cells and increase the risk of cancer. Supplementation with vitamin E is not indicated during treatment with chemotherapy or radiotherapy. Long-term use of high doses may cause nausea, diarrhea and blurred vision. The US National Institutes of Health, Office of Dietary Supplements, summarizes the research on health risks from excessive vitamin E.
|US vitamin E recommendations (mg per day)|
|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|
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin E in 2000. The current EAR for vitamin E for women and men ages 14 and up is 12 mg/day. The RDA is 15 mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. For infants up to 12 months the Adequate Intake (AI) is 4–5 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. Hemorrhagic effects in rats were selected as the critical endpoint to calculate the UL via starting with the lowest-observed-adverse-effect-level (LOAEL) and processing that through an uncertainty factor calculation. The end result was the UL set at 1000 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).
The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in 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. These PRIs are lower than the U.S. RDAs. The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day. The EU used an effect on blood clotting as a critical effect, identified that no adverse effects were observed in a human trial as 540 mg/day, used an uncertainty factor of 2 to get to a suggest UL of 270 mg/day, then rounded up to 300 mg/day.
The Japan National Institute of Health and Nutrition set lower AIs than the US RDAs or EU PRIs, and intermediate ULs: 6.5 mg/day (females) and 7.0 mg/day (males) for adult AIs, and 650-700 mg/day (females) and 750-900 mg/day (males) for adult ULs, amount depending on age. India recommends an intake of 8-10 mg/day and does not set a UL. The World Health Organization recommends that adults consume 10 mg/day.
Consumption is below government recommendations. A worldwide summary of more than one hundred studies reported a median dietary intake of 6.2 mg/d for alpha-tocopherol. Government survey results in the US reported average consumption for adult females at 8.4 mg/d and adult males 10.4 mg/d, below the RDA of 15 mg/day.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin E labeling purposes 100% of the Daily Value was 30 IU, but as of May 27, 2016 it was revised to 15 mg to bring it into agreement with the RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017 the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies. 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.
(mg / 100g)
|Wheat germ oil||150|
|Sunflower seed kernels||26.1|
(mg / 100g)
(mg / 100g)
(mg / 100g)
Vitamin E is fat soluble, so dietary supplement products are usually in the form of the vitamin dissolved in vegetable oil in a softgel capsule. 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 available from a few dietary supplement companies.
The World Health Organization does not have any recommendations for food fortification with vitamin E. The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E. There are breakfast cereals fortified with minerals and vitamins, including vitamin E.
The nutritional content of vitamin E is defined by α-tocopherol activity. The molecules that contribute α-tocopherol activity are four tocopherols and four tocotrienols, identified by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-). Natural tocopherols occur in the RRR-configuration only. The synthetic form contains eight different stereoisomers and is called 'all-rac'-α-tocopherol.
alpha-Tocopherol is a lipid-soluble antioxidant functioning within the glutathione peroxidase pathway, and protecting cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction. 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. Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.
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, R2 = H, R3= Methyl. For gamma(γ)-tocotrienol: R1 = H, R2 = Methyl, R3= Methyl. For delta(δ)-tocotrienol: R1 = H, R2 = H, R3= Methyl. Palm oil is a source. Preliminary clinical trials on dietary supplement tocotrienols indicate potential for anti-disease activity.
Testing for levels
Cystic fibrosis and other fat malabsorption conditions can result in low serum vitamin E. Dietary supplements will raise serum vitamin E. A worldwide summary of more than one hundred studies reported a median of 22.1 µmol/L for serum α-tocopherol (2.2 µmol/L for serum γ-tocopherol), defined deficiency as less than 12 µmol/L, and cited a recommendation that serum α-tocopherol concentration be ≥30 µmol/L to optimize health benefits. Serum concentration increases with age. This is attributed to fact that vitamin E circulates in blood incorporated into lipoproteins, and serum lipoprotein concentrations increase with age. Infants and young children have a higher risk of being below the deficiency threshold.
Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop and first isolated in a pure form by Evans and Gladys Anderson Emerson in 1935 at the University of California, Berkeley. 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. George M. Calhoun, Professor of Greek as the University of California, was credited with helping with the naming process. Erhard Fernholz elucidated its structure in 1938 and shortly afterwards the same year, Paul Karrer and his team first synthesized it.
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.
A role for vitamin E in coronary heart disease had first been proposed in 1946. More cardiovascular work from the same research group followed, including a proposal that megadoses of vitamin E could slow down and even reverse the development of atherosclerosis. However, a 2004 meta-analysis showed no association between vitamin E supplementation and cardiovascular events (nonfatal stroke or myocardial infarction) or cardiovascular mortality. There is a long history of belief that topical application of vitamin E containing oil benefits burn and wound healing. This belief persists even though scientific reviews repeatedly refuted this claim.
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. A 2003 Cochrane review concluded that vitamin E supplementation in preterm infants reduced the risk of intercranial hemorrhage and retinopathy, but noted an increased risk of sepsis.
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