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Vitamin E refers to a group of compounds that include both tocopherols and tocotrienols.[1][2] Of the many different forms of vitamin E, γ-tocopherol is the most common form found in the North American diet.[3] γ-Tocopherol can be found in corn oil, soybean oil, margarine, and dressings.[3][4] 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.[3][5] 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.[3][6][1] Regular consumption of more than 1,000 mg (1,500 IU) of tocopherols per day[1] may be expected to cause hypervitaminosis E, with an associated risk of vitamin K deficiency and consequently of bleeding problems.

Vitamin E
Drug class
Tocopherol, alpha-.svg
The α-tocopherol form of vitamin E
Class identifiers
Use Vitamin E deficiency, antioxidant
ATC code A11H
Biological target Reactive oxygen species
Clinical data
Drugs.com MedFacts Natural Products
External links
MeSH D014810
In Wikidata

Contents

FunctionsEdit

Vitamin E has many biological functions, including its role as a fat-soluble antioxidant.[1][7]

  • 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.[8] 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 [9] and in hollow-fiber membrane cartridges used in extracorporeal hemodialysis therapy.[10]
  • 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.[11]
  • Vitamin E also has an effect on gene expression. Macrophages rich in cholesterol are found in atherosclerotic tissue.[12] Scavenger receptor CD36 is a class B scavenger receptor found to be up-regulated by oxidized low density lipoprotein (LDL) and binds it.[13] Treatment with α-tocopherol was found to downregulate the expression of the CD36 scavenger receptor gene and the scavenger receptor class A (SR-A)[13] and modulates expression of the connective tissue growth factor (CTGF).[14][15] The CTGF gene, when expressed, is responsible for the repair of wounds and regeneration of the extracellular tissue lost or damaged during atherosclerosis.[15]
  • Vitamin E also plays a role in eye and neurological functions,[1][16] and inhibition of platelet coagulation.[17][18][19]
  • Vitamin E also protects lipids and prevents the oxidation of polyunsaturated fatty acids.[20]

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.[21] 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.[22]

DeficiencyEdit

Vitamin E deficiency can cause:

Medical usesEdit

SupplementationEdit

Vitamin E supplementation has not been shown to have significant benefit for people who are healthy, and appears to be harmful.[27][28] It does not improve blood sugar control in an unselected group of people with diabetes mellitus[29] or decrease the risk of stroke.[30] Daily supplementation of vitamin E does not decrease the risk of prostate cancer, and may increase it.[1][31] 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.[32] 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.[33]

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.[34]

A meta-analysis showed no association between vitamin E supplementation and cardiovascular mortality.[35] 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.[36]

Topical usesEdit

Although there is widespread use of vitamin E as a topical medication, with claims for improved wound healing and reduced scar tissue, a 2015 review concluded that there is insufficient evidence to support these claims.[37]

ToxicityEdit

The LD50, or the toxic dose required to kill 50% of experimental rats or mice, is 4000 mg of vitamin E per kg.[38] Vitamin E can act as an anticoagulant, increasing the risk of bleeding, specifically acting synergistically with the blood-thinner, warfarin.[1][39] As a result, the U.S. Food and Nutrition Board has set a tolerable upper intake levels (UL) at 1,000 mg (1,500 IU) per day.[1][40] Hypervitaminosis E may also counteract vitamin K, leading to a vitamin K deficiency.[citation needed] In high doses, vitamin E has prooxidant properties, possibly causing oxidation which may damage cells and increase the risk of cancer or mortality.[39] Supplementation with vitamin E is not indicated during treatment with chemotherapy or radiotherapy.[1] Long-term use of high doses may cause nausea, diarrhea, or vision deficiencies.[39]

FormsEdit

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-).[41] Natural tocopherols occur in the RRR-configuration only. The synthetic form contains eight different stereoisomers and is called 'all-rac'-α-tocopherol.[42]

α-TocopherolEdit

 
Sample of α-tocopherol, one of the various forms of vitamin E

alpha-Tocopherol is a lipid-soluble antioxidant functioning within the glutathione peroxidase pathway,[43] and protecting cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction.[3][23] 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.[44] Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.[45]

TocotrienolsEdit

 
General chemical structure of tocotrienols. alpha(α)-Tocotrienol: R1 = Me, R2 = Me, R3 = Me; beta(β)-Tocotrienol: R1 = Me, R2 = H, R3= Me; gamma(γ)-Tocotrienol: R1 = H, R2 = Me, R3= Me; delta(δ)-Tocotrienol: R1 = H, R2 = H, R3= Me

Tocotrienols are members of the vitamin E family: four tocotrienols (alpha, beta, gamma, delta) similar in structure to the four tocopherols, with the critical difference is that tocopherols have saturated side chains whereas tocotrienols have unsaturated isoprenoid side chains with three double bonds. Preliminary clinical trials on dietary supplement tocotrienols indicate potential for anti-disease activity.[46] Tocotrienols have lower bioavailability in blood, potential for anticoagulant effects, and appear to be safe and well-tolerated.[46]

Dietary recommendationsEdit

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. RDA for pregnancy is 15 mg/day. RDA for lactation is 19 mg/day. For infants up to 12 months the Adequate Intake (AI) is 4-5 mg/day. For children ages 1–13 years the RDA increases with age from 6 to 11 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of vitamin E the UL is 1000 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[40]

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.[47] The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day.[48]

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 mg, but as of May 27, 2016 it was revised to 15 mg to bring it into agreement with the RDA.[49] 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.[50]

SourcesEdit

mg/(100 g)
[note 1]
Some foods with vitamin E content[3][1][51]
low high
150 Wheat germ oil
95 Almond oil
44 Canola/rapeseed oil
41 Sunflower oil
34 Safflower oil
26 Almonds
19 Wheat germ
15 Hazelnuts
14 Olive oil
8.33 Peanut
1.5 3.4 High-value green, leafy vegetables: spinach, turnip, beet greens, collard greens, and dandelion greens[note 2]
2.32 Butter
2 Avocados
1.8 Cocoa butter
1.4 Sesame oil
1.1 1.5 Asparagus[note 3]
1.5 Kiwifruit (green)
0.90 Cashew nuts
0.78 1.5 Broccoli[note 4]
0.8 1 Pumpkin[note 5]
0.26 0.94 Sweet potato[note 6]
0.9 Mangoes
0.7 Walnuts
0.54 0.56 Tomatoes[note 7]
0.13 0.22 Low-value green, leafy vegetables: lettuce[note 8]

HistoryEdit

Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop[52] and first isolated in a pure form by Gladys Anderson Emerson in 1935 at the University of California, Berkeley.[53] Erhard Fernholz elucidated its structure in 1938 and shortly afterwards the same year, Paul Karrer and his team first synthesized it.[54]

The first use for vitamin E as a therapeutic agent was conducted in 1938 by Widenbauer, who used wheat germ oil supplement on 17 premature newborn infants suffering from growth failure. Eleven of the original 17 patients recovered and were able to resume normal growth rates.[55]

In 1945, Drs. Evan V. Shute and Wilfred E. Shute, siblings from Ontario, Canada, published the first monograph arguing that megadoses of vitamin E can slow down and even reverse the development of atherosclerosis.[56] Peer-reviewed publications soon followed.[57][58] The same research team also demonstrated, in 1946, that α-tocopherol improved impaired capillary permeability and low platelet counts in experimental and clinical thrombocytopenic purpura.[59]

Later, in 1948, while conducting experiments on alloxan effects on rats, Gyorge and Rose noted rats receiving tocopherol supplements suffered from less hemolysis than those that did not receive tocopherol.[60] In 1949, Gerloczy administered all-rac-α-tocopheryl acetate to prevent and cure edema.[61][62] Methods of administration used were both oral, that showed positive response, and intramuscular, which did not show a response.[55] This early investigative work on the benefits of vitamin E supplementation was the gateway to curing the vitamin E deficiency-caused hemolytic anemia described during the 1960s. Since then, supplementation of infant formulas with vitamin E has eradicated this vitamin’s deficiency as a cause for hemolytic anemia.[55]

NotesEdit

  1. ^ "USDA Nutrient Data Laboratory".  In notes 2–11, USDA NDL Release 24 numbers are given as mg/(100 g). Low and high values vary some by raw versus cooked and by variety.
  2. ^ Spinach (2.0 raw, 2.1 cooked), turnip (2.9 raw, 1.9 cooked), beet (1.5 raw, 1.8 cooked), collard (2.3 raw, 0.88 cooked), and dandelion greens (3.4 raw, 2.4 cooked)
  3. ^ 1.1 raw, 1.5 cooked
  4. ^ 0.78 raw, 1.5 cooked
  5. ^ 1. raw, 0.8 cooked
  6. ^ 0.26 raw, 0.94 boiled
  7. ^ 0.54 raw, 0.56 cooked
  8. ^ Lettuce (0.18 iceberg, 0.22 green leaf, 0.13 romaine, 0.15 red leaf, 0.18 butterhead)

ReferencesEdit

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External linksEdit