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{{Short description|Class of 8 chemically related vitamins}} {{Good article}} {{Use American English|date=February 2024}} {{Use dmy dates|date=December 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug class | Image = Alpha-Tocopherol Structural Formulae V.1.svg | ImageClass = skin-invert-image | Alt = | Caption = The RRR alpha-tocopherol form of vitamin E | Use = [[Vitamin E deficiency]], [[antioxidant]] | Biological_target = [[Reactive oxygen species]] | ATC_prefix = A11HA03 | MeshID = D014810 | Drugs.com = {{Drugs.com|npp|vitamin-e}} | Consumer_Reports = | medicinenet = | rxlist = }} '''Vitamin E''' is a group of eight compounds related in molecular structure that includes four [[tocopherol]]s and four [[tocotrienol]]s. The tocopherols function as [[fat-soluble]] [[antioxidant]]s which may help protect cell membranes from [[reactive oxygen species]]. Vitamin E is classified as an [[essential nutrient]] for humans.<ref name=GOVe /><ref name=PKIN2020VitE>{{cite book |vauthors=Traber MG, Bruno RS |title = Present knowledge in nutrition, eleventh edition |chapter = Vitamin E | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 115–36 |isbn=978-0-323-66162-1}}</ref><ref name="lpi">{{cite web |title=Vitamin E |url=https://lpi.oregonstate.edu/mic/vitamins/vitamin-E |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University |access-date=3 August 2019 |date=October 2015 |archive-date=8 April 2015 |archive-url=https://web.archive.org/web/20150408104152/http://lpi.oregonstate.edu/infocenter/vitamins/vitaminE/ |url-status=live }}</ref> 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.<ref name=Peter2016 /> Sources rich in vitamin E include seeds, nuts, [[vegetable oil|seed oils]], [[Peanut butter#Nutritional profile|peanut butter]], [[food fortification|vitamin E–fortified foods]], and dietary supplements.<ref name=lpi/><ref name=GOVe/> 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.<ref name="DRItext" /> Deficiency can cause [[neurological disorder]]s.<ref name=GOVe>{{cite web|url=https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/|title=Vitamin E Fact Sheet for Health Professionals|publisher=Office of Dietary Supplements, U.S. National Institutes of Health|date=12 July 2019|access-date=20 October 2024|archive-date=5 August 2010|archive-url=https://web.archive.org/web/20100805084145/http://ods.od.nih.gov/factsheets/vitamine.asp|url-status=live}}</ref> 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.<ref name=GOVe /><ref name=Brigelius1999 /> All eight of these [[vitamer]]s feature a [[chromane]] double ring, with a [[Hydroxy group|hydroxyl group]] that can donate a hydrogen atom to reduce [[Radical (chemistry)|free radicals]], and a [[Hydrophobe|hydrophobic]] side chain that allows for penetration into biological membranes. Both natural and synthetic tocopherols are subject to oxidation, so dietary supplements are [[ester]]ified, creating [[tocopheryl acetate]] for stability purposes.<ref name="lpi" /><ref>{{cite book | vauthors = Braunstein MH |date=March 2006 |title=Focus on vitamin E research |publisher=Nova Science Publishers |page=vii |isbn=978-1-59454-971-7 }}</ref> 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 trial]]s using alpha-tocopherol as a supplement, with daily amounts as high as 2,000 mg per day, could not always replicate these findings.<ref name=lpi /> 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<ref name="Kim2014">{{cite journal |vauthors=Kim HJ, Giovannucci E, Rosner B, Willett WC, Cho E |date=March 2014 |title=Longitudinal and secular trends in dietary supplement use: Nurses' Health Study and Health Professionals Follow-Up Study, 1986–2006 |journal=Journal of the Academy of Nutrition and Dietetics |volume=114 |issue=3 |pages=436–43 |doi=10.1016/j.jand.2013.07.039 |pmc=3944223 |pmid=24119503}}</ref><ref name=Abner2011/><ref name=Curtis2014/> or actual negative consequences from high-dose vitamin E.<ref name="Kim2014" /><ref name="Tilburt2008">{{cite journal |vauthors=Tilburt JC, Emanuel EJ, Miller FG |date=September 2008 |title=Does the evidence make a difference in consumer behavior? Sales of supplements before and after publication of negative research results |journal=Journal of General Internal Medicine |volume=23 |issue=9 |pages=1495–8 |doi=10.1007/s11606-008-0704-z |pmc=2518024 |pmid=18618194}}</ref><ref name=Bjelakovic2014>{{cite journal | vauthors = Bjelakovic G, Nikolova D, Gluud C | title = Meta-regression analyses, meta-analyses, and trial sequential analyses of the effects of supplementation with beta-carotene, vitamin A, and vitamin E singly or in different combinations on all-cause mortality: do we have evidence for lack of harm? |journal = PLOS ONE| volume = 8 |issue = 9 |pages = e74558 |date = 2013 |pmid = 24040282 |pmc = 3765487 | doi = 10.1371/journal.pone.0074558 | bibcode = 2013PLoSO...874558B | doi-access = free | title-link = doi }}</ref> Vitamin E was discovered in 1922, isolated in 1935, and first synthesized in 1938. Because the vitamin activity was first identified as essential for [[Zygote|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''.<ref name=Evans1936/> 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 == [[File:Tocopherols.svg|350px|right|thumb|class=skin-invert-image|General chemical structure of tocopherols]] [[File:Alpha-Tocopherol Structural Formulae V.1.svg|350px|thumb|class=skin-invert-image|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 (CH<sub>3</sub>) 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.<ref name=Manolescu2008>{{cite journal |vauthors = Manolescu B, Atanasiu V, Cercasov C, Stoian I, Oprea E, Buşu C |title = So many options but one choice: the human body prefers alpha-tocopherol. A matter of stereochemistry |journal = Journal of Medicine and Life |volume = 1 |issue = 4 |pages = 376–82 | date = October–December 2008 |pmid = 20108516 |pmc = 5654212 }}</ref> === Stereoisomers === In addition to distinguishing tocopherols and tocotrienols by position of methyl groups, the tocopherols have a phytyl tail with three [[Chirality|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 ([[Racemic mixture|all-racemic]] or ''all-rac'' vitamin E, also dl-tocopherol) is equal parts of eight [[stereoisomer]]s 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.<ref name=Manolescu2008 /> {| class="wikitable" |- ! Form || Structure |- | [[alpha-Tocopherol|''alpha''-Tocopherol]] || [[File:Tocopherol, alpha-.svg|300px|class=skin-invert-image]] |- | [[beta-Tocopherol|''beta''-Tocopherol]] || [[File:Beta-tocopherol.png|300px|class=skin-invert-image]] |- | [[gamma-Tocopherol|''gamma''-Tocopherol]] || [[File:Gamma-tocopherol.png|300px|class=skin-invert-image]] |- | [[delta-Tocopherol|''delta''-Tocopherol]] || [[File:Delta-tocopherol.png|300px|class=skin-invert-image]] |- | [[Tocopheryl acetate]] || [[File:Tocopheryl acetate.png|300px|class=skin-invert-image]] |} === Tocopherols === [[Alpha-tocopherol]] is a [[fat-soluble]] [[antioxidant]] functioning within the [[glutathione peroxidase]] pathway,<ref>{{cite journal | vauthors = Wefers H, Sies H | title = The protection by ascorbate and glutathione against microsomal lipid peroxidation is dependent on vitamin E | journal = European Journal of Biochemistry | volume = 174 | issue = 2 | pages = 353–7 | date = June 1988 | pmid = 3383850 | doi = 10.1111/j.1432-1033.1988.tb14105.x | doi-access = free | title-link = doi }}</ref> and protecting [[cell membrane]]s from oxidation by reacting with lipid radicals produced in the [[lipid peroxidation]] [[chain reaction]].<ref name=lpi /><ref name=traber>{{cite journal | vauthors = Traber MG, Atkinson J | title = Vitamin E, antioxidant and nothing more | journal = Free Radical Biology & Medicine | volume = 43 | issue = 1 | pages = 4–15 | date = July 2007 | pmid = 17561088 | pmc = 2040110 | doi = 10.1016/j.freeradbiomed.2007.03.024 }}</ref> 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 [[Organic redox reaction|reduction]] by other [[antioxidant]]s, such as [[ascorbate]], [[retinol]] or [[ubiquinol]].<ref>{{cite journal | vauthors = Wang X, Quinn PJ | title = Vitamin E and its function in membranes | journal = Progress in Lipid Research | volume = 38 | issue = 4 | pages = 309–36 | date = July 1999 | pmid = 10793887 | doi = 10.1016/S0163-7827(99)00008-9 }}</ref> Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a [[nucleophile]] that can react with [[electrophile|electrophilic]] [[mutagen]]s.<ref name=Brigelius1999>{{cite journal | vauthors = Brigelius-Flohé R, Traber MG | title = Vitamin E: function and metabolism | journal = FASEB Journal | volume = 13 | issue = 10 | pages = 1145–55 | date = July 1999 | pmid = 10385606 | doi = 10.1096/fasebj.13.10.1145 | s2cid = 7031925 | doi-access = free | title-link = doi }}</ref> === Tocotrienols === The four [[tocotrienol]]s (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 (CH<sub>3</sub>) 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 [[chirality|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 supplement]]s are extracted from palm oil or rice bran oil.<ref name="Ahsan2015">{{cite journal |vauthors=Ahsan H, Ahad A, Siddiqui WA |title=A review of characterization of tocotrienols from plant oils and foods |journal=J Chem Biol |volume=8 |issue=2 |pages=45–59 |date=April 2015 |pmid=25870713 |pmc=4392014 |doi=10.1007/s12154-014-0127-8 }}</ref> 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 [[Biomarker (medicine)|biomarkers]] for [[inflammation]] and [[cardiovascular disease]], although those reviews did not report any information on clinically significant disease outcomes.<ref>{{cite journal |url = http://www.eurekaselect.com/article/19696 |vauthors = Prasad K |title = Tocotrienols and cardiovascular health |journal = Current Pharmaceutical Design |volume = 17 |issue = 21 |pages = 2147–54 |date = 2011 |pmid = 21774782 |doi = 10.2174/138161211796957418 |access-date = 12 December 2022 |archive-date = 10 December 2022 |archive-url = https://web.archive.org/web/20221210053123/http://www.eurekaselect.com/article/19696 |url-status = live }}</ref><ref>{{cite journal |vauthors=Khor BH, Tiong HC, Tan SC, Wong SK, Chin KY, Karupaiah T, Ima-Nirwana S, Abdul Gafor AH |title=Effects of tocotrienols supplementation on markers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials |journal=PLOS ONE |volume=16 |issue=7 |pages=e0255205 |date=2021 |pmid=34297765 |pmc=8301652 |doi=10.1371/journal.pone.0255205 | doi-access = free | title-link = doi |bibcode=2021PLoSO..1655205K |url=}}</ref><ref>{{cite journal |vauthors=Rafique S, Khan DA, Farhat K, Khan MA, Noor M, Sharif M |title=Comparative efficacy of tocotrienol and tocopherol (vitamin E) on atherosclerotic cardiovascular diseases in humans |journal=J Pak Med Assoc |volume=74 |issue=6 |pages=1124–29 |date=June 2024 |pmid=38948984 |doi=10.47391/JPMA.9227 |url=| doi-access = free | title-link = doi |doi-broken-date=17 February 2025 }}</ref> Biomarkers for other diseases were not affected by tocotrienol supplementation.<ref>{{cite journal |vauthors=Li F, Xu B, Soltanieh S, Zanghelini F, Abu-Zaid A, Sun J |title=The effects of tocotrienols intake on obesity, blood pressure, inflammation, liver and glucose biomarkers: a meta-analysis of randomized controlled trials |journal=Crit Rev Food Sci Nutr |volume=62 |issue=26 |pages=7154–67 |date=2022 |pmid=33909529 |doi=10.1080/10408398.2021.1911926 |url=}}</ref> == Functions == [[File:TocophMech.svg|thumb|right|360px|class=skin-invert-image|Tocopherols function by donating H atoms to radicals (X).]] Vitamin E may have various roles as a [[vitamin]].<ref name=GOVe /> Many biological functions have been postulated, including a role as a [[lipid-soluble]] [[antioxidant]].<ref name=GOVe /> In this role, vitamin E acts as a radical scavenger, delivering a hydrogen (H) atom to free radicals. At 323 [[Joule#Multiples|kJ]]/[[Mole (unit)|mol]], the O-H bond in tocopherols is about 10% weaker than in most other [[phenol]]s.<ref>{{cite web |url=https://hbcp.chemnetbase.com/faces/contents/ContentsSearch.xhtml |title=Handbook of chemistry and physics 102nd edition |publisher=[[CRC Press]] |access-date=12 December 2022 |url-status=live |archive-url=https://web.archive.org/web/20210424192827/https://hbcp.chemnetbase.com/faces/contents/ContentsSearch.xhtml |archive-date=24 April 2021 }}</ref> This weak bond allows the vitamin to donate a hydrogen atom to the [[peroxyl radical]] and other [[Radical (chemistry)|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]].<ref>{{cite journal | vauthors = Traber MG, Stevens JF | title = Vitamins C and E: beneficial effects from a mechanistic perspective | journal = Free Radical Biology & Medicine | volume = 51 | issue = 5 | pages = 1000–13 | date = September 2011 | pmid = 21664268 | pmc = 3156342 | doi = 10.1016/j.freeradbiomed.2011.05.017 }}</ref> Vitamin E affects [[gene expression]]<ref name=Azzi2018>{{cite journal | vauthors = Azzi A | title = Many tocopherols, one vitamin E | journal = Molecular Aspects of Medicine | volume = 61 | pages = 92–103 | date = June 2018 | pmid = 28624327 | doi = 10.1016/j.mam.2017.06.004 | s2cid = 36083439 }}</ref> 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.<ref>{{cite journal | vauthors = Schneider C | title = Chemistry and biology of vitamin E | journal = Molecular Nutrition & Food Research | volume = 49 | issue = 1 | pages = 7–30 | date = January 2005 | pmid = 15580660 | doi = 10.1002/mnfr.200400049 }}</ref> == Synthesis == === Biosynthesis === [[File:Synthesis Tocopheryl acetate.svg|thumb|right|460px|class=skin-invert-image|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 [[tocopherol]]s, polyunsaturated for [[tocotrienol]]s). 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.<ref name=Mene2017>{{cite journal | vauthors = Mène-Saffrané L | title = Vitamin E biosynthesis and its regulation in plants | journal = Antioxidants | volume = 7 | issue = 1 |pages = 2 |date = January 2018 |pmid = 29295607 |pmc = 5789312 |doi = 10.3390/antiox7010002| doi-access = free | title-link = doi }}</ref><ref name=Fritsche2017>{{cite journal | vauthors = Fritsche S, Wang X, Jung C | title = Recent advances in our understanding of tocopherol biosynthesis in plants: an overview of key genes, functions, and breeding of vitamin E improved crops | journal = Antioxidants |volume = 6 |issue = 4 |pages = 99 | date = December 2017 |pmid = 29194404 |pmc = 5745509 |doi = 10.3390/antiox6040099 | doi-access = free | title-link = doi }}</ref> Biosynthesis takes place in the [[plastids]].<ref name=Fritsche2017 /> 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.<ref name=Mene2017 /> Located in chloroplast membranes in close proximity to the photosynthetic process,<ref name=Fritsche2017 /> 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.<ref name=Falk2010>{{cite journal | vauthors = Falk J, Munné-Bosch S | title = Tocochromanol functions in plants: antioxidation and beyond | journal = Journal of Experimental Botany | volume = 61 | issue = 6 |pages = 1549–66 |date = June 2010 | pmid = 20385544 | doi = 10.1093/jxb/erq030 | doi-access = free | title-link = doi }}</ref> Seeds are lipid-rich to provide energy for [[germination]] and early growth. Tocochromanols protect the seed lipids from oxidizing and becoming rancid.<ref name=Mene2017 /><ref name=Fritsche2017 /> The presence of tocochromanols extends seed longevity and promotes successful germination and seedling growth.<ref name=Falk2010 /> 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.<ref name=Mene2017 /><ref name=Fritsche2017 /><ref name=Shahidi2016>{{cite journal | vauthors = Shahidi F, de Camargo AC | title = Tocopherols and tocotrienols in common and emerging dietary sources: occurrence, applications, and health benefits | journal = International Journal of Molecular Sciences | volume = 17 | issue = 10 | pages = 1745 | date = October 2016 | pmid = 27775605 | pmc = 5085773 | doi = 10.3390/ijms17101745 | doi-access = free | title-link = doi }}</ref> Of the commonly used food oils, palm oil is unique in that tocotrienol content is higher than tocopherol content.<ref name=Shahidi2016 /> 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.<ref name=Kodad2017>{{cite journal | vauthors = Kodad O, Socias i Company R, Alonso JM | title = Genotypic and environmental effects on tocopherol content in almond | journal = Antioxidants | volume = 7 | issue = 1 | pages = 6 | date = January 2018 | pmid = 29303980 | pmc = 5789316 | doi = 10.3390/antiox7010006 | doi-access = free | title-link = doi }}</ref> Vitamin E biosynthesis occurs in the plastid and goes through two different pathways: the Shikimate pathway and the Methylerythritol Phosphate pathway (MEP pathway).<ref name=Mene2017/> 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]].<ref name=Mene2017/> === Industrial synthesis === The synthetic product is all-rac-alpha-tocopherol,<ref name="EFSA2012"/> 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."<ref name="EFSA2012">{{cite journal|title=Scientific opinion on the safety and efficacy of synthetic alpha-tocopherol for all animal species |journal= EFSA Journal|volume=10 |issue=7 |pages=2784 |date=July 2012 |doi=10.2903/j.efsa.2012.2784 | doi-access = free | title-link = doi }}</ref> The natural alpha tocopherol extracted from plants is RRR-alpha tocopherol, referred to as d-alpha-tocopherol.<ref>{{cite journal | vauthors = Brigelius-Flohé R, Traber MG | title = Vitamin E: function and metabolism | journal = FASEB Journal | volume = 13 | issue = 10 | pages = 1145–1155 | date = July 1999 | pmid = 10385606 | doi = 10.1096/fasebj.13.10.1145 | doi-access = free | title-link = doi }}</ref> The synthetic has 73.5% of the potency of the natural.<ref>{{cite journal | vauthors = Traber MG | title = Utilization of vitamin E | journal = BioFactors | volume = 10 | issue = 2–3 | pages = 115–120 | date = 1999 | pmid = 10609871 | doi = 10.1002/biof.5520100205 | s2cid = 26970237 }}</ref> 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.<ref name="lpi"/><ref>{{cite journal |vauthors=Zou Z, Dai L, Liu D, Du W |title= Research progress in enzymatic synthesis of vitamin E ester derivatives|journal=Catalysts |volume=11 |issue=6 |page=739 |date=June 2021 |doi= 10.3390/catal11060739| doi-access = free | title-link = doi }}</ref> == Deficiency == {{Main|Vitamin E deficiency}} A worldwide summary of more than one hundred human studies reported a median of 22.1 μmol/L for [[Serum (blood)|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.<ref name=Peter2016 /> In contrast, the U.S. Dietary Reference Intake text for vitamin E concluded that a [[blood plasma|plasma]] concentration of 12 μmol/L was sufficient to achieve normal ex vivo hydrogen peroxide-induced [[hemolysis]].<ref name="DRItext" /> 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.<ref name=Traber2014>{{cite journal | vauthors = Traber MG | title = Vitamin E inadequacy in humans: causes and consequences | journal = Advances in Nutrition | volume = 5 | issue = 5 | pages = 503–14 | date = September 2014 | pmid = 25469382 | pmc = 4188222 | doi = 10.3945/an.114.006254 }}</ref> 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.<ref name="DRItext" /> Cystic fibrosis and other fat malabsorption conditions can result in low serum vitamin E.<ref name=GOVe /> 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.<ref name=Min2007>{{cite book |vauthors=Christopher Min K |title=Structure and function of alpha-tocopherol transfer protein: implications for vitamin E metabolism and AVED |volume=76 |pages=23–43 |date=2007 |pmid=17628170 |doi=10.1016/S0083-6729(07)76002-8 |series=Vitamins & Hormones |isbn=978-0-12-373592-8 |chapter=Structure and Function of α-Tocopherol Transfer Protein: Implications for Vitamin e Metabolism and AVED }}</ref><ref name=Niki2012>{{cite journal |vauthors = Niki E, Traber MG | title = A history of vitamin E |journal = Annals of Nutrition & Metabolism |volume = 61 |issue = 3 |pages = 207–12 |date = November 2012 |pmid = 23183290 |doi = 10.1159/000343106 | s2cid = 25667777 }}</ref> [[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.<ref name=Chen2024>{{cite journal |vauthors=Chen L, Chen Y, Yu X, Liang S, Guan Y, Yang J, Guan B |title=Long-term prevalence of vitamin deficiencies after bariatric surgery: a meta-analysis |journal=Langenbecks Arch Surg |volume=409 |issue=1 |pages=226 |date=July 2024 |pmid=39030449 |doi=10.1007/s00423-024-03422-9 |url=}}</ref> There are guidelines for multivitamin supplementation, but adherence rates are reported to be less than 20%.<ref name=Ha2021>{{cite journal |vauthors=Ha J, Kwon Y, Kwon JW, Kim D, Park SH, Hwang J, Lee CM, Park S |title=Micronutrient status in bariatric surgery patients receiving postoperative supplementation per guidelines: Insights from a systematic review and meta-analysis of longitudinal studies |journal=Obes Rev |volume=22 |issue=7 |pages=e13249 |date=July 2021 |pmid=33938111 |doi=10.1111/obr.13249 |url=}}</ref> Vitamin E deficiency due to either malabsorption or metabolic anomaly can cause [[Neurological disorder|nerve problems]] due to poor conduction of electrical impulses along [[nerve]]s due to changes in [[Myelin|nerve membrane]] structure and function. In addition to ataxia, vitamin E deficiency can cause [[peripheral neuropathy]], [[myopathy|myopathies]], [[retinopathy]], and impairment of immune responses.<ref name="DRItext" /><ref name=GOVe /> == Drug interactions == The amounts of alpha-tocopherol, other tocopherols, and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of alpha-tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with [[aspirin]], [[warfarin]], [[tamoxifen]] and [[cyclosporine A]] in ways that alter function.<ref name=Podszun2014/> For aspirin and warfarin, high amounts of vitamin E may potentiate anti-blood clotting action.<ref name=GOVe /><ref name=Podszun2014>{{cite journal | vauthors = Podszun M, Frank J | title = Vitamin E-drug interactions: molecular basis and clinical relevance | journal = Nutrition Research Reviews | volume = 27 | issue = 2 | pages = 215–31 | date = December 2014 | pmid = 25225959 | doi = 10.1017/S0954422414000146 | s2cid = 38571160 | doi-access = free | title-link = doi }}</ref> In multiple clinical trials, vitamin E lowered blood concentration of the immunosuppressant medication cyclosporine A.<ref name=Podszun2014 /> 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.<ref name=GOVe /> == Dietary recommendations == {|class="wikitable" style="float:right;" |- ! style="text-align:center;" colspan="2"|US vitamin E recommendations ([[milligram|mg]] per day)<ref name="DRItext" /> |- |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 Requirement|estimated average requirements]] (EARs) and [[Recommended Dietary Allowance|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 intake]]s (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.<ref name="DRItext">{{cite book | last1 = Institute of Medicine | title = Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids | chapter = Vitamin E | publisher = The National Academies Press | year = 2000 | location = Washington, DC | pages = 186–283 | chapter-url = https://www.nap.edu/read/9810/chapter/8 | doi = 10.17226/9810 | pmid = 25077263 | isbn = 978-0-309-06935-9 | author1-link = Institute of Medicine | access-date = 26 February 2018 | archive-date = 26 February 2018 | archive-url = https://web.archive.org/web/20180226152013/https://www.nap.edu/read/9810/chapter/8 | url-status = live }}</ref> As for safety, [[tolerable upper intake level]]s ("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.<ref name="DRItext" /> Collectively the EARs, RDAs, AIs and ULs are referred to as [[Dietary Reference Intake]]s.<ref name="DRItext" /> 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.<ref name=EFSA-PRI>{{cite web| title = Overview on dietary reference values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| access-date = 2 September 2017| archive-date = 28 August 2017| archive-url = https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| url-status = live}}</ref> 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.<ref name=EFSA-UL>{{citation| title = Tolerable upper intake levels For vitamins and minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| access-date = 5 May 2016| archive-date = 19 September 2017| archive-url = https://web.archive.org/web/20170919040144/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| url-status = live}}</ref> The People's Republic of China publishes dietary guidelines without specifics for individual vitamins or minerals.<ref>{{cite web |title=Eight key recommendations from Dietary Guidelines for Chinese Residents (2022) |url=https://en.chinacdc.cn/health_topics/nutrition_health/202206/t20220616_259702.html |date=June 2022 |website=Chinese Center for Disease Control and Prevention |access-date=23 September 2024 |archive-date=23 September 2024 |archive-url=https://web.archive.org/web/20240923092126/https://en.chinacdc.cn/health_topics/nutrition_health/202206/t20220616_259702.html |url-status=live }}</ref> The United Kingdom recommends 4 mg/day for adult men and 3 mg/day for adult women.<ref>{{cite web |url=https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-e/ |title=Vitamin E |vauthors= |date=23 October 2017 |website=United Kingdom National Health Services |access-date=7 January 2022 |archive-date=8 January 2022 |archive-url=https://web.archive.org/web/20220108004558/https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-e/ |url-status=live }}</ref> 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).<ref>{{cite journal |vauthors=Tanaka K, Terao J, Shidoji Y, Tamai H, Imai E, Okano T |title=Dietary reference intakes for Japanese 2010: fat-soluble vitamins |journal=Journal of Nutritional Science and Vitaminology |date=2012 |volume=59 |issue=Supplement |pages=S57–66 |doi=10.3177/jnsv.59.S57 | doi-access = free | title-link = doi }}</ref> India recommends an adult intake of 7.5–10 mg/day and does not set an upper limit.<ref>{{cite web |url=https://www.nin.res.in/RDA_Full_Report_2024.html |title=ICMR-NIN Expert Group on Nutrient Requirement for Indians, Recommended Dietary Allowances and Estimated Average Requirements (2020) |website=Indian Council for Medical Research |access-date=17 November 2024 |archive-date=11 September 2024 |archive-url=https://web.archive.org/web/20240911231350/https://www.nin.res.in/RDA_Full_Report_2024.html |url-status=live }}</ref> The [[World Health Organization]] recommends that adults consume 10 mg/day.<ref name=Peter2016 /> Consumption tends to be below these recommendations. A worldwide summary reported a median dietary intake of 6.2 mg/d for alpha-tocopherol.<ref name=Peter2016>{{cite journal | vauthors = Péter S, Friedel A, Roos FF, Wyss A, Eggersdorfer M, Hoffmann K, Weber P | title = A systematic review of global alpha-tocopherol status as assessed by nutritional intake levels and blood serum concentrations | journal = International Journal for Vitamin and Nutrition Research | volume = 85 | issue = 5–6 | pages = 261–81 | date = December 2015 | pmid = 27414419 | doi = 10.1024/0300-9831/a000281 | doi-access = free | title-link = doi }}</ref> === Food labeling === For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value. For vitamin E labeling purposes 100% of the daily value was 30 [[international unit]]s (IUs), but as of May 2016, it was revised to 15 mg to bring it into agreement with the RDA.<ref name="FedReg">{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 food labeling: revision of the nutrition and supplement facts labels. FR page 33982. |access-date=31 August 2017 |archive-date=8 August 2016 |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |url-status=live }}</ref> 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.<ref>{{cite journal |title=Regulation (EU) No 1169/2011 of the European Parliament and of the Council |journal=Official Journal of the European Union |volume=22 |issue=11 |pages=18–63 |year=2011 |url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:304:0018:0063:EN:PDF |access-date=21 February 2018 |archive-date=26 July 2017 |archive-url=https://web.archive.org/web/20170726215901/http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ%3AL%3A2011%3A304%3A0018%3A0063%3AEN%3APDF |url-status=live }}</ref> 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.<ref name=NIH-Calc>{{cite web |title=Unit conversions |url=https://dietarysupplementdatabase.usda.nih.gov/Conversions.php |publisher=National Institutes of Health |access-date=21 November 2018 |archive-date=27 April 2021 |archive-url=https://web.archive.org/web/20210427102806/https://dietarysupplementdatabase.usda.nih.gov/Conversions.php |url-status=live }}</ref> 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.<ref>{{cite web|archive-url=https://web.archive.org/web/20120219164132/http://www.nal.usda.gov/fnic/foodcomp/Data/SR20/SR20_doc.pdf |archive-date=19 February 2012 |url=https://www.ars.usda.gov/ARSUserFiles/80400525/Data/SR20/SR20_doc.pdf |title=Composition of foods raw, processed, prepared USDA national nutrient database for standard reference, Release 20 |publisher=USDA |date=February 2008 |url-status=dead }}</ref> The EFSA has never used an IU unit, and their measurement only considers RRR-alpha-tocopherol.<ref>{{cite journal |title=Scientific opinion on dietary reference values for vitamin E as α-tocopherol |journal=EFSA Journal |date=July 2015 |volume=13 |issue=7 |doi=10.2903/j.efsa.2015.4149 |s2cid=79232649 |quote=only 2R-α-tocopherol stereoisomers were found to meet human requirements for the vitamin... Currently, only RRR-α-tocopherol is considered to be the physiologically active vitamer.| doi-access = free | title-link = doi }}</ref> == Sources == Of the different forms of vitamin E, gamma-tocopherol ([[Gamma-Tocopherol|γ-tocopherol]]) is the most common form found in the North American diet, but alpha-tocopherol ([[Alpha-Tocopherol|α-tocopherol]]) is the most biologically active.<ref name=lpi /><ref>{{cite journal | vauthors = Reboul E, Richelle M, Perrot E, Desmoulins-Malezet C, Pirisi V, Borel P | title = Bioaccessibility of carotenoids and vitamin E from their main dietary sources | journal = Journal of Agricultural and Food Chemistry | volume = 54 | issue = 23 | pages = 8749–55 | date = November 2006 | pmid = 17090117 | doi = 10.1021/jf061818s | bibcode = 2006JAFC...54.8749R }}</ref> 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,<ref name=USDA-NDL /> as are some alpha-tocopherol fortified sources such as ready-to-eat cereals, infant formulas, and liquid nutrition products.<ref name=USDA-NDL /> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Plant source<ref name=USDA-NDL>{{cite web |url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=323&nutrient2=&nutrient3=&subset=0&sort=c&measureby=g |archive-url=https://web.archive.org/web/20180303225135/https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=323&nutrient2=&nutrient3=&subset=0&sort=c&measureby=g |url-status=dead |archive-date=3 March 2018 |title=USDA Food Composition Databases | date=2015 |website=United States Department of Agriculture, Agricultural Research Service. Release 28 |access-date=18 August 2018}}</ref> ! colspan=2 | Amount<br /> (mg / 100 g) |- |[[Wheat germ oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 150 | style="border-left-style:none;"| |- |[[Hazelnut]] oil | style="text-align:right; padding-right:0; border-right-style:none;"| 47 | style="border-left-style:none;"| |- |[[Canola]]/[[rapeseed]] oil | style="text-align:right; padding-right:0; border-right-style:none;"| 44 | style="border-left-style:none;"| |- |[[Sunflower oil]] | style="text-align:right; padding-right:0; border-right:none;"| 41 | style="padding-left:0; border-left:none;"| .1 |- |[[Almond oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 39 | style="padding-left:0; border-left-style:none;"| .2 |- |[[Safflower]] oil | style="text-align:right; padding-right:0; border-right-style:none;"| 34 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Grapeseed oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 28 | style="padding-left:0; border-left-style:none;"| .8 |- |[[Sunflower seed]] kernels | style="text-align:right; padding-right:0; border-right-style:none;"| 26 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Almonds]] | style="text-align:right; padding-right:0; border-right-style:none;"| 25 | style="padding-left:0; border-left-style:none;"| .6 |} </div> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Plant source<ref name=USDA-NDL /> ! colspan=2 | Amount<br /> (mg / 100 g) |- |[[Palm oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 15 | style="padding-left:0; border-left-style:none;"| .9 |- |[[Peanut oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 15 | style="padding-left:0; border-left-style:none;"| .7 |- |[[Margarine]], tub | style="text-align:right; padding-right:0; border-right-style:none;"| 15 | style="padding-left:0; border-left-style:none;"| .4 |- |[[Hazelnuts]] | style="text-align:right; padding-right:0; border-right-style:none;"| 15 | style="padding-left:0; border-left-style:none;"| .3 |- |[[Corn oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 14 | style="padding-left:0; border-left-style:none;"| .8 |- |[[Olive oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 14 | style="padding-left:0; border-left-style:none;"| .3 |- |[[Soybean oil]] | style="text-align:right; padding-right:0; border-right-style:none;"| 12 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Pine nuts]] | style="text-align:right; padding-right:0; border-right-style:none;"| 9 | style="padding-left:0; border-left-style:none;"| .3 |- |[[Peanut butter]] | style="text-align:right; padding-right:0; border-right-style:none;"| 9 | style="border-left-style:none;"| |} </div> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Plant source<ref name=USDA-NDL /> ! colspan=2 | Amount<br /> (mg / 100 g) |- |[[Pistachio]] nuts | style="text-align:right; padding-right:0; border-right-style:none;"| 2 | style="padding-left:0; border-left-style:none;"| .8 |- |[[Avocados]] | style="text-align:right; padding-right:0; border-right-style:none;"| 2 | style="padding-left:0; border-left-style:none;"| .6 |- |[[Spinach]], raw | style="text-align:right; padding-right:0; border-right-style:none;"| 2 | style="border-left-style:none;"| |- |[[Asparagus]] | style="text-align:right; padding-right:0; border-right-style:none;"| 1 | style="padding-left:0; border-left-style:none;"| .5 |- |[[Broccoli]] | style="text-align:right; padding-right:0; border-right-style:none;"| 1 | style="padding-left:0; border-left-style:none;"| .4 |- |[[Cashew]] nuts | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .9 |- |[[Bread]] | colspan=2 style="text-align:center;"| 0.2–0.3 |- |[[Rice]], brown | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .2 |- |[[Potato]], [[Pasta]] | style="text-align:right; padding-right:0; border-right-style:none;"| < 0 | style="padding-left:0; border-left-style:none;"| .1 |} </div> <div style="float:left; padding: 1em;"> {|class="wikitable" |- !Animal source<ref name=USDA-NDL /> ! colspan=2 | Amount<br /> (mg / 100 g) |- |[[fish as food|Fish]] | colspan=2 style="text-align:center;"| 1.0–2.8 |- |[[Oysters]] | style="text-align:right; padding-right:0; border-right-style:none;"| 1 | style="padding-left:0; border-left-style:none;"| .7 |- |[[Butter]] | style="text-align:right; padding-right:0; border-right-style:none;"| 1 | style="padding-left:0; border-left-style:none;"| .6 |- |[[Egg as food|Eggs]] | style="text-align:right; padding-right:0; border-right-style:none;"| 1 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Cheese]] | colspan=2 style="text-align:center;"| 0.6–0.7 |- |[[chicken as food|Chicken]] | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .3 |- |[[Beef]], [[Pork]] | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Milk]], whole | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .1 |- |[[Milk]], skim | style="text-align:right; padding-right:0; border-right-style:none;"| 0 | style="padding-left:0; border-left-style:none;"| .01 |} </div>{{Clear}} 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.<ref name="Tan et al">{{cite book | veditors =Tan B, Watson RR, Preedy VR | title =Tocotrienols: Vitamin E Beyond Tocopherols | place =Boca Raton | publisher =CRC Press | year =2013 | edition =2nd | isbn = 9781439884416}}</ref><ref name="Babura2017">{{cite journal |vauthors=Babura SR, Abdullah SN, Khaza Ai H |title=Advances in Genetic Improvement for Tocotrienol Production: A Review |journal=J Nutr Sci Vitaminol (Tokyo) |volume=63 |issue=4 |pages=215–221 |date=2017 |pmid=28978868 |doi=10.3177/jnsv.63.215 |url=| doi-access = free | title-link = doi }}</ref> === Supplements === [[File:Codliveroilcapsules.jpg|thumb|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.<ref name=lpi /> 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.<ref name="Ahsan2015"/> === Fortification === The World Health Organization does not have any recommendations for food fortification with vitamin E.<ref>{{cite web |url=https://www.who.int/publications/i/item/9241594012 |title=Guidelines on food fortification with micronutrients |date=2006 |website=[[World Health Organization]] |access-date=12 December 2022 |archive-date=12 December 2022 |archive-url=https://web.archive.org/web/20221212124940/https://www.who.int/publications/i/item/9241594012 |url-status=live }}</ref> The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E.<ref>{{cite web |url=https://www.ffinetwork.org/savelives |title=Food Fortification Initiative - Why fortify? |website=Food Fortification Initiative, Enhancing Grains for Better Lives |access-date=12 December 2022 |archive-date=8 March 2023 |archive-url=https://web.archive.org/web/20230308151817/https://www.ffinetwork.org/savelives |url-status=live }}</ref> 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.<ref name=USDA-NDL /> === Non-nutrient food additives === Various forms of vitamin E are common [[food additive]]s in oily food, used to deter [[rancidity]] caused by peroxidation. Those with an [[E number]] include:<ref name="efsa">{{cite journal |title=Scientific opinion on the re-evaluation of tocopherol-rich extract (E 306), α-tocopherol (E 307), γ-tocopherol (E 308) and δ-tocopherol (E 309) as food additives |journal=EFSA Journal |date=September 2015 |volume=13 |issue=9 |doi=10.2903/j.efsa.2015.4247| doi-access = free | title-link = doi }}</ref> # E306 Tocopherol-rich extract (mixed, natural, can include tocotrienol) # E307 Alpha-tocopherol (synthetic) # E308 Gamma-tocopherol (synthetic) # E309 Delta-tocopherol (synthetic) These E numbers include all racemic forms and acetate esters thereof.<ref name="efsa"/> 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]].<ref>{{cite web|url=http://www.faia.org.uk/faq2_4.php|title=Frequently asked questions {{!}} Why food additives|website=Food Additives and Ingredients Association UK & Ireland- Making life taste better|access-date=27 October 2010|url-status=live |archive-url=https://web.archive.org/web/20190601015633/https://www.faia.org.uk/faqs/|archive-date=1 June 2019}}</ref> ==Absorption, metabolism, excretion == Tocotrienols and tocopherols, the latter including the stereoisomers of synthetic alpha-tocopherol, are absorbed from the intestinal lumen, incorporated into [[chylomicron]]s, and secreted into the [[portal vein]], leading to the [[liver]]. Absorption efficiency is estimated at 51% to 86%,<ref name="DRItext" /> and that applies to all of the vitamin E family – there is no discrimination among the vitamin E [[vitamer]]s during absorption. Bile is necessary for chylomicron formation, so disease conditions such as [[cystic fibrosis]] result in biliary insufficiency and vitamin E malabsorption.<ref name=PKIN2020VitE/> When consumed as an alpha-tocopheryl acetate dietary supplement, absorption is promoted when consumed with a fat-containing meal.<ref name=PKIN2020VitE/> 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.<ref name="DRItext" /><ref name=Manolescu2008 /> 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 [[glucuronidation|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.<ref name="DRItext" /><ref name=Manolescu2008 /> 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.<ref name=Manolescu2008 /> 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.<ref name=Min2007 /> The role of α-TTP is to move α-tocopherol to the plasma membrane of [[hepatocyte]]s (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.<ref name=Manolescu2008 /> '''Affinity of α-TTP for vitamin E vitamers'''<ref name=Manolescu2008 /> {| class="wikitable" |- !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 == 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.<ref name=GOVe /> Vitamin E has been studied as a treatment for skin health and skin ageing, immune function,<ref>{{cite journal | vauthors = Lee GY, Han SN | title = The Role of Vitamin E in Immunity | journal = Nutrients | volume = 10 | issue = 11 | pages = 1614 | date = November 2018 | pmid = 30388871 | pmc = 6266234 | doi = 10.3390/nu10111614 | doi-access = free | title-link = doi }}</ref> and managing conditions like cardiovascular disease<ref name="Mangione2022" /> or [[Alzheimer's disease]] (AD),<ref name="Wang2021"/> or certain types of cancer.<ref name="Mangione2022" /> 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.<ref name=GOVe /> 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.<ref name="Tilburt2008" /> In 2022, it was the 244th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Vitamin E Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/VitaminE | access-date = 30 August 2024 | archive-date = 24 September 2024 | archive-url = https://web.archive.org/web/20240924115107/https://clincalc.com/DrugStats/Drugs/VitaminE | url-status = live }}</ref> === All-cause mortality === Two [[meta-analysis|meta-analyses]] concluded that as a dietary supplement, vitamin E neither improved nor impaired all-cause mortality.<ref name=Abner2011>{{cite journal | vauthors = Abner EL, Schmitt FA, Mendiondo MS, Marcum JL, Kryscio RJ | title = Vitamin E and all-cause mortality: a meta-analysis | journal = Current Aging Science | volume = 4 | issue = 2 | pages = 158–70 | date = July 2011 | pmid = 21235492 | pmc = 4030744 | doi = 10.2174/1874609811104020158 }}</ref><ref name=Curtis2014>{{cite journal |vauthors=Curtis AJ, Bullen M, Piccenna L, McNeil JJ |title=Vitamin E supplementation and mortality in healthy people: a meta-analysis of randomised controlled trials |journal=Cardiovasc Drugs Ther |volume=28 |issue=6 |pages=563–73 |date=December 2014 |pmid=25398301 |doi=10.1007/s10557-014-6560-7 |s2cid=23820017 }}</ref> 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).<ref name=Bjelakovic2014 /> === Age-related macular degeneration === A [[Cochrane (organisation)|Cochrane]] review concluded that there were no changes seen for risk of developing [[macular degeneration|age-related macular degeneration]] (AMD) from long-term vitamin E supplementation and that supplementation may slightly increase the chances of developing late AMD.<ref>{{cite journal | vauthors = Evans JR, Lawrenson JG | title = Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD000253 | date = July 2017 | issue = 7 | pmid = 28756617 | pmc = 6483250 | doi = 10.1002/14651858.CD000253.pub4 }}</ref> === Cognitive impairment and Alzheimer's disease === Two meta-analyses reported lower vitamin E blood levels in AD people compared to healthy, age-matched people.<ref>{{cite journal | vauthors = Dong Y, Chen X, Liu Y, Shu Y, Chen T, Xu L, Li M, Guan X |title = Do low-serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta-analysis of case-control studies |journal = International Journal of Geriatric Psychiatry |volume = 33 |issue = 2 |pages = e257–e63 |date = February 2018 |pmid = 28833475 | doi = 10.1002/gps.4780 |s2cid = 44859128 }}</ref><ref name="Ashley2021">{{cite journal |vauthors=Ashley S, Bradburn S, Murgatroyd C |title=A meta-analysis of peripheral tocopherol levels in age-related cognitive decline and Alzheimer's disease |journal=Nutr Neurosci |volume=24 |issue=10 |pages=795–809 |date=October 2021 |pmid=31661399 |doi=10.1080/1028415X.2019.1681066 |url=}}</ref> 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.<ref name="Wang2021">{{cite journal |vauthors=Wang W, Li J, Zhang H, Wang X, Zhang X |title=Effects of vitamin E supplementation on the risk and progression of AD: a systematic review and meta-analysis |journal=Nutr Neurosci |volume=24 |issue=1 |pages=13–22 |date=January 2021 |pmid=30900960 |doi=10.1080/1028415X.2019.1585506 |url=}}</ref> === Cancer === 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.<ref name="Mangione2022">{{cite journal |vauthors=Mangione CM, Barry MJ, Nicholson WK, Cabana M, Chelmow D, Coker TR, Davis EM, Donahue KE, Doubeni CA, Jaén CR, Kubik M, Li L, Ogedegbe G, Pbert L, Ruiz JM, Stevermer J, Wong JB |title=Vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer: US preventive services task force recommendation statement |journal=JAMA |volume=327 |issue=23 |pages=2326–33 |date=June 2022 |pmid=35727271 |doi=10.1001/jama.2022.8970 |s2cid=249886842 |url=| doi-access = free | title-link = doi }}</ref> 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.<ref>{{cite journal | vauthors = Shen C, Huang Y, Yi S, Fang Z, Li L | title = Association of vitamin E intake with reduced risk of kidney cancer: a meta-analysis of observational Studies | journal = Medical Science Monitor | volume = 21 | pages = 3420–6 | date = November 2015 | pmid = 26547129 | pmc = 4644018 | doi = 10.12659/MSM.896018 }}</ref><ref>{{cite journal | vauthors = Wang YY, Wang XL, Yu ZJ | title = Vitamin C and E intake and risk of bladder cancer: a meta-analysis of observational studies | journal = International Journal of Clinical and Experimental Medicine | volume = 7 | issue = 11 | pages = 4154–64 | date = 2014 | pmid = 25550926 | pmc = 4276184 }}</ref> A large clinical trial reported no difference in bladder cancer cases between treatment and placebo.<ref>{{cite journal | vauthors = Lotan Y, Goodman PJ, Youssef RF, Svatek RS, Shariat SF, Tangen CM, Thompson IM, Klein EA | title = Evaluation of vitamin E and selenium supplementation for the prevention of bladder cancer in SWOG coordinated SELECT | journal = The Journal of Urology | volume = 187 | issue = 6 | pages = 2005–10 | date = June 2012 | pmid = 22498220 | pmc = 4294531 | doi = 10.1016/j.juro.2012.01.117 }}</ref> An inverse relationship between dietary vitamin E and [[lung cancer]] was reported in observational studies,<ref>{{cite journal |vauthors = Zhu YJ, Bo YC, Liu XX, Qiu CG | title = Association of dietary vitamin E intake with risk of lung cancer: a dose-response meta-analysis |journal = Asia Pacific Journal of Clinical Nutrition |volume = 26 |issue = 2 | pages = 271–7 |date = March 2017 |pmid = 28244705 |doi = 10.6133/apjcn.032016.04 }}</ref> but a large clinical trial in male tobacco smokers reported no impact on lung cancer between treatment and placebo,<ref>{{cite journal | title = The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers | journal = The New England Journal of Medicine | volume = 330 | issue = 15 | pages = 1029–35 | date = April 1994 | pmid = 8127329 | doi = 10.1056/NEJM199404143301501 | vauthors = ((Alpha-Tocopherol)), ((Beta Carotene Cancer Prevention Study Group)) | doi-access = free | title-link = doi }}</ref> 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.<ref name="Slatore2008">{{cite journal | vauthors = Slatore CG, Littman AJ, Au DH, Satia JA, White E | title = Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer | journal = American Journal of Respiratory and Critical Care Medicine |volume = 177 |issue = 5 |pages = 524–30 |date = March 2008 |pmid = 17989343 |pmc = 2258445 |doi = 10.1164/rccm.200709-1398OC }}</ref> For [[prostate cancer]], there are also conflicting results. A meta-analysis based on serum alpha-tocopherol content reported an inverse correlation in relative risk,<ref>{{cite journal | vauthors = Cui R, Liu ZQ, Xu Q | title = Blood α-tocopherol, γ-tocopherol levels and risk of prostate cancer: a meta-analysis of prospective studies | journal = PLOS ONE| volume = 9 | issue = 3 | pages = e93044 | date = 2014 | pmid = 24667740 | pmc = 3965522 | doi = 10.1371/journal.pone.0093044 | bibcode = 2014PLoSO...993044C | doi-access = free | title-link = doi }}</ref> but a second meta-analysis of observational studies reported no such relationship.<ref>{{cite journal | vauthors = Kim Y, Wei J, Citronberg J, Hartman T, Fedirko V, Goodman M | title = Relation of vitamin E and selenium exposure to prostate cancer risk by smoking Status: A Review and Meta-Analysis | journal = Anticancer Research | volume = 35 | issue = 9 | pages = 4983–96 | date = September 2015 | pmid = 26254398 }}</ref> A large clinical trial with male tobacco smokers and reported a 32% decrease in the incidence of prostate cancer,<ref>{{cite journal | vauthors = Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK | title = Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial | journal = Journal of the National Cancer Institute | volume = 90 | issue = 6 | pages = 440–6 | date = March 1998 | pmid = 9521168 | doi = 10.1093/jnci/90.6.440 | doi-access = free | title-link = doi }}</ref> 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.<ref>{{cite journal | vauthors = Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL, Baker LH | title = Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) | journal = JAMA | volume = 306 | issue = 14 |pages = 1549–56 | date = October 2011 | pmid = 21990298 | pmc = 4169010 | doi = 10.1001/jama.2011.1437 }}</ref> For [[colorectal cancer]], a systematic review of randomized clinical trials and the large SELECT trial reported no statistically significant change in relative risk.<ref>{{cite journal | vauthors = Arain MA, Abdul Qadeer A | title = Systematic review on "vitamin E and prevention of colorectal cancer" | journal = Pakistan Journal of Pharmaceutical Sciences | volume = 23 | issue = 2 | pages = 125–30 | date = April 2010 | pmid = 20363687 }}</ref><ref>{{cite journal | vauthors = Lance P, Alberts DS, Thompson PA, Fales L, Wang F, San Jose J, Jacobs ET, Goodman PJ, Darke AK, Yee M, Minasian L, Thompson IM, Roe DJ | title = Colorectal adenomas in participants of the SELECT randomized trial of selenium and vitamin E for prostate cancer prevention | journal = Cancer Prevention Research | volume = 10 | issue = 1 | pages = 45–54 | date = January 2017 | pmid = 27777235 | pmc = 5510661 | doi = 10.1158/1940-6207.CAPR-16-0104 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE | title = Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial |journal = JAMA | volume = 294 |issue = 1 | pages = 56–65 |date = July 2005 | pmid = 15998891 | doi = 10.1001/jama.294.1.56 }}</ref> 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.<ref>{{cite book | vauthors = Jensen SK, Lauridsen C | title = Alpha-tocopherol stereoisomers | volume = 76 | pages = 281–308 |year = 2007 |pmid = 17628178 | doi = 10.1016/S0083-6729(07)76010-7 |isbn = 978-0-12-373592-8 |series = Vitamins & Hormones |chapter = Α-Tocopherol Stereoisomers }}</ref> 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.<ref name="Slatore2008" /> ==== Cancer health claims ==== 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.<ref>{{cite web |url=https://www.fda.gov/Food/LabelingNutrition/ucm2006877.htm |title=Qualified health claims |website=Overview from the US Food & Drug Administration |access-date=24 August 2018 |archive-date=7 September 2018 |archive-url=https://web.archive.org/web/20180907203827/https://www.fda.gov/Food/LabelingNutrition/ucm2006877.htm |url-status=live }}</ref> 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.<ref>{{cite web |url=https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm306866.htm |archive-url=https://wayback.archive-it.org/7993/20171114183722/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm306866.htm |url-status=dead |archive-date=14 November 2017 |title=Alliance for Natural Health v. Sebelius, Case No. 09-1546 (D.D.C.) | date=2012 |website=US Food & Drug Administration |access-date=24 August 2018}}</ref> === Cataracts === A review measured serum tocopherol and reported higher serum concentration was associated with a 23% reduction in relative risk of age-related [[cataract]]s (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract.<ref name=Zhang2015>{{cite journal | vauthors = Zhang Y, Jiang W, Xie Z, Wu W, Zhang D | title = Vitamin E and risk of age-related cataract: a meta-analysis | journal = Public Health Nutrition | volume = 18 | issue = 15 | pages = 2804–14 | date = October 2015 | pmid = 25591715 | doi = 10.1017/S1368980014003115 | pmc = 10271701 | s2cid = 3168065 }}</ref> In contrast, meta-analyses reporting on clinical trials of alpha-tocopherol supplementation reported no statistically significant change to risk of ARC compared to placebo.<ref name=Zhang2015 /><ref>{{cite journal | vauthors = Mathew MC, Ervin AM, Tao J, Davis RM | title = Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 6 | pages = CD004567 | date = June 2012 | pmid = 22696344 | pmc = 4410744 | doi = 10.1002/14651858.CD004567.pub2 }}</ref> === Cardiovascular diseases === 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.<ref name="Mangione2022" /> Research on the effects of vitamin E on [[cardiovascular disease]] has produced conflicting results. In theory, oxidative modification of [[Low-density lipoprotein|LDL-cholesterol]] promotes blockages in coronary arteries that lead to [[atherosclerosis]] and [[myocardial infarction|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.<ref name=Kirmizis2009>{{cite journal | vauthors = Kirmizis D, Chatzidimitriou D | title = Antiatherogenic effects of vitamin E: the search for the Holy Grail | journal = Vascular Health and Risk Management | volume = 5 | pages = 767–74 | date = 2009 | pmid = 19774218 | pmc = 2747395 | doi = 10.2147/vhrm.s5532 | doi-access = free | title-link = doi }}</ref> 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.<ref name=Kirmizis2009 /><ref>{{cite journal | vauthors = Gaziano JM | title = Vitamin E and cardiovascular disease: observational studies | journal = Annals of the New York Academy of Sciences | volume = 1031 | issue = 1 |pages = 280–91 |date = December 2004 | pmid = 15753154 | doi = 10.1196/annals.1331.028 | bibcode = 2004NYASA1031..280G | s2cid = 26369772 }}</ref> 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.<ref name=Kirmizis2009 /> A meta-analysis of [[randomized clinical trial]]s (RCTs) reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%.<ref name=Loffredo2015>{{cite journal | vauthors = Loffredo L, Perri L, Di Castelnuovo A, Iacoviello L, De Gaetano G, Violi F | title = Supplementation with vitamin E alone is associated with reduced myocardial infarction: a meta-analysis | journal = Nutrition, Metabolism, and Cardiovascular Diseases | volume = 25 | issue = 4 | pages = 354–63 | date = April 2015 | pmid = 25779938 | doi = 10.1016/j.numecd.2015.01.008 }}</ref> 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,<ref name=Sesso2008>{{cite journal | vauthors = Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM |title = Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial | journal = JAMA |volume = 300 |issue = 18 |pages = 2123–33 | date = November 2008 | pmid = 18997197 | pmc = 2586922 | doi = 10.1001/jama.2008.600 }}</ref> or else a higher risk of heart failure in the alpha-tocopherol group.<ref>{{cite journal | vauthors = Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J, Dagenais GR | title = Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial | journal = JAMA | volume = 293 | issue = 11 | pages = 1338–47 | date = March 2005 | pmid = 15769967 | doi = 10.1001/jama.293.11.1338 | doi-access = free | title-link = doi }}</ref> Vitamin E supplementation does not reduce the incidence of [[Brain ischemia|ischemic]] or [[Intracerebral hemorrhage|hemorrhagic]] [[stroke]].<ref>{{cite journal | vauthors = Bin Q, Hu X, Cao Y, Gao F | title = The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomized controlled trials | journal = Thrombosis and Haemostasis| volume = 105 | issue = 4 | pages = 579–85 | date = April 2011 | pmid = 21264448 | doi = 10.1160/TH10-11-0729 | s2cid = 23237227 }}</ref><ref name=Maggio2024/> However, supplementation of vitamin E with other antioxidants reduced risk of ischemic stroke by 9% while increased the risk for hemorrhagic stroke by 22%.<ref name=Maggio2024>{{cite journal |vauthors=Maggio E, Bocchini VP, Carnevale R, Pignatelli P, Violi F, Loffredo L |title=Vitamin E supplementation (alone or with other antioxidants) and stroke: a meta-analysis |journal=Nutr Rev |volume=82 |issue=8 |pages=1069–78 |date=August 2024 |pmid=37698992 |doi=10.1093/nutrit/nuad114 |url=}}</ref> ==== Denial of cardiovascular health claims ==== In 2001, the U.S. [[Food and Drug Administration]] rejected proposed health claims for vitamin E and cardiovascular health.<ref>{{cite web |url=https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073251.htm |archive-url=https://wayback.archive-it.org/7993/20171115122059/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073251.htm |url-status=dead |archive-date=15 November 2017 |title=Letter regarding dietary supplement health claim for vitamin E and heart disease (Docket No 99P-4375) |website=U.S. Food and Drug Administration |access-date=24 August 2018}}</ref> 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."<ref name="GOVe" /> 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.<ref>{{cite journal |doi=10.2903/j.efsa.2010.1816 |title=Scientific Opinion on the substantiation of health claims related to vitamin E and protection of DNA, proteins and lipids from oxidative damage (ID 160, 162, 1947), maintenance of the normal function of the immune system (ID 161, 163), maintenance of normal bone (ID 164), maintenance of normal teeth (ID 164), maintenance of normal hair (ID 164), maintenance of normal skin (ID 164), maintenance of normal nails (ID 164), maintenance of normal cardiac function (ID 166), maintenance of normal vision by protection of the lens of the eye (ID 167), contribution to normal cognitive function (ID 182, 183), regeneration of the reduced form of vitamin C (ID 203), maintenance of normal blood circulation (ID 216) and maintenance of normal a scalp (ID 2873) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 |journal=EFSA Journal |volume=8 |issue=10 |pages=1816 |year=2010 | doi-access = free | title-link = doi }}</ref> === Nonalcoholic fatty liver disease === 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,<ref name=Sato2015>{{cite journal | vauthors = Sato K, Gosho M, Yamamoto T, Kobayashi Y, Ishii N, Ohashi T, Nakade Y, Ito K, Fukuzawa Y, Yoneda M | title = Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials | journal = Nutrition | volume = 31 | issue = 7–8 | pages = 923–30 | date = 2015 | pmid = 26059365 | doi = 10.1016/j.nut.2014.11.018 }}</ref><ref>{{cite journal |vauthors=Vadarlis A, Antza C, Bakaloudi DR, Doundoulakis I, Kalopitas G, Samara M, Dardavessis T, Maris T, Chourdakis M |title=Systematic review with meta-analysis: The effect of vitamin E supplementation in adult patients with non-alcoholic fatty liver disease |journal=J Gastroenterol Hepatol |volume=36 |issue=2 |pages=311–19 |date=February 2021 |pmid=32810309 |doi=10.1111/jgh.15221 |s2cid=221181369 }}</ref><ref>{{cite journal |vauthors=Wang MY, Prabahar K, Găman MA, Zhang JL |title=Vitamin E supplementation in the treatment on nonalcoholic fatty liver disease (NAFLD): Evidence from an umbrella review of meta-analysis on randomized controlled trials |journal=J Dig Dis |volume=24 |issue=6–7 |pages=380–89 |date=2023 |pmid=37503812 |doi=10.1111/1751-2980.13210 |url=}}</ref> but not in children.<ref>{{cite journal |vauthors=Amanullah I, Khan YH, Anwar I, Gulzar A, Mallhi TH, Raja AA |title=Effect of vitamin E in non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials |journal=Postgrad Med J |volume=95 |issue=1129 |pages=601–11 |date=November 2019 |pmid=31434683 |doi=10.1136/postgradmedj-2018-136364 |s2cid=201275520 |url=| doi-access = free | title-link = doi }}</ref><ref>{{cite journal |vauthors=Lin M, Zeng H, Deng G, Lei J, Li J |title=Vitamin E in pediatric non-alcoholic fatty liver disease: a meta-analysis |journal=Clin Res Hepatol Gastroenterol |volume=45 |issue=3 |pages=101530 |date=May 2021 |pmid=33272889 |doi=10.1016/j.clinre.2020.08.008 |s2cid=227282863 }}</ref> ===Exercise recovery=== 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]].<ref name=Lima2024>{{cite journal |vauthors=de Lima KS, Schuch F, Righi NC, Neto LJ, Nunes GS, Puntel G, Chagas P, da Silva AM, Signori LU |title=Vitamin E Does not Favor Recovery After Exercises: Systematic Review and Meta-analysis |journal=Int J Sports Med |volume=45 |issue=7 |pages=485–95 |date=June 2024 |pmid=38346687 |doi=10.1055/a-2221-5688 |url=}}</ref> === Parkinson's disease === For [[Parkinson's disease]], there is an observed inverse correlation seen with dietary vitamin E, but no confirming evidence from placebo-controlled clinical trials.<ref>{{cite journal | vauthors = Etminan M, Gill SS, Samii A | title = Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson's disease: a meta-analysis | journal = The Lancet. Neurology | volume = 4 | issue = 6 | pages = 362–5 | date = June 2005 | pmid = 15907740 | doi = 10.1016/S1474-4422(05)70097-1 | s2cid = 25691968 }}</ref><ref>{{cite journal |vauthors=Chang MC, Kwak SG, Kwak S |title=Effect of dietary vitamins C and E on the risk of Parkinson's disease: A meta-analysis |journal=Clin Nutr |volume=40 |issue=6 |pages=3922–30 |date=June 2021 |pmid=34139465 |doi=10.1016/j.clnu.2021.05.011 |s2cid=235470579 }}</ref> === Pregnancy === Supplementation with a combination of vitamins E and C during pregnancy is not recommended by the [[World Health Organization]].<ref name=":0">{{Cite web |title=Vitamin E and C supplementation during pregnancy |url=https://www.who.int/tools/elena/interventions/vitaminsec-pregnancy |date=August 2023 |access-date=21 October 2024 |website=[[World Health Organization]] |archive-date=27 November 2024 |archive-url=https://web.archive.org/web/20241127221649/https://www.who.int/tools/elena/interventions/vitaminsec-pregnancy |url-status=live }}</ref> 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.<ref name=CochraneVitE>{{cite journal | vauthors = Rumbold A, Ota E, Hori H, Miyazaki C, Crowther CA | title = Vitamin E supplementation in pregnancy | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD004069 | date = September 2015 | volume = 2016 | pmid = 26343254 | doi = 10.1002/14651858.CD004069.pub3 | pmc = 8406700 }}</ref> ===Topical applications=== There is widespread use of [[tocopheryl acetate]] in some [[cosmetics|skincare]] and wound-treatment products as a [[topical medication]], with claims for improved [[wound healing]] and reduced [[scar]] tissue,<ref name=Panin2004>{{cite journal | vauthors = Panin G, Strumia R, Ursini F | title = Topical alpha-tocopherol acetate in the bulk phase: eight years of experience in skin treatment | journal = Annals of the New York Academy of Sciences | volume = 1031 | issue = 1 | pages = 443–7 | date = December 2004 | pmid = 15753192 | doi = 10.1196/annals.1331.069 | bibcode = 2004NYASA1031..443P | s2cid = 45771699 }}</ref> but reviews have repeatedly concluded that there is insufficient evidence to support these claims.<ref name=Sidgwick2015>{{cite journal |vauthors = Sidgwick GP, McGeorge D, Bayat A |title = A comprehensive evidence-based review on the role of topicals and dressings in the management of skin scarring |journal = Archives of Dermatological Research |volume = 307 |issue = 6 |pages = 461–77 |date = August 2015 |pmid = 26044054 | pmc = 4506744 |doi = 10.1007/s00403-015-1572-0}}</ref><ref name=Tanaydin2016>{{cite journal | vauthors = Tanaydin V, Conings J, Malyar M, van der Hulst R, van der Lei B | title = The role of topical vitamin E in scar management: a systematic review | journal = Aesthetic Surgery Journal | volume = 36 | issue = 8 | pages = 959–65 | date = September 2016 | pmid = 26977069 | doi = 10.1093/asj/sjw046 | doi-access = free | title-link = doi }}</ref> 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.<ref name=Kosari2010>{{cite journal | vauthors = Kosari P, Alikhan A, Sockolov M, Feldman SR | title = Vitamin E and allergic contact dermatitis | journal = Dermatitis | volume = 21 | issue = 3 | pages = 148–53 | date = 2010 | pmid = 20487657 | doi = 10.2310/6620.2010.09083| s2cid = 38212099 }}</ref> == Vaping-associated lung injury == {{Main|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.<ref name=CDC2019_02>{{cite report |url=https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html |title=Outbreak of lung injury associated with e-cigarette use, or 'vaping' |publisher=Centers for Disease Control and Prevention |date=11 February 2020 |access-date=14 October 2024 |archive-date=12 April 2021 |archive-url=https://web.archive.org/web/20210412020842/https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html |url-status=live }}{{PD-notice}}</ref> In September 2019, the US [[Food and Drug Administration]] had announced that vape liquids linked to [[2019–20 vaping lung illness outbreak|recent vaping related lung disease outbreak in the United States]], tested positive for [[tocopheryl acetate|vitamin E acetate]]<ref>{{cite news|url=https://www.washingtonpost.com/health/2019/09/05/contaminant-found-vaping-products-linked-deadly-lung-illnesses-state-federal-labs-show/|title=Contaminant found in marijuana vaping products linked to deadly lung illnesses, tests show|vauthors=Sun L|date=6 September 2019|newspaper=The Washington Post|access-date=9 September 2019|archive-date=3 January 2021|archive-url=https://web.archive.org/web/20210103010305/https://www.washingtonpost.com/health/2019/09/05/contaminant-found-vaping-products-linked-deadly-lung-illnesses-state-federal-labs-show/|url-status=live}}</ref> which had been used as a [[cutting agent|thickening agent]] by illicit THC vape cartridge manufacturers.<ref>{{cite journal |vauthors=Blount BC, Karwowski MP, Shields PG, Morel-Espinosa M, Valentin-Blasini L, Gardner M, Braselton M, Brosius CR, Caron KT, Chambers D, Corstvet J, Cowan E, De Jesús VR, Espinosa P, Fernandez C, Holder C, Kuklenyik Z, Kusovschi JD, Newman C, Reis GB, Rees J, Reese C, Silva L, Seyler T, Song MA, Sosnoff C, Spitzer CR, Tevis D, Wang L, Watson C, Wewers MD, Xia B, Heitkemper DT, Ghinai I, Layden J, Briss P, King BA, Delaney LJ, Jones CM, Baldwin GT, Patel A, Meaney-Delman D, Rose D, Krishnasamy V, Barr JR, Thomas J, Pirkle JL |display-authors=6 |title=Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI |journal=N Engl J Med |volume=382 |issue=8 |pages=697–705 |date=February 2020 |pmid=31860793 |pmc=7032996 |doi=10.1056/NEJMoa1916433 |url=}}</ref> 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]].<ref>{{cite web|url=https://www.cdc.gov/media/releases/2019/t1108-telebriefing-vaping.html|title=Transcript of CDC telebriefing: update on lung injury associated with e-cigarette use, or vaping|publisher=Centers for Disease Control and Prevention|date=8 November 2019|access-date=10 November 2019|archive-date=18 March 2021|archive-url=https://web.archive.org/web/20210318014742/https://www.cdc.gov/media/releases/2019/t1108-telebriefing-vaping.html|url-status=live}}{{PD-notice}}</ref><ref>{{cite journal |vauthors=Boudi FB, Patel S, Boudi A, Chan C |title=Vitamin E acetate as a plausible cause of acute vaping-related illness |journal=Cureus |volume=11 |issue=12 |pages=e6350 |date=December 2019 |pmid=31938636 |pmc=6952050 |doi=10.7759/cureus.6350 | doi-access = free | title-link = doi }}</ref> [[Pyrolysis]] of vitamin E acetate produces exceptionally toxic [[ketene]] gas, along with carcinogenic [[alkene]]s and [[benzene]].<ref>{{cite journal | vauthors = Wu D, O'Shea DF | title = Potential for release of pulmonary toxic ketene from vaping pyrolysis of vitamin E acetate | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 12 | pages = 6349–55 | date = March 2020 | pmid = 32156732 | doi = 10.1073/pnas.1920925117 | pmc = 7104367 | bibcode = 2020PNAS..117.6349W | doi-access = free | title-link = doi }}</ref> == History == Vitamin E was discovered in 1922 by [[Herbert McLean Evans]] and [[Katharine Bishop|Katharine Scott Bishop]]<ref name=Evans1922>{{cite journal | vauthors = Evans HM, Bishop KS | journal = Science | volume = 56 | issue = 1458 | pages = 650–1 | date = December 1922 | pmid = 17838496 | doi = 10.1126/science.56.1458.650 | bibcode = 1922Sci....56..650E | jstor = 1647181 | title = On the existence of a hitherto unrecognized dietary factor essential for reproduction | url = https://zenodo.org/record/1448277 | access-date = 13 December 2020 | archive-date = 27 October 2022 | archive-url = https://web.archive.org/web/20221027063908/https://zenodo.org/record/1448277 | url-status = live }}</ref> and first isolated in a pure form by Evans and [[Gladys Anderson Emerson]] in 1935 at the [[University of California, Berkeley]].<ref name=EWS>{{citation |title=Encyclopedia of world scientists |pages=211–2 |isbn=978-1-4381-1882-6 | vauthors = Oakes EH |year=2007 |chapter=Emerson, Gladys Anderson|publisher=Infobase |chapter-url=https://books.google.com/books?id=uPRB-OED1bcC&pg=PA211}}</ref> 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.<ref name=Evans1936/> George M. Calhoun, Professor of Greek at the University of California, was credited with helping with the naming process.<ref name=Evans1936>{{cite journal|author1=Evans HM |author2=Emerson OH |author3=Emerson GA | title = The isolation from wheat germ oil of an alcohol, a-tocopherol, having the properties of vitamin E| journal = Journal of Biological Chemistry| date=1936| volume = 113 | issue = 1| pages = 319–32 |doi=10.1016/S0021-9258(18)74918-1 | doi-access = free | title-link = doi }}</ref> [[Erhard Fernholz]] elucidated its structure in 1938 and shortly afterward the same year, [[Paul Karrer]] and his team first synthesized it.<ref name=Karrer1938>{{cite journal | vauthors = Karrer P, Fritzsche H, Ringier BH, Salomon H | year = 1938 | title = Synthesis of α-tocopherol (vitamin E) | journal = Nature | volume = 141 | issue = 3580| page = 1057 | doi = 10.1038/1411057d0 | bibcode = 1938Natur.141.1057K | s2cid = 4118327 | doi-access = free | title-link = doi }}</ref> 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.<ref>{{cite journal |doi = 10.1001/jama.1967.03130030065018 |volume=201 |issue=3 |title=Vitamin in search of a disease |year=1967 |journal=JAMA: The Journal of the American Medical Association | pages=195–6}}</ref> A role for vitamin E in coronary heart disease was first proposed in 1946 by [[Evan Shute]] and colleagues.<ref>{{cite journal | vauthors = Vogelsang A, Shute EV | title = Effect of vitamin E in coronary heart disease | journal = Nature | volume = 157 | issue = 3997 | pages = 772 | date = June 1946 | pmid = 21064771 | doi = 10.1038/157772b0 | bibcode = 1946Natur.157..772V | s2cid = 4099854 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Skelton F, Shute E, Skinner HG, Waud RA | title = Antipurpuric action of α-tocopherol (vitamin E) | journal = Science | volume = 103 | issue = 2687 | pages = 762 | date = June 1946 | pmid = 17836459 | doi = 10.1126/science.103.2687.762-b | bibcode = 1946Sci...103R.762S | s2cid = 35677118 }}</ref> More cardiovascular work from the same research group followed,<ref>{{cite journal | vauthors = Shute EV, Vogelsang AB | title = The influence of vitamin E on vascular disease | journal = Surgery, Gynecology & Obstetrics | volume = 86 | issue = 1 | pages = 1–8 | date = January 1948 | pmid = 18920873 }}</ref> including a proposal that megadoses of vitamin E could slow down and even reverse the development of [[atherosclerosis]].<ref>Shute WE, Shute EV. ''Alpha-tocopherol (vitamin E) in cardiovascular disease'' Toronto, Ontario, Canada: Ryerson Press, 1954</ref> Subsequent research showed no association between vitamin E supplementation and cardiovascular events such as nonfatal stroke or myocardial infarction, or cardiovascular mortality.<ref>{{cite journal | vauthors = Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH | title = Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease | journal = Archives of Internal Medicine | volume = 164 | issue = 14 | pages = 1552–6 | date = July 2004 | pmid = 15277288 | doi = 10.1001/archinte.164.14.1552 }}</ref> There is a long history of belief that topical application of vitamin E containing oil benefits burn and wound healing.<ref name=Panin2004 /> This belief persists even though scientific reviews refuted this claim.<ref name=Sidgwick2015 /><ref name=Tanaydin2016 /> 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]].<ref name=Bell1987>{{cite journal | vauthors = Bell EF | title = History of vitamin E in infant nutrition | journal = The American Journal of Clinical Nutrition | volume = 46 | issue = 1 Suppl | pages = 183–6 | date = July 1987 | pmid = 3300257 | doi = 10.1093/ajcn/46.1.183 }}</ref> 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.<ref>{{cite journal | vauthors = Brion LP, Bell EF, Raghuveer TS | title = Vitamin E supplementation for prevention of morbidity and mortality in preterm infants | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD003665 | year = 2003 | volume = 2010 | pmid = 14583988 | doi = 10.1002/14651858.CD003665 | doi-access = free | title-link = doi | pmc = 8725195 }}</ref> == References == {{Reflist}} == External links == * {{commonscat-inline}} * Vitamin E: {{pubchem|2116}} * alpha-Tocepherol: {{pubchem|14985}} {{Vitamins}} {{Antioxidants}} {{Portal bar | Medicine}} {{Authority control}} [[Category:Vitamin E| ]] [[Category:Heterocyclic compounds with 2 rings]] [[Category:Food antioxidants]] [[Category:Oxygen heterocycles]]
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