Editing Tocopherol

{{Short description|Antioxidant compounds with vitamin E activity}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
'''Tocopherols''' ({{IPAc-en|t|oʊ|ˈ|k|ɒ|f|ə|ˌ|r|ɒ|l}};<ref>{{Dictionary.com|Tocopherol|access-date=28 February 2018}}</ref> '''TCP''') are a class of [[organic compound]]s comprising various [[Methyl group|methylated]] [[phenol]]s, many of which have [[vitamin E]] activity. Because the [[vitamin]] activity was first identified in 1936 from a dietary fertility factor in rats, it was named ''tocopherol'', from Greek [[wiktionary:τόκος|τόκος]] ''tókos'' 'birth' and [[wiktionary:φέρειν|φέρειν]]  ''phérein'' 'to bear or carry', that is 'to carry a pregnancy', with the ending ''-ol'' signifying its status as a chemical [[Alcohol (chemistry)|alcohol]].

[[Α-tocopherol|α-Tocopherol]] is the main source found in supplements and in the European diet, where the main dietary sources are olive and sunflower oils,<ref name='Wagner et al, 2004'>{{cite journal | vauthors = Wagner KH, Kamal-Eldin A, Elmadfa I | title = Gamma-tocopherol--an underestimated vitamin? | journal = Annals of Nutrition & Metabolism | volume = 48 | issue = 3 | pages = 169–88 | year = 2004 | pmid = 15256801 | doi = 10.1159/000079555 | s2cid = 24827255 | quote = In North America, the intake of γ-tocopherol has been estimated to exceed that of α-tocopherol by a factor of 2–4 ... due to the fact that soybean oil is the predominant vegetable oil in the American diet (76.4%) followed by corn oil and canola oil (both 7%) ... The supply of dietary fats ... is much more diverse in Europe ... The oils mainly consumed in Europe, i.e. sunflower, olive and canola oil, provide less γ-tocopherol but more α-tocopherol ... [T]he ratio of α-:γ-tocopherol is at least 1:2. Therefore, the average γ-tocopherol intake may be estimated as 4–6 mg/day, which is about 25–35% of the USA intake. In accordance with the lower estimated European intake of γ-tocopherol, the serum levels of γ-tocopherol in European populations are 4–20 times lower than that of α-tocopherol }}</ref> while [[G-tocopherol|γ-tocopherol]] is the most common form in the American diet due to a higher intake of soybean and corn oil.<ref name="Wagner et al, 2004"/><ref name="gamma"/>

==Forms==
[[Vitamin E]] exists in eight different forms, four tocopherols and four [[tocotrienol]]s. All feature a [[chromane]] ring, with a [[hydroxyl]] group that can donate a [[hydrogen]] atom to [[redox|reduce]] [[free radical]]s and a [[hydrophobic]] [[side chain]] that allows for penetration into [[biological membrane]]s. Both the tocopherols and [[tocotrienols]] occur in α (alpha), β (beta), γ (gamma), and δ (delta) forms, determined by the number and position of [[methyl]] groups on the chromanol ring.{{cn|date=December 2024}} <!--The alpha is most highly methylated (3 methyls on the chromanol ring) with the beta, gamma, and delta forms having two, one, and no methyl groups on the chromanol ring, respectively.-->

{| class="wikitable"
! Form || Structure
|-
| [[α-Tocopherol]] || [[File:Tocopherol, alpha-.svg|300px|class=skin-invert-image]]
|-
| [[β-Tocopherol]] ||  [[File:Beta-tocopherol.png|300px|class=skin-invert-image]]
|-
| [[γ-Tocopherol]] || [[File:Gamma-tocopherol.png|300px|class=skin-invert-image]]
|-
| [[δ-Tocopherol]]   ||  [[File:Delta-tocopherol.png|300px|class=skin-invert-image]]
|}

The [[tocotrienols]] have the same methyl structure at the ring and the same Greek-letter methyl notation, but differ from the analogous tocopherols by the presence of three [[double bond]]s in the hydrophobic side chain. The unsaturation of the tails gives [[tocotrienols]] only a single stereoisomeric carbon (and thus two possible isomers per structural formula, one of which occurs naturally), whereas tocopherols have three centers (and eight possible stereoisomers per structural formula, again, only one of which occurs naturally).

<!--[[File:VitE.png|450px|center]] -->
Each form has a different [[biological activity]].<ref name=fao1>{{cite report |author1=Food and Agriculture Organization |author2=World Health Organization |author1-link=Food and Agriculture Organization |author2-link=World Health Organization |date=2001 |title=Joint FAO/WHO Expert Consultation on Human Vitamin and Mineral Requirements |url=http://www.fao.org/3/Y2809E/y2809e00.htm |publisher=FAO Rome |location=Bangkok, Thailand |chapter= 9. Vitamin E |chapter-url=http://www.fao.org/3/Y2809E/y2809e0f.htm#bm15}}</ref><ref>{{cite journal | last1=Burton |first1= G. W. |last2= Ingold |first2= K. U. |title= Autoxidation of biological molecules. 1. Antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro |journal= Journal of the American Chemical Society |year= 1981 |volume= 103 |issue= 21 |pages= 6472–6477 |doi=10.1021/ja00411a035 |bibcode= 1981JAChS.103.6472B }}</ref>
In general, the unnatural l-isomers of tocotrienols lack almost all vitamin activity, and half of the possible 8 isomers of the tocopherols (those with 2S chirality at the ring–tail junction) also lack vitamin activity. Of the stereoisomers that retain activity, increasing methylation, especially full methylation to the α-form, increases vitamin activity. In tocopherols, this is due to the higher binding energy of the α-tocopherol form of the vitamin to the tocopherol binding protein.

As a [[food additive]], tocopherol is labeled with these [[E number]]s: '''E306''' (tocopherol), '''E307''' (α-tocopherol), '''E308''' (γ-tocopherol), and '''E309''' (δ-tocopherol). All of these are approved in the US,<ref>{{cite web|url=https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm#ftnT |title=Listing of Food Additives Status Part II |website=[[Food and Drug Administration]] |access-date=2011-10-27 |url-status=dead |archive-url=https://web.archive.org/web/20111108002304/https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm |archive-date=November 8, 2011 }}</ref> EU,<ref>{{cite web |url=http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |title=Current EU approved additives and their E Numbers |website=UK Food Standards Agency |access-date=2011-10-27 |url-status=live |archive-url=https://web.archive.org/web/20101007124435/http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |archive-date=2010-10-07 }}</ref> and Australia and New Zealand<ref>{{cite web |url=http://www.comlaw.gov.au/Details/F2011C00827 |title=Australia New Zealand Food Standards Code. Standard 1.2.4 – Labelling of ingredients |website=Federal Register of Legislation |publisher=Australian Government |date=8 September 2011 }}</ref> for use as antioxidants.

===α-Tocopherol===
{{Main|α-Tocopherol}}
α-Tocopherol is the form of vitamin E that is preferentially absorbed and accumulated in humans.<ref>{{cite journal | vauthors = Rigotti A | title = Absorption, transport, and tissue delivery of vitamin E | journal = Molecular Aspects of Medicine | volume = 28 | issue = 5–6 | pages = 423–436 | year = 2007 | pmid = 17320165 | doi = 10.1016/j.mam.2007.01.002 }}</ref> The measurement of "vitamin&nbsp;E" activity in [[international unit]]s (IU) was based on fertility enhancement by the prevention of miscarriages in pregnant rats relative to α-tocopherol.

Although the mono-methylated form ddd-γ-tocopherol is the most prevalent form of vitamin E in oils, there is evidence that rats can methylate this form to the preferred α-tocopherol, since several generations of rats retained α-tocopherol tissue levels, even when those generations were fed only γ-tocopherol through their lives.

There are three [[stereocenter]]s in α-tocopherol, so this is a [[Chirality (chemistry)|chiral]] molecule.<ref name=Jensen/> The eight [[Stereoisomerism|stereoisomers]] of α-tocopherol differ in the arrangement of groups around these stereocenters. In the image of ''RRR''-α-tocopherol below, all three stereocenters are in the ''R'' form. However, if the middle of the three stereocenters were changed (so the hydrogen was now pointing down and the [[methyl group]] pointing up), this would become the structure of ''RSR''-α-tocopherol. These stereoisomers also may be named in an alternative older nomenclature, where the stereocenters are either in the ''d'' or ''l'' form.<ref name=Traber/>

[[File:Alpha-Tocopherol Structural Formulae V.1.svg|thumb|250px|class=skin-invert-image|''RRR'' [[Stereoisomerism|stereoisomer]] of α-tocopherol, bonds around the [[stereocenter]]s are shown as dashed lines (pointing down) or wedges (pointing up).]]

1 IU of tocopherol is defined as {{frac|2|3}} milligrams of ''RRR''-α-tocopherol (formerly named d-α-tocopherol or sometimes ddd-α-tocopherol). 1&nbsp;IU is also defined as 1&nbsp;milligram of an equal mix of the eight stereoisomers, which is a [[racemic mixture]] called [[tocopheryl acetate|''all-rac''-α-tocopheryl acetate]]. This mix of stereoisomers is often called dl-α-tocopheryl acetate, even though it is more precisely {{chem name|dl,dl,dl-α-tocopheryl acetate}}). However, 1&nbsp;IU of this racemic mixture is not now considered equivalent to 1&nbsp;IU of natural (RRR) α-tocopherol, and the [[Institute of Medicine]] and the [[USDA]] now convert IU's of the racemic mixture to milligrams of equivalent RRR using 1&nbsp;IU racemic mixture = 0.45 "milligrams α-tocopherol".{{r|USDA-NDL|pp=20–21}}

===Tocotrienols===
{{Main|Tocotrienol}}
Tocotrienols also belong to the vitamin E family. Tocotrienols have four natural 2' d-isomers (they have a stereoisomeric carbon only at the 2' ring-tail position). The four tocotrienols (in order of decreasing methylation: d-α-, d-β-, d-γ-, and d-δ-tocotrienol) have structures corresponding to the four tocopherols, except with an unsaturated bond in each of the three [[isoprene]] units that form the hydrocarbon tail, whereas tocopherols have a saturated phytyl tail (the phytyl tail of tocopherols gives the possibility for 2 more stereoisomeric sites in these molecules that tocotrienols do not have). Tocotrienols have seen less research as compared to tocopherols.<ref>{{cite journal | vauthors = Sen CK, Khanna S, Roy S | title = Tocotrienols: Vitamin E beyond tocopherols | journal = Life Sciences | volume = 78 | issue = 18 | pages = 2088–2098 | date = March 2006 | pmid = 16458936 | pmc = 1790869 | doi = 10.1016/j.lfs.2005.12.001 }}</ref>

==Function and dietary recommendations==
{{Main|Vitamin E}}
[[File:TocophMech.svg|thumb|left|360px|class=skin-invert-image|Tocopherols function by donating H atoms to radicals (X).]]

===Mechanism of action===
Tocopherols are radical scavengers, delivering an H atom to quench free radicals. At 323&nbsp;kJ/mol, the O–H bond in tocopherols is approximately 10% weaker than in most other [[phenol]]s.<ref>{{RubberBible87th}}</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 relatively unreactive, but reverts 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 = 1000–1013 | date = September 2011 | pmid = 21664268 | pmc = 3156342 | doi = 10.1016/j.freeradbiomed.2011.05.017 }}</ref> As they are fat-soluble, tocopherols are incorporated into cell membranes, which are thus protected from oxidative damage.

===Dietary considerations===
The U.S. Recommended Dietary Allowance (RDA) for adults is 15&nbsp;mg/day.<ref name="DRItext"/> The RDA is based on the α-tocopherol form because it is the most active form as originally tested. Vitamin E supplements are absorbed best when taken with meals.<ref>{{cite journal | vauthors = Iuliano L, Micheletta F, Maranghi M, Frati G, Diczfalusy U, Violi F | title = Bioavailability of vitamin E as function of food intake in healthy subjects: effects on plasma peroxide-scavenging activity and cholesterol-oxidation products | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 21 | issue = 10 | pages = E34–E37 | date = October 2001 | pmid = 11597949 | doi = 10.1161/hq1001.098465 | doi-access = free }}</ref> The U.S. Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E at 1,000&nbsp;mg (1,500&nbsp;IU) per day.<ref name="GOVe">{{cite web |author1=National Institutes of Health |author1-link=NIH |title=Vitamin E: Facts Sheet for Health Professionals |url=https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/ |website=Dietary Supplement Fact Sheets |publisher=Office of Dietary Supplements |access-date=19 May 2021 |language=en |date=26 March 2021}}</ref> The [[European Food Safety Authority]] sets UL at 300&nbsp;mg α-tocopherol equivalents per 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 |url-status = live |archive-url = https://web.archive.org/web/20160316225123/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf |archive-date = 2016-03-16}}.</ref>

===α-Tocopherol equivalents===
For dietary purposes, vitamin E activity of vitamin E [[isomers]] is expressed as α-tocopherol equivalents (a-TEs). One a-TE is defined by the biological activity of 1&nbsp;mg (natural) d-α-tocopherol in the resorption-gestation test. According to listings by [[FAO]] and others β-tocopherol should be multiplied by 0.5, γ-tocopherol by 0.1, and α-tocotrienol by 0.3.<ref name=fao1 /> The IU is converted to aTE by multiplying it with 0.67.<ref>{{cite web |url=http://www.ncc.umn.edu/products/databaseNUTvitamins.html |title=Vitamins |access-date=2013-03-26 |url-status=dead |archive-url=https://web.archive.org/web/20130320015716/http://www.ncc.umn.edu/products/databaseNUTvitamins.html |archive-date=2013-03-20 |publisher=University of Minnesota Nutrition Coordinating Center on Vitamins}}</ref> These factors do not correlate with the antioxidant activity of vitamin&nbsp;E isomers, where [[tocotrienols]] show even much higher activity in vivo.<ref name="pmid11160563">{{cite journal | vauthors = Packer L, Weber SU, Rimbach G | title = Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling | journal = The Journal of Nutrition | volume = 131 | issue = 2 | pages = 369S–373S | date = February 2001 | pmid = 11160563 | doi = 10.1093/jn/131.2.369S | doi-access = free }}</ref>

==Sources==
{{Main|Vitamin E}}
The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015.<ref name=USDA-NDL>{{cite report |author= Nutrient Data Laboratory |date= September 2015 |title= Composition of Foods Raw, Processed, Prepared: USDA National Nutrient Database for Standard Reference, Release 28 |url= https://www.ars.usda.gov/ARSUserFiles/80400535/Data/SR/sr28/sr28_doc.pdf |publisher= Beltsville Human Nutrition Research Center, [[Agricultural Research Service]], [[United States Department of Agriculture]] |edition= Slightly revised |location= Beltsville, MA |pages= 20–21 |docket= SR28}}</ref> In general, food sources with the highest concentrations of vitamin E are [[vegetable oil]]s, followed by [[Nut (fruit)|nuts]] and [[seed]]s. Adjusting for typical portion sizes, however, for many people in the [[United States]] the most important sources of vitamin E include fortified [[breakfast cereal]]s.<ref name=USDA-NDL/>

==Deficiency==
{{Main|Vitamin E deficiency}}
Vitamin E deficiency is rare, and in almost all instances caused by an underlying disease rather than a diet low in vitamin E.<ref name="GOVe"/> Vitamin E deficiency causes neurological problems due to poor nerve conduction. These include neuromuscular problems such as [[spinocerebellar ataxia]] and [[myopathy|myopathies]].<ref name=Traber>{{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 }}</ref> Deficiency also may cause [[anemia]], due to oxidative damage to red blood cells.

==Supplements==
Commercial vitamin E supplements may be classified into several distinct categories:
* Fully synthetic vitamin E, "dl-α-tocopherol", the most inexpensive, most commonly sold supplement form usually as the acetate ester
* Semi-synthetic "natural source" vitamin E esters, the "natural source" forms used in tablets and multiple vitamins; these are highly fractionated d-α-tocopherol or its esters, often made by synthetic methylation of gamma and beta {{chem name|d,d,d tocopherol}} vitamers extracted from plant oils.
* Less fractionated "natural mixed tocopherols" and high d-γ-tocopherol fraction supplements

===Synthetic all-racemic===
Synthetic vitamin E derived from petroleum products is manufactured as all-[[racemic]] α-tocopheryl acetate with a mixture of eight stereoisomers. In this mixture, one α-tocopherol molecule in eight molecules are in the form of ''RRR''-α-tocopherol (12.5% of the total).<ref>{{cite journal | vauthors = Weiser H, Riss G, Kormann AW | title = Biodiscrimination of the eight α-tocopherol stereoisomers results in preferential accumulation of the four 2R forms in tissues and plasma of rats | journal = The Journal of Nutrition | volume = 126 | issue = 10 | pages = 2539–49 | date = October 1996 | pmid = 8857515 | doi = 10.1093/jn/126.10.2539 | doi-access = free }}</ref>

The 8-isomer ''all-rac'' vitamin E is always marked on labels simply as '''dl-tocopherol''' or '''dl-tocopheryl acetate''', even though it is (if fully written out) {{chem name|dl,dl,dl-tocopherol}}. The present largest manufacturers of this type are [[DSM (company)|DSM]] and [[BASF]].

Natural α-tocopherol is the RRR-α (or ddd-α) form. The synthetic {{chem name|dl,dl,dl-α}} ("dl-α") form is not so active as the natural ddd-α ("d-α") tocopherol form. This is mainly due to reduced vitamin activity of the four possible stereoisomers that are represented by the ''l'' or ''S'' enantiomer at the first stereocenter (an S or l configuration between the chromanol ring and the tail, i.e., the SRR, SRS, SSR, and SSS stereoisomers).<ref name=Jensen>{{cite book |last1=Jensen |first1=S |last2=Lauridsen |first2=C |title=α-Tocopherol Stereoisomers |journal=Vitamins & Hormones |volume=76 |pages=281–308 |year=2007 |doi=10.1016/S0083-6729(07)76010-7 |pmid=17628178|isbn=9780123735928 }}</ref> The three unnatural "2R" stereoisomers with natural R configuration at this 2' stereocenter, but S at one of the other centers in the tail (i.e., RSR, RRS, RSS), appear to retain substantial RRR vitamin activity, because they are recognized by the [[alpha-tocopherol transfer protein]], and thus maintained in the plasma, where the other four stereoisomers (SRR, SRS, SSR, and SSS) are not. Thus, the synthetic all-rac-α-tocopherol, in theory, would have approximately half the vitamin activity of RRR-α-tocopherol in humans. Experimentally, the ratio of activities of the 8 stereoisomer racemic mixture to the natural vitamin, is 1 to 1.36 in the rat pregnancy model (suggesting a measured activity ratio of 1/1.36 = 74% of natural, for the 8-isomer racemic mix).<ref>"Taken together, these data indicate that of the eight stereoisomers (RRR, RSR, RRS, RSS, SRR, SSR, SRS, SSS) in all-rac-α-tocopherol, only the four 2R-forms (RRR, RSR, RSS, RRS) are recognized by α-TTP and maintained in the plasma. Indeed, the Food and Nutrition Board (Food and Nutrition Board and Institute of Medicine, 2000) has defined that only α-tocopherol, specifically the 2R-forms of α-tocopherol, can fulfill the human requirement for vitamin E. Thus, all-rac-α-tocopherol has only half the activity of RRR-α-tocopherol." Taken from the discussion in {{cite journal | vauthors = Lauridsen C, Engel H, Craig AM, Traber MG | title = Relative bioactivity of dietary RRR- and all-rac-α-tocopheryl acetates in swine assessed with deuterium-labeled vitamin E | journal = Journal of Animal Science | volume = 80 | issue = 3 | pages = 702–7 | date = March 2002 | pmid = 11890405 | doi = 10.2527/2002.803702x | url = http://jas.fass.org/cgi/reprint/80/3/702.pdf | access-date = 2008-03-12 | archive-url = https://web.archive.org/web/20081217124036/http://jas.fass.org/cgi/reprint/80/3/702.pdf | url-status = dead | archive-date = 2008-12-17 }}</ref>

Although it is clear that mixtures of stereoisomers are not so active as the natural ''RRR''-α-tocopherol form, in the ratios discussed above, specific information on any side effects of the seven synthetic vitamin E stereoisomers is not readily available.

===Esters===
[[File:Tocopherylacetat.svg|thumb|200px|class=skin-invert-image|α-tocopheryl acetate, an [[acetate]] [[ester]] of α-tocopherol ]]

Manufacturers also commonly convert the phenol form of the vitamins (with a free [[hydroxyl]] group) to [[ester]]s, using acetic or succinic acid. These tocopheryl esters are more stable and are easy to use in vitamin supplements. α-Tocopheryl esters are de-esterified in the gut and then absorbed as the free tocopherol.<ref name=Mathias>{{cite journal | vauthors = Mathias PM, Harries JT, Peters TJ, Muller DP | title = Studies on the in vivo absorption of micellar solutions of tocopherol and tocopheryl acetate in the rat: demonstration and partial characterization of a mucosal esterase localized to the endoplasmic reticulum of the enterocyte | journal = Journal of Lipid Research | volume = 22 | issue = 5 | pages = 829–37 | date = July 1981 | doi = 10.1016/S0022-2275(20)37355-7 | pmid = 7288289 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ajandouz EH, Castan S, Jakob S, Puigserver A | title = A fast, sensitive HPLC method for the determination of esterase activity on α-tocopheryl acetate | journal = Journal of Chromatographic Science | volume = 44 | issue = 10 | pages = 631–3 | year = 2006 | pmid = 17254374 | doi = 10.1093/chromsci/44.10.631 |doi-access=free}}</ref> [[Tocopheryl nicotinate]], [[tocopheryl linolate]], and [[tocopheryl palmitate]] esters are also used in cosmetics and some pharmaceuticals.

===Mixed tocopherols===
"Mixed tocopherols" in the USA contain at least 20% w/w other natural R, R,R- tocopherols, i.e. R, R,R-α-tocopherol content plus at least 25% R, R,R-β-, R, R,R-γ-, R, R,R-δ-tocopherols.{{Citation needed|date=October 2012}}

Some brands may contain 20.0% w/w or more of the other tocopherols and measurable tocotrienols. Some mixed tocopherols with higher γ-tocopherol content are marketed as "High Gamma-Tocopherol". The label should report each component in milligrams, except R, R,R-α-tocopherol may still be reported in IU. Mixed tocopherols also may be found in other nutritional supplements.{{Citation needed|date=October 2012}}

==Uses==
{{Main|Vitamin E}}
Observational studies that measure dietary intake and/or serum concentration, and experimental studies that ideally are [[randomized clinical trial]]s (RCTs), are two means of examining the effects or lack thereof of a proposed intervention on human health.<ref>{{cite book |vauthors=Munnangi S, Boktor SW |chapter=Epidemiology of Study Design |title=StatPearls |date=18 December 2018 |publisher=StatPearls |pmid=29262004 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK470342/}}</ref> Healthcare outcomes may be expected to be in accord between reviews of observational and experimental studies. If there is a lack of agreement, then factors other than design need to be considered.<ref>{{Cite journal |last1=Toews |first1=Ingrid |last2=Anglemyer |first2=Andrew |last3=Nyirenda |first3=John Lz |last4=Alsaid |first4=Dima |last5=Balduzzi |first5=Sara |last6=Grummich |first6=Kathrin |last7=Schwingshackl |first7=Lukas |last8=Bero |first8=Lisa |date=2024-01-04 |title=Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials: a meta-epidemiological study |journal=The Cochrane Database of Systematic Reviews |volume=1 |issue=1 |pages=MR000034 |doi=10.1002/14651858.MR000034.pub3 |issn=1469-493X |pmc=10765475 |pmid=38174786}}</ref> In observational studies on vitamin E, an inverse correlation between dietary intake and risk of a disease, or serum concentration and risk of a disease, may be considered suggestive, but any conclusions also should rest on randomized clinical trials of sufficient size and duration to measure clinically significant results. One concern with correlations is that other nutrients and non-nutrient compounds (such as polyphenols) may be higher in the same diets that are higher in vitamin E. Another concern for the relevance of RCTs described below is that while observational studies are comparing disease risk between low and high dietary intake of naturally occurring vitamin E from food (when worldwide, the adult median dietary intake is 6.2&nbsp;mg/d for d-α-tocopherol; 10.2&nbsp;mg/day when all of the tocopherol and tocotrienol isomers are included),<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 = 261–281 | date = December 2015 | pmid = 27414419 | doi = 10.1024/0300-9831/a000281 | doi-access = free }}</ref> the prospective RCTs often used 400 IU/day of synthetic dl-α-tocopherol as the test product, equivalent to 268&nbsp;mg of α-tocopherol equivalents.<ref name="GOVe"/>

===Supplement popularity over time===
In the US, the popularity for vitamin E as a dietary supplement may have peaked around 2000. The [[Nurses' Health Study]] (NHS) and the Health Professionals Follow-up Study (HPFS) tracked dietary supplement use by people over the age of 40 during years 1986–2006. For women, user prevalence was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but had decreased to 19.8% in 2006. Similarly, for men, prevalence for same years was 18.9%, 52.0%, 49.4%, and 24.5%. The authors theorized that declining use in these health science aware populations may have been due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements.<ref>{{cite journal | vauthors = Kim HJ, Giovannucci E, Rosner B, Willett WC, Cho E | 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 | date = March 2014 | pmid = 24119503 | pmc = 3944223 | doi = 10.1016/j.jand.2013.07.039 }}</ref> There is other evidence for declining use of vitamin E. Within the U.S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%.<ref>{{cite journal | vauthors = Morioka TY, Bolin JT, Attipoe S, Jones DR, Stephens MB, Deuster PA | title = Trends in Vitamin A, C, D, E, K Supplement Prescriptions From Military Treatment Facilities: 2007 to 2011 | journal = Military Medicine | volume = 180 | issue = 7 | pages = 748–53 | date = July 2015 | pmid = 26126244 | doi = 10.7205/MILMED-D-14-00511 | doi-access = free }}</ref> A report on vitamin E sales volume in the USA documented a 50% decrease between 2000 and 2006,<ref>{{cite journal | vauthors = Tilburt JC, Emanuel EJ, Miller FG | 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 | date = September 2008 | pmid = 18618194 | pmc = 2518024 | doi = 10.1007/s11606-008-0704-z }}</ref> with a significant cause attributed to a well-publicized meta-analysis that had concluded that high-dosage vitamin E increased all-cause mortality.<ref name=Miller2005>{{cite journal | vauthors = Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E | title = Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality | journal = Annals of Internal Medicine | volume = 142 | issue = 1 | pages = 37–46 | date = January 2005 | pmid = 15537682 | doi = 10.7326/0003-4819-142-1-200501040-00110 | s2cid = 35030072 }}</ref>

=== Age-related macular degeneration ===
A Cochrane review published in 2017 (updated in 2023) on antioxidant vitamin and mineral supplements for slowing the progression of [[Macular degeneration|age-related macular degeneration]] (AMD) identified only one vitamin E clinical trial.<ref name=":0">{{Cite journal |last1=Evans |first1=Jennifer R. |last2=Lawrenson |first2=John G. |date=2023-09-13 |title=Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration |journal=The Cochrane Database of Systematic Reviews |volume=2023 |issue=9 |pages=CD000254 |doi=10.1002/14651858.CD000254.pub5 |issn=1469-493X |pmc=10498493 |pmid=37702300 }}</ref> That trial compared 500 IU/day of α-tocopherol to placebo for four years and reported no effect on the progression of AMD in people already diagnosed with the condition.<ref name=":0" /> Another Cochrane review, same year, same authors, reviewed the literature on α-tocopherol preventing the development of AMD. This review identified four trials, duration 4–10 years, and reported no change to risk of developing AMD.<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> A large clinical trial known as AREDS compared [[β-carotene]] (15&nbsp;mg), [[vitamin C]] (500&nbsp;mg), and α-tocopherol (400 IU) to placebo for up to ten years, with a conclusion that the anti-oxidant combination significantly slowed progression. However, because there was no group in the trial receiving only vitamin E, no conclusions could be drawn as to the contribution of the vitamin to the effect.<ref>{{cite journal | vauthors = Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Kurinij N, Davis MD | title = Long-term effects of vitamins C and E, β-carotene, and zinc on age-related macular degeneration: AREDS report no. 35 | journal = Ophthalmology | volume = 120 | issue = 8 | pages = 1604–11.e4 | date = August 2013 | pmid = 23582353 | pmc = 3728272 | doi = 10.1016/j.ophtha.2013.01.021 }}</ref>

=== Complementary and alternative medicine ===
Proponents of [[megavitamin therapy]] and [[orthomolecular medicine]] advocate ''natural tocopherols.''<ref name="gamma">{{cite journal | vauthors = Jiang Q, Christen S, Shigenaga MK, Ames BN | title = gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention | journal = The American Journal of Clinical Nutrition | volume = 74 | issue = 6 | pages = 714–22 | date = December 2001 | pmid = 11722951 | doi = 10.1093/ajcn/74.6.714 | doi-access = free }}</ref> Meanwhile, clinical trials have largely concentrated on use of either a synthetic, all-racemic d-α-tocopheryl acetate or synthetic dl-α-tocopheryl acetate.{{citation needed|date=April 2018}}

====Antioxidant theory====
{{Main|Antioxidant}}
Tocopherol is described as functioning as an antioxidant. A dose-ranging trial was conducted in people with chronic oxidative stress attributed to elevated serum cholesterol. Plasma F2-isoprostane concentration was selected as a biomarker of free radical-mediated lipid peroxidation. Only the two highest doses - 1600 and 3200 IU/day - significantly lowered F2-isoprostane.<ref>{{cite journal | vauthors = Roberts LJ, Oates JA, Linton MF, Fazio S, Meador BP, Gross MD, Shyr Y, Morrow JD | title = The relationship between dose of vitamin E and suppression of oxidative stress in humans | journal = Free Radical Biology & Medicine | volume = 43 | issue = 10 | pages = 1388–93 | date = November 2007 | pmid = 17936185 | pmc = 2072864 | doi = 10.1016/j.freeradbiomed.2007.06.019 }}</ref>

=== Alzheimer's disease ===
[[Alzheimer's disease]] (AD) and [[vascular dementia]] are common causes of decline of brain functions that occur with age. AD is a chronic neurodegenerative disease that worsens over time.<ref>{{cite journal | vauthors = Burns A, Iliffe S | title = Alzheimer's disease | journal = BMJ | volume = 338 | pages = b158 | date = February 2009 | pmid = 19196745 | doi = 10.1136/bmj.b158 | s2cid = 8570146 }}</ref> The disease process is associated with [[Senile plaques|plaques]] and [[Neurofibrillary tangle|tangles]] in the brain.<ref name=Lancet2011>{{cite journal | vauthors = Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E | title = Alzheimer's disease | journal = Lancet | volume = 377 | issue = 9770 | pages = 1019–31 | date = March 2011 | pmid = 21371747 | doi = 10.1016/S0140-6736(10)61349-9 | s2cid = 20893019 }}</ref> Vascular dementia may be caused by ischemic or hemorrhagic [[infarct]]s affecting multiple brain areas, including the [[anterior cerebral artery]] territory, the [[parietal lobe]]s, or the [[cingulate gyrus]].<ref>{{cite journal | vauthors = Love S | title = Neuropathological investigation of dementia: a guide for neurologists | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 76 Suppl 5 | issue = supplement 5 | pages = v8-14 | date = December 2005 | pmid = 16291923 | pmc = 1765714 | doi = 10.1136/jnnp.2005.080754 }}</ref> Both types of dementia may be present. Vitamin E status (and that of other antioxidant nutrients) is conjectured as having a possible impact on risk of Alzheimer's disease and vascular dementia. A review of dietary intake studies reported that higher consumption of vitamin E from foods lowered the risk of developing AD by 24%.<ref>{{cite journal | vauthors = Li FJ, Shen L, Ji HF | title = Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis | journal = Journal of Alzheimer's Disease | volume = 31 | issue = 2 | pages = 253–8 | date = 2012 | pmid = 22543848 | doi = 10.3233/JAD-2012-120349 }}</ref> A second review examined serum vitamin E levels and reported lower serum vitamin E in AD patients 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–e263 | date = February 2018 | pmid = 28833475 | doi = 10.1002/gps.4780 | s2cid = 44859128 }}</ref> In 2017 a consensus statement from the British Association for Psychopharmacology included that until further information is available, vitamin E cannot be recommended for treatment or prevention of Alzheimer's disease.<ref>{{cite journal | vauthors = O'Brien JT, Holmes C, Jones M, Jones R, Livingston G, McKeith I, Mittler P, Passmore P, Ritchie C, Robinson L, Sampson EL, Taylor JP, Thomas A, Burns A | title = Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology | journal = Journal of Psychopharmacology | volume = 31 | issue = 2 | pages = 147–168 | date = February 2017 | pmid = 28103749 | doi = 10.1177/0269881116680924 | s2cid = 52848530 | url = https://eprints.soton.ac.uk/408021/1/BAP_Guidelines_AntiDementia.pdf }}</ref>

===Cancer===
From reviews of observational studies, diets higher in vitamin E content were associated with a lower relative risk of [[kidney cancer]],<ref name=Shen2015>{{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> [[bladder cancer]],<ref name=Wang2014>{{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> and [[lung cancer]]<ref name=Zhu2017>{{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 = 271–277 | date = March 2017 | pmid = 28244705 | doi = 10.6133/apjcn.032016.04 }}</ref> When comparisons were made between the lowest and highest groups for dietary vitamin E consumption from food, the average reductions in relative risk were in the range of 16-19%. For all of these reviews, the authors noted that the findings needed to be confirmed by prospective studies.<ref name=Shen2015/><ref name=Wang2014/><ref name=Zhu2017/> From [[randomized clinical trial]]s (RCTs) in which α-tocopherol was administered as a dietary supplement, results differed from the dietary intake reviews. A RCT of 400 IU/day of α-tocopherol did not reduce risk of bladder cancer.<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> In male tobacco smokers, 50&nbsp;mg/day had no impact on developing lung cancer.<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 | last1 = Alpha-Tocopherol | first1 = Beta Carotene Cancer Prevention Study Group | doi-access = free }}</ref> A review of RCTs for [[colorectal cancer]] reported lack of a statistically significant reduction in 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> In male tobacco smokers, 50&nbsp;mg/day reduced prostate cancer risk by 32%,<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 α-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 }}</ref> but in a different trial, majority non-smokers, 400 IU/day increased risk by 17%.<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> In women who consumed either placebo or 600 IU of natural-source vitamin E on alternate days for an average of 10.1 years there were no significant differences for [[breast cancer]], lung cancer, or colon cancer.<ref>{{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 | doi-access = free }}</ref>

The U.S. [[Food and Drug Administration]] initiated a process of reviewing and approving food and dietary supplement health claims in 1993. A Qualified Health Claim issued in 2012 allows product label claims that vitamin E may reduce risk of renal, bladder, and colorectal cancers, with a stipulation that the label must include a mandatory qualifier sentence: “FDA has concluded that there is very little scientific evidence for this claim.”<ref name=FDA2012>[https://wayback.archive-it.org/7993/20171114183722/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm306866.htm Alliance for Natural Health v. Sebelius, Case No. 09-1546 (D.D.C.)] U.S. Food & Drug Administration May 17, 2012</ref> The [[European Food Safety Authority]] (EFSA) reviews proposed health claims for the [[European Union]] countries. As of March 2018, EFSA has not evaluated any vitamin E and cancer prevention claims.

===Cataracts===
A meta-analysis from 2015 reported that for studies that reported serum tocopherol, higher serum concentration was associated with a 23% reduction in relative risk of age-related [[cataract]]s (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract - the three major classifications of age-related cataracts.<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 | doi-access = free }}</ref> However, this article and a second meta-analysis reporting on clinical trials of α-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.<ref name=Zhang2015/><ref name="pmid22696344">{{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 | issue = 6 | pages = CD004567 | date = June 2012 | volume = 2012 | pmid = 22696344 | pmc = 4410744 | doi = 10.1002/14651858.CD004567.pub2 }}</ref>

===Cardiovascular diseases===
Research on the effects of vitamin E on [[cardiovascular disease]] has produced conflicting results. An inverse relation has been observed between [[coronary heart disease]] and the consumption of foods high in vitamin E, and also higher serum concentration of α-tocopherol.<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 }}</ref> In one of the largest observational studies, almost 90,000 healthy nurses were tracked for eight years. Compared to those in the lowest fifth for reported vitamin E consumption (from food and dietary supplements), those in the highest fifth were at a 34% lower risk of major coronary disease.<ref name=Stampher1993>{{cite journal | vauthors = Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC | title = Vitamin E consumption and the risk of coronary disease in women | journal = The New England Journal of Medicine | volume = 328 | issue = 20 | pages = 1444–9 | date = May 1993 | pmid = 8479463 | doi = 10.1056/NEJM199305203282003 | doi-access = free }}</ref> Diet higher in vitamin E also may be higher in other, unidentified components that promote heart health, or people choosing such diets may be making other healthy lifestyle choices.<ref name=Kirmizis2009/><ref name=Stampher1993/> There is some supporting evidence from [[randomized clinical trial]]s (RCTs). A meta-analysis on the effects of α-tocopherol supplementation in RCTs on aspects of cardiovascular health reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%.<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> The results were not consistent for all of the individual trials incorporated into the meta-analysis. For example, the Physicians' Health Study II did not show any benefit after 400 IU every other day for eight years, for heart attack, stroke, coronary mortality, or all-cause mortality.<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> The effects of vitamin E supplementation on incidence of stroke were summarized in 2011. There were no significant benefits for vitamin E versus placebo for risk of stroke, or for subset analysis for [[ischaemic stroke]], [[haemorrhagic stroke]], fatal stroke, or non-fatal stroke.<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 randomised 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>

In 2001 the U.S. [[Food and Drug Administration]] rejected proposed health claims for vitamin E and cardiovascular health.<ref>[https://wayback.archive-it.org/7993/20171115122059/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073251.htm Letter Regarding Dietary Supplement Health Claim for Vitamin E and Heart Disease (Docket No 99P-4375)] U.S. Food and Drug Administration.</ref> The U.S. National Institutes of Health also reviewed the literature and concluded there was not sufficient evidence to support the idea that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality.<ref name="GOVe"/> In 2010 the [[European Food Safety Authority]] reviewed and rejected claims that a cause and effect relationship has been established between the dietary intake of vitamin E and maintenance of normal cardiac function or of normal blood circulation.<ref>[https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2010.1816 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 normal cardiac function (ID 166),... maintenance of normal blood circulation (ID 216)... pursuant to Article 13(1) of Regulation (EC) No 1924/2006] European Food Safety Authority EFSA Journal 2010;8(10):1816.</ref>

=== Pregnancy===
Antioxidant vitamins as dietary supplements have been proposed as having benefits if consumed during pregnancy. For the combination of vitamin E with vitamin C supplemented to pregnant women, a Cochrane review of 21 clinical trials concluded that the data do not support vitamin E supplementation - majority of trials α-tocopherol at 400 IU/day plus vitamin C at 1000&nbsp;mg/day - as being efficacious for reducing risk of [[stillbirth]], [[neonatal death]], [[preterm birth]], [[preeclampsia]], or any other maternal or infant outcomes, either in healthy women or those considered at risk for pregnancy complications.<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> The review identified only three small trials in which vitamin E was supplemented without co-supplementation with vitamin C. None of these trials reported any clinically meaningful information.<ref name=CochraneVitE/>

=== Topical ===
Although there is widespread use of vitamin E as a [[topical medication]], with claims for improved [[wound healing]] and reduced [[scar]] tissue, reviews have repeatedly concluded that there is insufficient evidence to support these claims.<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 }}</ref>

==Side effects==
The U.S. Food and Nutrition Board set a [[Tolerable upper intake levels|Tolerable upper intake level (UL)]] at 1,000&nbsp;mg (1,500 IU) per day derived from animal models that demonstrated bleeding at high doses.<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 | doi = 10.17226/9810 | pmid = 25077263 | isbn = 978-0-309-06935-9 | chapter-url = https://www.nap.edu/read/9810/chapter/8 | url-status = live | archive-url = https://web.archive.org/web/20180226152013/https://www.nap.edu/read/9810/chapter/8 | archive-date = 2018-02-26 | author1-link = Institute of Medicine }}</ref> The [[European Food Safety Authority]] reviewed the same safety question and set a UL at 300&nbsp;mg/day.<ref name=EFSA-UL/> A meta-analysis of long-term clinical trials reported a non-significant 2% increase in all-cause mortality when α-tocopherol was the only supplement used.<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 }}</ref> Another meta-analysis reported a non-significant 1% increase in all-cause mortality when α-tocopherol was the only supplement. Subset analysis reported no difference between natural (plant extracted) or synthetic α-tocopherol, or whether the amount used was less than or more than 400 IU/day.<ref>{{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 = Cardiovascular Drugs and Therapy | volume = 28 | issue = 6 | pages = 563–73 | date = December 2014 | pmid = 25398301 | doi = 10.1007/s10557-014-6560-7 | s2cid = 23820017 }}</ref> There are reports of vitamin E-induced allergic contact dermatitis from use of vitamin-E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products. Incidence is low despite widespread use.<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>

===Drug interactions===
The amounts of α-tocopherol, other tocopherols and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of α-tocopherol as a dietary supplement in amounts in excess of 300&nbsp;mg/day may lead to interactions with [[aspirin]], [[warfarin]], [[tamoxifen]], and [[cyclosporine A]] in ways that alter function. 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 | doi-access = free }}</ref> One small trial demonstrated that vitamin E at 400&nbsp;mg/day reduced blood concentration of the anti-breast cancer drug tamoxifen. In multiple clinical trials, vitamin E lowered blood concentration of the immuno-suppressant drug, cyclosporine A.<ref name=Podszun2014/> The U.S. 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 cited reported instances of reduced treatment adverse effects, but also poorer cancer survival, raising the possibility of tumor protection from the oxidative damage intended by the treatments.<ref name=GOVe/>

==Synthesis==
Naturally sourced d-α-tocopherol can be extracted and purified from seed oils, or γ-tocopherol can be extracted, purified, and methylated to create d-alpha-tocopherol. In contrast to α-tocopherol extracted from plants, which also is called d-α-tocopherol, industrial synthesis creates dl-α-tocopherol. "It is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-α-tocopherol, using iron in the presence of hydrogen chloride gas as a catalyst. The reaction mixture obtained is filtered and extracted with aqueous caustic soda. Toluene is removed by evaporation and the residue (all rac-α-tocopherol) is purified by vacuum distillation." Specification for the ingredient is >97% pure.<ref>[https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2012.2784 Scientific Opinion on the safety and efficacy of synthetic α-tocopherol for all animal species] (2012) European Food Safety Authority EFSA Journal 2012;10(7):2784</ref> This synthetic dl-α-tocopherol has approximately 50% of the potency of d-α-tocopherol. Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to an [[ester]] using either [[acetic acid]] or [[succinic acid]] because the esters are more chemically stable, providing for a longer shelf-life. The ester forms are de-esterified in the gut and absorbed as free α-tocopherol.

==History==
During feeding experiments with rats [[Herbert McLean Evans]] concluded in 1922 that besides vitamins B and C, an unknown vitamin existed.<ref>{{cite journal | vauthors = Evans HM, Bishop KS | title = On the Existence of a Hitherto Unrecognized Dietary Factor Essential for Reproduction  | 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 | url = https://zenodo.org/record/1448277 }}</ref> Although every other nutrition was present, the rats were not fertile. This condition could be changed by additional feeding with wheat germ. It took several years until 1936 when the substance was isolated from wheat germ and the formula C<sub>29</sub>H<sub>50</sub>O<sub>2</sub> was determined. Evans also found that the compound reacted like an [[Alcohol (chemistry)|alcohol]] and concluded that one of the oxygen atoms was part of an OH (hydroxyl) group. As noted in the introduction, the vitamin was given its name by Evans from Greek words meaning "to bear young" with the addition of the -ol as an alcohol.<ref>{{cite journal| author1 = Evans H. M.| author2 = Emerson O. H.| author3 = Emerson G. A.| title = The isolation from wheat germ oil of an alcohol, a-tocopherol, having the properties of vitamin E| journal = Journal of Biological Chemistry| date = 1 February 1936| volume = 113| issue = 1| pages = 319–332| doi = 10.1016/S0021-9258(18)74918-1| url = http://www.jbc.org/cgi/reprint/113/1/319| url-status = live| archive-url = https://web.archive.org/web/20070929091434/http://www.jbc.org/cgi/reprint/113/1/319| archive-date = 29 September 2007| doi-access = free}}</ref>
The structure was determined shortly thereafter in 1938.<ref>{{cite journal |last1=Fernholz |first1=E. |journal=Journal of the American Chemical Society |volume=60 |pages=700–705 |year=1938 |doi=10.1021/ja01270a057 |issue=3 |title=On the Constitution of α-Tocopherol|bibcode=1938JAChS..60..700F }}</ref>

== See also ==
* [[α-Tocopherol]]
* [[Tocotrienol]]
* [[Vitamin E]]

== References ==
{{Reflist|30em}}

== External links ==
* [http://ods.od.nih.gov/factsheets/vitamine.asp US Office of Dietary Supplements article on Vitamin E]
* [http://www.food.gov.uk/multimedia/pdfs/evm_e.pdf Vitamin E risk assessment] {{Webarchive|url=https://web.archive.org/web/20060102223534/http://www.food.gov.uk/multimedia/pdfs/evm_e.pdf |date=2006-01-02 }}, Expert Group on Vitamins and Minerals, UK [[Food Standards Agency]], 2003

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[[Category:Food antioxidants]]
[[Category:Dietary antioxidants]]
[[Category:Cosmetics chemicals]]
[[Category:Meroterpenoids]]
[[Category:Vitamers]]
[[Category:Vitamin E]]
[[Category:E-number additives]]