Vitamin E

What is Vitamin E?

Eight fat-soluble substances make up vitamin E, including four tocopherols and four tocotrienols. Nerve issues can result from a vitamin E deficit, which is uncommon and typically caused by an underlying issue with the digestion of dietary fat rather than from a diet low in the vitamin.

As an antioxidant that is fat-soluble, vitamin E may aid in shielding cell membranes from reactive oxygen species. Government agencies from all throughout the world advise adults to take between 3 and 15 milligrams daily.

In 2016, a global assessment of over one hundred studies revealed a median daily food intake of 6.2 mg of alpha-tocopherol, which was below recommended levels.

According to population studies, there was a lower incidence of heart disease, cancer, dementia, and other disorders among those who ate more foods high in vitamin E or who took vitamin E supplements on their own.

Even at daily doses of up to 2,000 mg of alpha-tocopherol, placebo-controlled clinical trials were not always able to confirm these results. The use of vitamin E supplements peaked in the US in 2002, but by 2006, usage had decreased by more than half.

The scientists hypothesized that the release of sizable placebo-controlled trials that either revealed no benefits at all or real harm from high-dose vitamin E could have contributed to the decline in use.

Because synthetic and natural tocopherols can oxidize, tocopheryl acetate is produced through esterification in dietary supplements to provide stability.

Tocopherols and tocotrienols are classified into four different forms based on the quantity and location of methyl groups on the chromanol ring: α (alpha), β (beta), γ (gamma), and δ (delta).

The chromane double ring present in all eight of these vitamers has a hydrophobic side chain that permits entry into cellular membranes and a hydroxyl group that can donate a hydrogen atom to lower free radicals.

First produced in 1938, vitamin E was first isolated in 1935 after its discovery in 1922. The vitamin activity was originally named “tocopherol” after Greek words meaning “birth” and “to bear or carry,” because it was shown to be necessary for fertilized eggs to produce live births (in rats).

Whether it is found naturally in plant oils or, more frequently, synthesized as tocopheryl acetate, alpha-tocopherol is marketed as a popular dietary supplement that can be taken on its own, in multivitamin products, or in oils or lotions for external application.

Chemistry

The equivalency of vitamin E to 100% RRR-configuration α-tocopherol activity determines its nutritional content.

The four tocopherols and four tocotrienols, each grouping of four denoted by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-), are the molecules that contribute to α-tocopherol activity.

Each of the three “R” sites of alpha(α)-tocopherol has a methyl group (CH3) linked to it. R1 is a methyl group, R2 is an H, and R3 is a methyl group for beta(β)-tocopherol. R1 = H, R2 = methyl group, and R3 = methyl group for gamma(γ)-tocopherol. R1 = H, R2 = H, and R3 = methyl group for delta(δ)-tocopherol.

The tocotrienols have identical structures as the tocopherols, with the exception that the hydrophobic side chain has three carbon-carbon double bonds and the saturated side chain has one.

Stereoisomers

Tocopherols can be distinguished from tocotrienols by the location of their methyl groups, as well as by the phytyl tail, which has three chiral points or centers that can be oriented either left or right.

The synthetic form of alpha-tocopherol, also known as all-racemic or all-rac vitamin E, also known as dl-tocopherol, is made up of equal parts of eight stereoisomers, namely RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR, with progressively decreasing biological equivalency.

As a result, 1.36 mg of dl-tocopherol is thought to be equivalent to 1.0 mg of d-tocopherol, the naturally occurring form. Put another way, 73.5% of the efficacy of the natural is present in the synthetic.

Tocopherols

As a lipid-soluble antioxidant that works with the glutathione peroxidase pathway to combat lipid radicals created during the lipid peroxidation chain reaction, alpha-tocopherol shields cell membranes from oxidation.

This stops the oxidation reaction from proceeding and eliminates the free radical intermediates. Other antioxidants like ubiquinol, retinol, or ascorbate can convert the oxidized α-tocopheroxyl radicals created in this process back to their active reduced form.

Different forms of vitamin E possess distinct characteristics; for instance, γ-tocopherol can react with electrophilic mutagens as a nucleophile.

Tocotrienols

The fundamental structural difference between the four tocopherols and the four tocotrienols (alpha, beta, gamma, and delta) is that the tocopherols have saturated side chains, whereas the former have hydrophobic side chains with three carbon-carbon double bonds.

Each of the three “R” sites of alpha(α)-tocotrienol has a methyl group (CH3) connected to it. R1 is a methyl group, R2 is an H, and R3 is a methyl group for beta (β)-tocotrienol. R1 = H, R2 = methyl group, R3 = methyl group for gamma(γ)-tocotrienol.

R1 = H, R2 = H, and R3 = methyl group for delta(δ)- tocotrienol. Alpha and gamma tocotrienols can be found in palm oil. Tocotrienols only contain one chiral center, which is located at the carbon of the 2′ chromanol ring, where the isoprenoid tail connects to the ring.

Because of unsaturation (C-C double bonds) at these locations, the other two corresponding centers in the phytyl tail of the corresponding tocopherols do not exist as chiral centers for tocotrienols.

D-tocotrienols are the dextrorotatory stereoisomers of tocotrienols that are isolated from plants. Theoretically, levorotatory tocotrienols (l-tocotrienols) might also exist; these would have a 2S instead of a 2R configuration at the solitary chiral center of the molecule.

However, in contrast to synthetic dl-alpha-tocopherol, commercially available tocotrienol dietary supplements are derived from palm oil.

Tocotrienols have been linked to several health advantages, such as a lower risk of heart disease and age-related cognitive decline. and cancer. The proof is inconclusive.

Functions

As a vitamin, vitamin E may have a number of purposes. Numerous biological roles have been proposed, one of which is that of a fat-soluble antioxidant.

In this capacity, vitamin E scavenges radicals by giving free radicals an atom of hydrogen (H). Tocopherols’ O-H bond is approximately 10% weaker than that of the majority of other phenols, with 323 kJ/mol.

Because of this weak link, the vitamin can reduce the harmful effects of the peroxyl radical and other free radicals by giving them a hydrogen atom.

When a hydrogen donor, like vitamin C, is involved in a redox process, the resulting tocopheryl radical is recycled back into tocopherol.

Vitamin E has an impact on gene expression and regulates the activity of enzymes. One example of an enzyme that influences smooth muscle formation is protein kinase C (PKC), which vitamin E helps deactivate to prevent smooth muscle growth.

Synthesis

Biosynthesis

Tocochromanols, a chemical family of compounds consisting of four tocopherols and four tocotrienols, are produced by photosynthesizing plants, algae, and cyanobacteria.

This family of chemicals is known as Vitamin E in the context of nutrition. The first step in biosynthesis is the creation of homogentisic acid (HGA), the molecule’s closed-ring portion. For tocopherols, the side chain is connected; for tocotrienols, it is polyunsaturated.

Both follow the same process, which results in the creation of gamma-, alpha-, or delta-, and beta-compounds from there. The plastids are where biosynthesis occurs. The primary explanation for plants’ production of tocochromanols seems to be their antioxidant properties.

Different tocochromanols predominate in different plant sections and species. α-tocopherol is the type that is mostly found in leaves, and therefore, in leafy green vegetables. It is situated near the photosynthetic process in the chloroplast membranes.

Its purpose is to shield the body from solar damage caused by UV radiation. It seems that α-tocopherol is not necessary for normal growth conditions because other photo-protective chemicals exist, and plants that have lost their ability to produce α-tocopherol due to mutations nevertheless grow normally.

On the other hand, if a plant has normal synthesis under stressful growing conditions like drought, high temperatures, or salt-induced oxidative stress, its physiological status is superior. Lipid-rich seeds are designed to supply energy for early development and germination.

The seed lipids are shielded against oxidation and rancidity by tocochromanols. Tocochromanols increase the lifetime of seeds and facilitate successful germination and seedling growth.

With a few exceptions, gamma-tocopherol predominates in the seeds of most plant species.

The ratio of γ-tocopherol to α-tocopherol is higher in canola, corn, and soybean oils; however, the opposite is true for safflower, sunflower, and olive oils. Palm oil stands out among the frequently used food oils in that its tocotrienol level is larger than its tocopherol content.

Stressors in the environment also affect the tocochromanol concentration of seeds. For instance, drought or high temperatures in almonds increase the amount of α- and γ-tocopherol in the nuts.

Drought is mentioned in the same piece as an increase in tocopherol content. of olives, and boiled soybeans in the same manner. The two distinct routes that are involved in the manufacture of vitamin E in plastids are the Shikimate pathway and the Methylerythritol Phosphate pathway (MEP pathway).

The hydrophobic tail that separates tocopherol and tocotrienol is produced by the MEP pathway, whereas the chromanol ring is produced by the Shikimate pathway from homogeneous acid (HGA).

Which molecule the particular tail comes from determines how it is synthesized. Whereas the phytyl tail of a tocotrienol originates from a phytyl diphosphate, the prenyl tail of a-tocopherol comes from the geranylgeranyl diphosphate (GGDP) group.

Specifically, tocopherols are synthesized by reacting Phytyl-PP with HGA to produce 2-Methyl-6-phytylhydroquinone, which is the first of its derivatives.

Two distinct paths can be followed by 2-methyl-6-phytylhydroquinone at this stage of the synthesis.

At C3, the molecule is methylated via the first pathway. A 2,3-Dimethyl-5-phytylhydroquinone is the product of this. Next, the hydroxyl group at C1 undergoes cyclization, producing the first derivative, γ-Tocopherol.

After cyclization, γ-tocopherol undergoes additional methylation at position C5, which yields α-tocopherol. Using the identical 2-methyl-6-phytylhydroquinone, the second route cyclizes the hydroxyl group at C1, yielding δ-Tocopherol.

After that, β-Tocopherol, the final product, is produced through a cycle of methylation at position C5. Tocotrienol undergoes a similar complete synthesis using prenyl-PP, which is produced from a group that uses GGDP in place of phytyl-PP.

Industrial synthesis

All-rac-alpha-tocopherol, commonly known as dl-alpha-tocopherol, is the synthetic form of the substance.

It is made up of eight stereoisomers in equal amounts: RRR, RRS, RSS, RSR, SRR, SSR, SRS, and SSS. It’s made by reacting a combination of toluene and 2,3,5-trimethyl-hydroquinone with isophytol to produce all-rac-alpha-tocopherol, employing iron as a catalyst in the presence of hydrogen chloride gas.

Aqueous caustic soda is used to filter and extract the resultant reaction mixture. The residue (all rac-alpha-tocopherol) is refined by vacuum distillation after toluene is eliminated by evaporation. d-alpha-tocopherol, also known as RRR-alpha tocopherol, is the term used to describe the synthetic tocopherol that is produced from plants.

The potency of the synthetic is 73.5% that of the natural. The phenol is transformed by producers of dietary supplements and fortified foods for people or domesticated animals.

form of the vitamin to an ester with either succinic acid or acetic acid, as the esters have a longer shelf life due to their greater chemical stability.

Deficiency

In humans, vitamin E insufficiency is uncommon and results from anomalies in the absorption or metabolism of dietary fat rather than from a diet deficient in the nutrient.

Alpha-tocopherol transfer protein (α-TTP) gene mutations are one type of genetic aberration in metabolism. Despite taking normal quantities of vitamin E, individuals with this genetic mutation display a progressive neurological condition known as ataxia with vitamin E deficiency (AVED).

To make up for the loss of α-TTP, large doses of dietary supplements containing alpha-tocopherol are required.

Due to alterations in the structure and function of neuron membranes, a vitamin E shortage brought on by malabsorption or a metabolic abnormality can create issues with the conduction of electrical impulses along nerves.

Apart from ataxia, vitamin Peripheral neuropathy, myopathies, retinopathy, and compromised immunological responses can all result from an E deficit.

Drug interactions

When ingested through food, the levels of alpha-tocopherol, other tocopherols, and tocotrienols that make up dietary vitamin E don’t seem to interact with medications.

When alpha-tocopherol is taken as a dietary supplement in doses higher than 300 mg/day, it may interact in ways that change how aspirin, warfarin, and cyclosporine A work.

High levels of vitamin E may enhance the anti-blood-clotting effects of aspirin and warfarin.

Vitamin E reduced the blood levels of cyclosporine A, an immunosuppressant drug, in several clinical trials.

The US National Institutes of Health, Office of Dietary Supplements, advises against the co-administration of vitamin E in these situations due to concerns that it may interfere with the mechanisms of anti-cancer radiation treatment and some forms of chemotherapy. patient cohorts.

The references it listed described cases of decreased side effects from therapy but also of lower cancer survival rates, suggesting that tumors may be shielded from the medicines’ intended oxidative damage.

Dietary recommendations

In 2000, the National Academy of Medicine in the United States revised the recommended dietary allowances (RDAs) and estimated average needs (EARs) for vitamin E. In order to determine levels that will cover persons with greater than average requirements, RDAs are higher than EARs.

When the information needed to set EARs and RDAs is lacking, adequate intakes (AIs) are found. For both men and women ages 14 and up, the EAR for vitamin E is 12 mg/day. There is a 15 mg daily RDA.

Regarding safety, where there is enough data, acceptable upper intake levels, often known as upper limits” or “ULs,” are established for vitamins and minerals.

Rat hemorrhagic effects were chosen as the crucial endpoint in order to compute the upper limit by beginning at the lowest amount of unfavorable effect that was detected.

An upper limit for humans was the outcome, capped at 1000 milligrams per day. Dietary Reference Intakes is the term used to refer to the EARs, RDAs, AIs, and ULs together.

The combined collection of data is referred to as dietary reference values by the European Food Safety Authority (EFSA), which uses average needs in place of EARs and population reference intakes (PRIs) in place of RDAs.

The definitions of AIs and ULs are the same as they are in the US. The PRIs are 11 and 13 mg/day for males and women, respectively, who are 10 years of age and older. PRI is 11 mg/day throughout pregnancy and 11 mg/day during lactation.

The PRIs rise with age in children aged 1 to 9 years, from 6 to 9 mg/day. Blood clotting was identified by the EFSA as a safety-critical consequence.

It determined that no negative effects were seen in a human experiment at 540 mg/day and employed an uncertainty factor of two to arrive at a recommendation for a maximum of half of that, rounded to the nearest 300 mg each day.

The top limits of adult AIs, which vary according to age, were defined by the Japan National Institute of Health and Nutrition at 6.5 mg/day for females 7.0 mg/day for males, and 650–700 mg/day for females and 750–900 mg/day for males.

India does not specify a maximum amount and suggests a daily intake of 8–10 mg.

The World Health Organization advises adults to take 10 milligrams daily. The UK stands out since it suggests 4 mg per day for adult males and 3 mg per day for adult women.

The amount consumed is less than what the government advises. The average consumption for adult males and females in the United States was 10.4 mg/d and 8.4 mg/d, respectively, according to government survey statistics.

The RDA of 15 mg per day is not met by either. A global overview of over one hundred studies found that the median daily consumption of alpha-tocopherol was 6.2 mg.

US vitamin E recommendations	(mg per day)
AI (children ages 0–6 months)	4
AI (children ages 7–12 months)	5
RDA (children ages 1–3 years)	6
RDA (children ages 4–8 years)	7
RDA (children ages 9–13 years)	11
RDA (children ages 14–18 years)	15
RDA (adults ages 19+)	15
RDA (pregnancy)	15
RDA (lactation)	19
UL (adults)	1000

Food labeling

The quantity in a serving is stated as a percentage of daily value for the purposes of food and dietary supplement labeling in the United States.

100% of the daily value for vitamin E was 30 international units for labeling purposes; however, starting of May 27, 2016, it was changed to 15 mg to comply with the RDA. firms with annual food sales of at least US$10 million were required to comply with the new labeling laws by January 1, 2020, and firms with lower volume food sales had to comply by January 1, 2021. Reference Daily Intake provides a table with the current and old adult daily values.Labels must list energy, protein, fat, saturated fat, carbs, sugars, and salt in accordance with EU rules. If nutrients are present in substantial quantities, they may be shown voluntarily. Amounts are expressed as a percentage of reference intakes (RIs) rather than as daily values.

In 2011, a 100% RI of 12 mg was established for vitamin E. The United States employed the international unit of measurement from 1968 to 2016.

As the then-measured relative potency of stereoisomers, 1 IU is the biological equivalent to approximately 0.667 mg d (RRR)-alpha-tocopherol (2/3 mg precisely), or 0.90 mg of dl-alpha-tocopherol.

The measurements were changed in May 2016 such that 1 mg of “Vitamin E” is now equivalent to either 1 mg of d-alpha-tocopherol or 2 mg of dl-alpha-tocopherol.

The IOM removed vitamin E forms other than alpha-tocopherol from dietary estimates in 2000, which marked the beginning of the shift.

The UL figure does not account for conversion. The EFSA solely takes into account RRR- alpha-tocopherol in their measurement, and they have never used an IU unit.

Sources

Alpha-tocopherol consumption is below recommended levels globally, according to a synthesis of over 100 research, with a median daily dietary intake of 6.2 mg.

While alpha-tocopherol (α-tocopherol) is the most physiologically active form of vitamin E, gamma-tocopherol (γ-tocopherol) is the form most frequently found in the food of North Americans.

One source of tocotrienols is palm oil. A database on food composition is kept up to date by the Agricultural Research Services of the U.S. Department of Agriculture (USDA).

September 2015’s Release 28 was the most recent significant update. Alpha-tocopherol is added to a variety of foods, including infant formulae, liquid nutrition products, and several ready-to-eat cereals, in addition to the naturally occurring sources listed in the table.

Plant source	Amount (mg / 100 g)
Wheat germ oil	150
Hazelnut oil	47
Canola/rapeseed oil	44
Sunflower oil	41.1
Almond oil	39.2
Safflower oil	34.1
Grapeseed oil	28.8
Sunflower seed kernels	26.1
Almonds	25.6
Almond butter	24.2

Plant source	Amount (mg / 100 g)
Canola oil	17.5
Palm oil	15.9
Peanut oil	15.7
Margarine, tub	15.4
Hazelnuts	15.3
Corn oil	14.8
Olive oil	14.3
Soybean oil	12.1
Pine nuts	9.3
Peanut butter	9.0

Plant source	Amount (mg / 100 g)
Popcorn	5.0
Pistachio nuts	2.8
Avocados	2.6
Spinach, raw	2.0
Asparagus	1.5
Broccoli	1.4
Cashew nuts	0.9
Bread	0.2-0.3
Rice, brown	0.2
Potato, Pasta	<0.1

Animal source	Amount (mg / 100 g)
Fish	1.0-2.8
Oysters	1.7
Butter	1.6
Cheese	0.6-0.7
Eggs	1.1
Chicken	0.3
Beef	0.1
Pork	0.1
Milk, whole	0.1
Milk, skim	0.01

Supplements

Due to its fat solubility, vitamin E is typically found in dietary supplement products as the actual vitamin, esterified with acetic acid to produce tocopheryl acetate, and then dissolved in vegetable oil within a soft gel capsule.

The quantities of alpha-tocopherol per serving vary from 100 to 1000 IU. Multivitamin/mineral tablets contain minuscule amounts.

Supplemental firms also offer gamma-tocopherol and tocotrienol supplements. The latter-nutrient food additives

Fortification

There are no guidelines for vitamin E food fortification from the World Health Organization. The list of nations with mandatory or optional vitamin E programs is absent from the Food Fortification Initiative.

Alpha-tocopherol is a component in baby formulae. Alpha-tocopherol is added to various brands of ready-to-eat cereals, liquid nutrition products, and other meals in specific countries.

Non-nutrient food additives

Different types of vitamin E are frequently added to fatty foods as food additives to prevent peroxidation-induced rancidity. The following people have an E number:

• E306 Natural, mixed extract rich in tocopherol; may contain tocotrienol
• E307 Synthetic Alpha-Tocopherol
• E308 Synthetic Gamma-Tocopherol
• E309 Synthetic Delta-Tocopherol

All racemic forms and their acetate esters are included in these E values. The European Food Safety Authority is in charge of evaluating and approving these ingredients, which are frequently seen on food labels in Europe and certain other nations.

Metabolism

The intestinal lumen absorbs tocotrienols and tocopherols, which include the stereoisomers of synthetic alpha-tocopherol. These compounds are then combined to form chylomicrons, which are then released into the portal vein that leads to the liver.

There is no difference in the vitamin E vitamers during absorption; the estimated absorption efficiency ranges from 51% to 86% for the whole vitamin E family.

Feces are the excretion of unabsorbed vitamin E. Furthermore, all of the vitamin E vitamers are digested before being eliminated by urine, and vitamin E is also expelled by the liver via bile into the intestinal lumen, where it is either reabsorbed or eliminated through feces.

Alpha-tocopherol transfer protein (α-TTP) preferentially absorbs RRR-alpha-tocopherol once it reaches the liver.

The phytic tail of the molecule is shortened in all other forms, leading to the degradation of 2′-carboxethyl-6-hydroxychromane (CEHC), which is then sulfated or glucuronidated.

As a result, the molecules become soluble in water and are eliminated through urine. The same process also breaks down alpha-tocopherol to 2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6- hydroxychromane (α-CEHC), although it does so more slowly since α-TTP partially protects it.

Elevated urine α-CEHC is a sign of large α-tocopherol intake, suggesting that this is a way for the body to get rid of extra vitamin E.

The TTPA gene on chromosome 8 codes for the alpha-tocopherol transfer protein. The hydrophobic pocket that binds RRR-α-tocopherol has a reduced affinity for beta, gamma, or delta-tocopherols, as well as for the stereoisomers that have an S configuration at the chiral 2 sites.

Furthermore, because the stiff structure created by the double bonds in the phytic tail is mismatched with the α-TTP pocket, tocotrienols do not fit well either.

Even in those who consume appropriate quantities of vitamin E, ataxia with vitamin E deficiency (AVED) is a progressive neurological condition caused by a rare hereditary mutation of the TTPA gene.

To make up for the loss of α-TTP, large doses of dietary supplements containing alpha-tocopherol are required.

α-TTP’s function is to transport α-tocopherol. reaching the hepatocytes’ (liver cells’) plasma membrane, where it can be integrated into freshly made VLDL (very low-density lipoprotein) molecules.

These transport α-tocopherol to the body’s remaining cells. The US diet provides about 70 mg/d of γ-tocopherol, and plasma concentrations are on the order of 2–5 µmol/L.

In contrast, dietary α-tocopherol is about 7 mg/d, but plasma concentrations are in the range of 11–37 µmol/L. This is an example of how the preferred treatment has affected the results.

Vitamin E compound	Affinity
RRR-alpha-tocopherol	100%
beta-tocopherol	38%
gamma-tocopherol	9%
delta-tocopherol	2%
SSR-alpha-tocopherol	11%
alpha-tocotrienol	RRR-alpha-tocopherol

Testing for levels

Serum α-tocopherol was found to have a median of 22.1 µmol/L in a global overview of over 100 human research. A α-tocopherol deficit was defined as less than 12 µmol/L.

It mentioned that for maximum health advantages, serum α-tocopherol concentrations should be ≥30 µmol/L.

On the other hand, a plasma concentration of 12 µmol/L was found to be enough for normal ex vivo hydrogen peroxide-induced hemolysis in the U.S.

Dietary Reference Intake literature for vitamin E. A review conducted in 2014 classified levels below 9 µmol/L as insufficient, between 9 and 12 µmol/L as borderline, and above 12 µmol/L as adequate.

As people age, their serum concentration rises. This is explained by the fact that serum lipoprotein concentrations rise with age and that vitamin E is circulated in the blood after being absorbed into lipoproteins.

Young children and infants are more likely to fall below the deficient threshold. Low serum vitamin E can be caused by illnesses such as cystic fibrosis and other fat malabsorption disorders. Serum vitamin E levels will rise with dietary supplementation.

Research

Results from randomized clinical trials (RCTs) do not necessarily support the observational evidence for the disorders listed below. This might have to do with quantity.

Based on food intake, observational studies contrast low and high consumers.

Increased vitamin E intake may not be the cause of the observed impact because diets higher in vitamin E may also contain other chemicals that have health advantages or be taken by individuals who lead non-diet lifestyles that reduce disease risk.

In the meantime, alpha-tocopherol levels in many of the published RCTs were 20–30 times greater than what is possible to obtain by diet.

Declining supplement use

The percentage of female health professionals in the United States who used vitamin E supplements was 16.1% in 1986, 46.2% in 1998, and 44.3% in 2002, but it dropped to 19.8% in 2006.

In the same years, the rates for male health professionals were 18.9%, 52.0%, 49.4%, and 24.5%. The authors postulated that research showing either no benefits or adverse effects from vitamin E supplements may have contributed to the decline in the use of these supplements in these populations.

Vitamin prescriptions written for active, reserve, and retired military personnel, as well as their dependents, were tracked throughout the United States military services between 2007 and 2011.

Prescriptions for vitamin E fell by 53%, while those for vitamin C stayed the same and those for vitamin D rose by 454%.

A 50% drop in vitamin E sales volume was reported in a US report. Ameta-analysis that found high dosage (≥400 IU/d for at least a year) of vitamin E was linked to an increase in all-cause mortality between 2000 and 2006 could be one possible explanation.

All-cause mortality

According to two meta-analyses, using vitamin E as a dietary supplement had no effect on all-cause mortality.

High dosage (≥400 IU/d for at least a year) of vitamin E was linked to an increase in all-cause mortality, according to an earlier meta-analysis.

The high-dose trials that were referenced, according to the authors, were frequently small-scale and involved participants who already had chronic illnesses.

When alpha-tocopherol was the only supplement used, a meta-analysis of long-term clinical studies found a non-significant 2% increase in all-cause death.

When beta-carotene, selenium, vitamin A, vitamin C, and/or alpha-tocopherol were combined with additional nutrients, the same meta-analysis showed a statistically significant 3% increase in results.

Age-related macular degeneration

Long-term vitamin E supplementation did not alter the risk of developing age-related macular degeneration, according to a Cochrane review.

Alzheimer’s disease

An earlier analysis of dietary intake studies found that eating more foods high in vitamin E reduced the incidence of Alzheimer’s disease (AD) by 24 percent.

Vitamin E has been linked to dietary benefits for moderate cognitive impairment (MCI) and Alzheimer’s disease, according to a 2017 Cochrane review.

The study revealed insufficient evidence for vitamin E supplementation to prevent the progression from mild cognitive impairment (MCI) to dementia, based on data from one trial in each category.

However, it did show that functional decline in individuals with AD was slowed down. The authors suggested more research because there were not enough trials or volunteers.

According to a 2018 meta-analysis, individuals with AD had lower blood levels of vitamin E than healthy, age-matched individuals.

A British Association consensus statement from 2017 for Psychopharmacology came to the conclusion that vitamin E cannot be advised for the treatment or prevention of Alzheimer’s disease until more data is available.

Cancer

The United States Preventive Services Task Force concluded in a 2022 update to a previous report that there is no net benefit of vitamin E supplementation and advised against its use for the prevention of cancer or cardiovascular disease.

The task force concluded that there was not enough evidence to evaluate the benefits and harms of the supplements, but it also concluded with a moderate degree of certainty that there was no benefit.

Regarding the literature on various cancer types, observational studies show an inverse link between dietary vitamin E and bladder and kidney cancer.

Comparing the highest and lowest intake groups revealed a 19% risk reduction.

The necessity of randomized controlled trials (RCTs) was determined by the authors. In a big trial, there was no difference in the number of bladder cancer cases between the placebo and all-rac-alpha-tocopherol group, which consumed 400 IU daily.

Observational studies have shown an inverse link between dietary vitamin E and lung cancer.

Comparing the highest and lowest intake groups revealed a 16% relative risk reduction. As dietary consumption increased from 2 mg/day to 16 mg/day, the effect became more pronounced.

The authors pointed out that further research is necessary to validate the results. In one such major trial, male tobacco smokers were given 50 mg alpha-tocopherol or a placebo; the results showed no effect on lung cancer.

A study that monitored participants who chose to take a vitamin E supplement found that those who took more than 215 mg of the vitamin daily had a higher chance of developing lung cancer. Results for prostate cancer are likewise contradictory.

An inverse link was found in a meta-analysis based on serum alpha-tocopherol content; the difference between the lowest and highest levels was associated with a 21% reduction in relative risk.

On the other hand, there was no correlation found for dietary vitamin E intake in a meta-analysis of observational studies. Large RCTs produced inconsistent outcomes as well.

For five to eight years, male tobacco smokers in the ATBC experiment were given either a placebo or 50 mg/day of alpha-tocopherol.

The study found a 32% reduction in the incidence of prostate cancer. However, males 55 years of age or older who were predominantly nonsmokers participated in the selenium and vitamin E for prostate cancer SELECT study and were randomly assigned to receive a 400 IU daily dietary supplement or a placebo.

Relative risk was shown to be statistically significantly greater by 17% for the group of vitamins. A comprehensive review found RCTs comparing vitamin E and placebo for colorectal cancer that were followed for seven to ten years.

In terms of relative risk, there was a non-significant 11% drop. Additionally, information on colorectal cancer was provided by the SELECT study (men over 55 years old; 400 IU/day or placebo).

When compared to the placebo, there was a non-significant 3% increase in the incidence of adenoma.

For an average of 10.1 years, the Women’s Health Study compared 600 IU of natural-source vitamin E on alternate days with a placebo.

Regarding the overall cancer incidence, cancer-related fatalities, or the incidence of breast, lung, or colon cancers in particular, there were no appreciable variations. The type and quantity of vitamin E utilized in prospective research are potential confounding variables.

Although synthetic, racemic mixes of vitamin E isomers are frequently utilized in clinical trials and as constituents in dietary supplements, they are not bioequivalent to natural, non-racemic mixtures.

More than 90% of the listed clinical trials employed the synthetic, racemic version of dl-alpha-tocopherol, according to one study, which found a slight increase in cancer risk associated with vitamin E administration.

Cancer health claims

In 1993, the U.S. Food and Drug Administration started the process of examining and approving health claims related to food and dietary supplements. Upon review of petitions, suggested claims are either accepted or denied.

Package labels may contain customized wording only with approval. A second procedure for reviewing claims was established in 1999. In the event that the entirety of the evidence is not agreed upon by scientists, a Qualified Health Claim (QHC) may be made.

The FDA does not “approve” requests for qualifying health claims. Rather, it publishes a Letter of Enforcement Discretion with extremely precise language about the claims and limitations of utilizing it.

In 2003, the first QHCs related to vitamin E were released. Consuming vitamins rich in antioxidants may reduce the risk of getting several cancers, according to specific scientific research.

The claims changed in 2009, becoming more precise and enabling vitamin E to potentially lower the risk of colon, bladder, and kidney cancers.

However, it was mandatory to note that the data was deemed weak and the benefits claimed to be highly doubtful.

A request to include lung, stomach, cervical, and brain malignancies was turned down. Vitamin E may lower the risk of colon, bladder, and kidney cancers, according to a May 2012 amendment that included the more succinct disclaimer, “FDA has concluded that there is very little scientific evidence for this claim.”

A disclaimer must appear on every product label issued by a corporation that makes cancer-related claims.

Proposed health claims for the nations that make up the European Union are examined by the European Food Safety Authority (EFSA). EFSA has not assessed any vitamin E and cancer protection claims as of September 2022.

Cataracts

Higher serum concentrations of tocopherol were linked to a 23% lower relative risk of age-related cataracts (ARC), according to a 2015 meta-analysis.

This effect was attributed to variations in nuclear cataracts rather than cortical or posterior subcapsular cataracts, the three main types of age-related cataracts.

Nevertheless, when compared to a placebo, neither this paper nor a second meta-analysis covering clinical trials of alpha-tocopherol supplementation found a statistically significant reduction in the risk of ARC.

Cardiovascular diseases

The United States Preventive Services Task Force concluded in a 2022 update to a previous report that there is no net benefit of vitamin E supplementation and advised against its use for the prevention of cancer or cardiovascular disease.

The task force concluded that there was not enough evidence to evaluate the benefits and harms of the supplements, but it also concluded with a moderate degree of certainty that there was no benefit.

There have been contradictory findings in studies on the relationship between vitamin E and cardiovascular disease.

Since LDL-oxidative-modified cholesterol is thought to cause coronary artery blockages that result in atherosclerosis and heart attacks, vitamin E’s antioxidant properties should lessen oxidized cholesterol and the risk of cardiovascular disease.

Anti-inflammatory activity, prevention of platelet adhesion and aggregation, and preservation of normal endothelial cell function—the cells lining the inner wall of arteries—have all been linked to vitamin E status.

Higher serum concentrations of alpha-tocopherol and the consumption of foods high in vitamin E have been found to have an inverse relationship with coronary heart disease.

In one of the biggest observational studies, eight years were spent monitoring nearly ninety thousand healthy nurses.

Individuals in the highest fifth of the group with the greatest reported consumption of vitamin E (from food and dietary supplements) had a 34% decreased risk of serious coronary disease.

Because of confounding variables, observational studies are unable to establish a link between vitamin E consumption and a lower risk of coronary heart disease.

greater vitamin E diets may also contain greater levels of other, as-yet-unidentified heart-healthy ingredients, or the individuals who choose these diets may be leading other healthful lifestyles.

Randomized clinical trials (RCTs) have provided some supporting data. When taken without any other antioxidant nutrient, alpha-tocopherol supplementation lowered the relative risk of heart attack by 18%, according to a meta-analysis of the effects of RCTs on several aspects of cardiovascular health.

Every single trial that was included in the meta-analysis had inconsistent results. For instance, the Physicians’ Health Study II found no advantage for heart attack, stroke, coronary mortality, or all-cause death after 400 IU every other day for eight years.

The alpha-tocopherol group in the HOPE/HOPE-TOO trial, which enrolled individuals with diabetes or pre-existing vascular disease in a multi-year trial at 400 IU/day, had a greater risk of heart failure.

Cardiovascular health claims

The Food and Drug Administration of the United States rejected proposed health claims pertaining to vitamin E and cardiovascular health in 2001.

“In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality,” the U.S. National Institutes of Health stated after reviewing literature up to 2008.

Proposed health claims for the nations that make up the European Union are examined by the European Food Safety Authority (EFSA).

Claims that a cause-and-effect link has been demonstrated between vitamin E consumption through diet and the preservation of normal heart function or normal blood circulation were examined and rejected by the EFSA in 2010.

Nonalcoholic fatty liver disease

According to meta-analyses, supplementing with vitamin E significantly decreased inflammation, fibrosis, steatosis, and elevated liver enzymes.

This suggests that the vitamin could be helpful in treating nonalcoholic fatty liver disease (NAFLD) and its more severe subset, nonalcoholic steatohepatitis (NASH), in adults, but not in children.

Parkinson’s disease

Although dietary vitamin E has been found to have an inverse link with Parkinson’s disease, there has been no conclusive evidence from placebo- controlled clinical trials.

Pregnancy

It has been suggested that taking antioxidant vitamins as dietary supplements can be beneficial if taken during pregnancy.

A Cochrane review found that the majority of trials using alpha-tocopherol at 400 IU/day plus vitamin C at 1,000 mg/day did not support vitamin E supplementation as being effective in lowering the risk of stillbirth, neonatal death, preterm birth, preeclampsia, or any other maternal or infant outcomes, in either healthy women or those who were thought to be at risk for pregnancy complications.

Only three short trials that supplemented vitamin E without also supplementing vitamin C were found in the review. These trials did not provide any data that could be applied clinically.

Skin Care

Certain cosmetics and wound-treatment products contain vitamin E, however, a 2015 meta-review revealed “limited clinical evidence” of the nutrient’s effectiveness.

The authors did point out a lack of research, noting that 23 of the 39 studies they analyzed had “individual flaws, including low patient numbers, poor randomization, blinding, and short follow-up periods, and were of limited quality.”

Topical

Tocopheryl acetate is a topical medicine that is widely used. Its benefits include reduced scar tissue and improved wound healing, although reviews have consistently found insufficient data to support these claims.

The usage of vitamin-E derivatives in skin care products, such as tocopheryl linoleate and tocopherol acetate, has been linked to cases of allergic contact dermatitis. Despite being widely used, the incidence is minimal.

Vaping-associated lung injury

The US Food and Drug Administration declared on September 5, 2019, that 10 out of 18 (or 56% ) of the vape liquid samples that states had sent in were linked to a recent outbreak of lung disease related to vaping in the US.

The samples tested positive for vitamin E acetate, which was used as a thickening agent by manufacturers of illicit THC vape cartridges.

The Centers for Disease Control and Prevention named vitamin E acetate as a very strong suspect in the illnesses linked to vaping on November 8, 2019, although they haven’t ruled out the possibility of other chemicals or toxicants being the cause.

Based on fluid samples taken from the lungs of 29 individuals who had pulmonary damage from vaping, these results showed clear evidence of vitamin E acetate at the central location of damage in each of the 29 lung fluid samples examined.

A review verified the causative agent status of vitamin E acetate. A variety of hazardous gasses are produced when vitamin E acetate is pyrolyzed.

History

Herbert McLean Evans and Katharine Scott Bishop made the discovery of vitamin E in 1922, and in 1935, Evans and Gladys Anderson Emerson at the University of California, Berkeley, isolated the nutrient in its purest form.

The vitamin activity was named “tocopherol” from the Greek words “τόκος” [tókos, birth] and “φέρειv” [phérein, to bear or carry], meaning, in sum, “to carry a pregnancy,” with the ending “-ol” denoting its status as a chemical alcohol.

This was because the vitamin activity was first found to be a dietary fertility factor in rats. The University of California Greek professor George M. Calhoun was acknowledged for his assistance in the naming process.

In 1938, Erhard Fernholz clarified its structure, and soon after, Paul Karrer and his colleagues made the first synthetic it.

“Research revealed many of the vitamin’s secrets, but no certain therapeutic use and no definite deficiency disease in man,” stated an editorial headed “Vitamin in search of a disease” in the Journal of the American Medical Association,nearly 50 years after vitamin E was discovered.

The animal experimentation had been necessary for a successful pregnancy, but there had been no discernible advantage for miscarrying women.

The vascular health evidence was deemed insufficient. The editorial concluded by mentioning some preliminary human data suggesting that young children are protected from hemolytic anemia.

It was Evan Shute and others who initially suggested in 1946 that vitamin E had a part in coronary heart disease. Subsequent cardiovascular research by the same team included a hypothesis that vitamin E megadoses could prevent or even reverse atherosclerosis.

A 2004 meta-analysis, however, found no link between vitamin E intake and cardiovascular mortality or cardiovascular events, such as nonfatal stroke or myocardial infarction.

The topical application of oil containing vitamin E has long been thought to aid in the healing of burns and wounds. Despite numerous denials of this assertion by scientific evaluations, this idea nevertheless endures.

There is a lengthy history of research on the function of vitamin E in newborn feeding. Studies conducted on premature newborns starting in 1949 revealed that oral alpha-tocopherol provided protection against hemolytic anemia, edema, cerebral hemorrhage, and retrolental fibroplasia.

According to a 2003 Cochrane analysis, vitamin E supplementation in premature newborns decreased the incidence of retinopathy and intercranial bleeding, but it also raised the risk of sepsis.

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