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The many forms of Vitamin EThe many forms of Vitamin E

Vitamin E is really a collection of eight compounds that offer different health benefits and supplementation considerations.

Robin Koon

November 6, 2013

11 Min Read
The many forms of Vitamin E

Vitamin E was the fifth vitamin (fat-soluble) discovered in 1922 when researchers Herbert McLean Evans and Katherine S. Bishop found a dietary deficiency in laboratory rats produced infertility. Upon feeding the animals wheat germ, the rats were able to become pregnant. An alcohol substance was isolated from wheat germ and the formula C29H50O2 was determined. The name "tocopherol" was derived from the Greek words tos (childbirth) and phero (to bring forth), and the chemical designation for an alcohol (ol). Further research continued, and in 1936, Evans isolated alpha-tocopherol. Vitamin E was initially proposed as an antioxidant in 1945. In 1968, vitamin E was proposed to be used as an antioxidant to protect cell lipids from free radicals. The research data was used to set the initial 1968 recommended dietary allowance (RDA) for vitamin E at 30 IU.

What is (are) Vitamin E?

Vitamin E is a lipid-soluble phenolic cellular antioxidant compound obtained from plant sources in the diet. Vitamin E is not a singular substance. It is a collective term for a family of eight homologues (stereoisomers) molecules that are synthesized naturally by plants from homogentisic acid. It is a series of organic compounds consisting of various methylated phenols. All eight are derivatives of six-chromanol (a chromanol ring with an alcohol hydroxy group), differing between them in the number and position of methyl groups, and a 12-carbon aliphatic side-chain. The compounds can act as an antioxidant by donating a hydrogen atom to reduce free radicals, and have a hydrophobic side chain, which allows for penetration into biological membranes.

The eight homologues are split into two groups: tocopherols and tocotrienols. Both the tocopherols and tocotrienols have four homologues each, named: alpha, beta, gamma and delta. The differences are in the side-chains: tocopherols homologues are saturated and the tocotrienols are unsaturated (containing three double bonds). Each form has slightly different biological activity. All of these various derivatives with vitamin E activity are technically referred to collectively as "vitamin E."

Historically, only one of those eight appeared to have the most nutritional importance, the d-alpha-tocopherol isomer form. It is what is commonly called vitamin E" on nutrition/supplement labels, and also the only form that can referred to as the RDA for vitamin E. Alpha-tocopherols naturally occur in the d- isomer form, which is more active than the synthetic racemic dl- isomer form. The alpha form of tocopherol was originally designated d-alpha-tocopherol on the basis of its optical activity. The International Union of Pure and Applied Chemistry (IUPAC) now advocates using an R & S system of stereoisomer designation, instead of current d- & l- prefixes, but this has not yet happened.

The alpha-tocopherol form constitutes 90 percent of the tocopherol found in humans, with the largest quantities in blood and tissues. Normal blood plasma consists of 83-percent d-alpha-tocopherol and 13-percent d-gamma-tocopherol. It has been found that long-term supplementation with just an d-alpha-tocopherol vitamin E supplement results in blood plasma levels of d-gamma-tocopherols being lowered by 30 to 50 percent. As a result, some researchers now recommend, to those who are interested in taking a vitamin E supplement, to select one with mixed tocopherols.

Types of Vitamin E

Vitamin E and other mixed tocopherols are isolated from vegetable oil distillate (VOD) and concentrated to contain d-alpha, d-beta, d-gamma and d-delta tocopherols. Tocopherols are also found in vegetable oils as well as grains, seeds and nuts. They naturally protect fats and oils from oxidation.

Vitamin E is found in a variety of foods including oils, meat, eggs and leafy vegetables.

Commercial available sources of vitamin E can be classified into several distinct categories or types:

Natural Vitamin E

This is what most people refer to as vitamin E; is the non-esterified form called d-alpha-tocopherol, an alcohol that occurs in nature as a single stereoisomer. These come from vegetable oils (primarily soy) and sunflower oil.

Semi-Synthetic, Esters

Manufacturers commonly convert the phenol form of the vitamin (with a free hydroxyl group) to esters, using acetic or succinic acid. An ester is a salt formed by a carboxylic acid [-C(OH)=O] and an alcohol [-OH] (tocopherol is the alcohol). These tocopheryl esters (e.g., alpha-tocopheryl acetate, tocopheryl succinate, tocopheryl nicotinate, tocopheryl linolate, alpha-tocopheryl phosphates, etc.) are more stable (esters are less susceptible to oxidation) during storage because they are not acting as an antioxidant in their esterified form. These ester forms are de-esterified in the gut (by the enzyme esterase) and then absorbed as the free tocopherol. Several studies indicate the rate of absorption of these forms of tocopheryl esters and free tocopherol have similar bioavailability.

Synthetic Vitamin E

The synthetic form of vitamin E, dl-alpha-tocopherol is made by coupling trimethylhydroquinone (a reduced benzoquinone) with isophytol (acyclic terpenoid). Synthetic vitamin E is racemic mixture containing all the eight isomers of alpha-tocopherol (all racemic) in approximately equal amounts, so it has approximately half of the biological activity of natural vitamin E.

Fractionated forms

The most-common fractionated forms are: natural mixed tocopherols and high d-gamma-tocopherol.


Current literature suggests the primary role in the body of vitamin E is to function as a major lipid antioxidant for free radicals formed from normal cellular metabolism.1 Free radicals are destructive to the cell membrane and other body components. Vitamin E acts as an antioxidant (a molecule capable of inhibiting the oxidation of other molecules), which then makes the free radical unreactive, thus undamaging. The phenolic vitamin E compound donates a hydrogen (from the hydroxyl (-OH) group on the ring structure) and itself becomes a relatively unreactive free radical as well. Other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of alpha-tocopherol.

Additionally, alpha-tocopherol also protects the fats in low-density lipoproteins (LDLs) from oxidation.2 Oxidized LDLs have been implicated in the development of cardiovascular disease (CVD).

Several studies have established vitamin E supplementation as a way to help prevent or treat various chronic disease states, including: aging, arthritis, cancer, CVD, cataracts, dementia (impaired cognitive function), immune function, platelet hyper-aggregation (reduction), prostaglandin production (reduction) and reproduction.3

Commercially, vitamin E is also used as an antioxidant to preserve many (bulk and finished product) polyunsaturated fatty acids (PUFAs) and oils from oxidation.


Gamma-tocopherol is actually the major form of vitamin E ingested in the U.S. diet. It is not as well-known as alpha-tocopherol. The function of gamma-tocopherol is not entirely clear, but both forms (alpha and gamma) are potent antioxidants. It was previously assumed that gamma-tocopherol is not important, because the body had much lower concentrations as alpha-tocopherol. The serum blood levels of gamma-tocopherol are generally 10-times lower than those of alpha-tocopherol.

Recent studies suggest gamma-tocopherol has properties that may be important to human health and are not shared by alpha-tocopherol. Gamma-tocopherol appears to scavenge another type of free radical (lipophilic electrophiles, such as reactive nitrogen oxide species [RNOS]), which can damage proteins, lipids and DNA.4 Additionally, gamma-tocopherol can inhibit cyclooxygenase activity, having anti-inflammatory properties. And studies have shown plasma concentrations of gamma-tocopherol are inversely associated with the incidence of CVD and prostate cancer.5,6 More research needs to be done.


There have been more studies on tocotrienols indicating they may have significant antioxidant and anti-cancer effects. Tocotrienols (in particular, gamma-tocotrienol) appear to act on a specific enzyme called 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) involved in cholesterol production in the liver. Tocotrienols suppress the production of this enzyme (similarly as statin drugs do, to lower cholesterol), which may result in less cholesterol being manufactured by liver cells.7,8 Many research claims of tocotrienols' health benefits have been made. More research needs to be done.

Pharmacokinetics of Vitamin E

  • Absorption: Vitamin E absorption is low in humans. Being a lipid, absorption from the intestinal lumen is dependent upon biliary and pancreatic secretions, micelle formation, uptake into enterocytes, and chylomicron secretion, and then into circulation via the lymphatic system. Absorption occurs in the median portion of the small intestine from the intestinal lumen. All forms of vitamin E (solubilized, natural and synthetic) have similar intestinal absorption.

  • Distribution: Vitamin E is fat soluble and is transported in the blood by the plasma lipoproteins and erythrocytes. It distributes throughout the body and is primarily stored in adipose (fat) tissue and various organs. The human body stores about 40 mg/kg and 77 percent is stored in adipose tissue. It is transported to the liver, packaged into very low density lipoproteins (VLDLs) and excreted back into the circulation.

  • Metabolism: Alpha-tocopherol is oxidized to the tocopheroxyl radical that can be reduced back to the un-oxidized form by reducing agents such as vitamin C. Further oxidation of the a-tocopheroxyl forms tocopheryl quinone. The tocopheryl quinone is not converted back to tocopherol and eventually excreted.

  • Excretion: Vitamin E is excreted mainly via bile, urine, feces and the skin. But the major route of excretion of ingested vitamin E is fecal elimination. Vitamin E metabolites appear to be primarily eliminated via the kidneys. This occurs when the vitamin is oxidized and forms hydroquinone and then is conjugated to form glucuronate. Once formed the glucuronate can be excreted into bile or further degraded in the kidneys and excreted in the urine.

  • Deficiency: Vitamin E deficiency is rare, but deficiency has been observed in individuals with severe malnutrition, genetic defects affecting the alpha-tocopherol transfer protein and fat malabsorption. It has been estimated that more than 90 percent of Americans do not meet daily dietary recommendations for vitamin E.

  • Measurement: Although supplement product labels continue to express measurements of vitamin E activity in international units (IU), it was changed in 1980 to a new unit of measure, expressed as alpha-tocopherol equivalent (ATE). This term was established to account for the differences in biological activity of the various forms of vitamin E. It is important to note IU measurement only provides partial information on the true vitamin E value of a product. IUs do not tell us if the product has tocopherols other than alpha-tocopherol, if the alpha-tocopherol is natural or synthetic or if the alpha-tocopherol is esterified. For nutritional supplements, the IU claim is from alpha-tocopherol content only, the other tocopherols and tocotrienols have a zero IU value.

  • Conversions: The only form of vitamin E that has a standard conversion formula from milligrams to international units is alpha-tocopherol. The other forms of vitamin E, do not have a conversion formula and therefore should be listed only in milligrams on the label.

Hypervitaminosis E (Toxicity)

Hypervitaminosis E is a state of vitamin E toxicity. Vitamin E toxicity has rarely been documented in humans. Doses up to 1,600 IU have been commonly administered in studies without observable adverse side effects. Toxicity may be difficult because of the wide variation in daily blood vitamin E levels. Increasing vitamin E levels in muscle tissue is especially difficult to attain, and toxic levels are difficult to achieve. The tocopherol-binding protein is likely to control the amount of vitamin E that can be physiologically stored. Excess amounts of the vitamin are likely excreted by the body. The binding protein may actually exhibit a protective role via this mechanism, but this hypothesis needs further investigation.

 Few side effects have been noted in adults taking supplements of less than 2,000 mg/d of alpha-tocopherol. The most worrisome possibility is that of impaired blood clotting, which may increase the likelihood of hemorrhage in some individuals. The Food and Nutrition Board of the Institute of Medicine (IOM) established a tolerable upper intake level (UL) for alpha-tocopherol supplements based on the prevention of hemorrhage. The board felt that 1,000 mg/day of alpha-tocopherol in any form would be the highest dose unlikely to result in hemorrhage in almost all adults. Although only certain isomers of alpha-tocopherol are retained in the circulation, all forms are absorbed and metabolized by the liver. The rationale that any form of alpha-tocopherol (natural or synthetic) can be absorbed and thus could be potentially harmful is the basis for a UL that refers to all forms of alpha-tocopherol.

Some physicians recommend discontinuing high-dose vitamin E supplementation one month before elective surgery to decrease the risk of hemorrhage. Premature infants appear to be especially vulnerable to adverse effects of alpha-tocopherol supplementation, which should be used only under controlled supervision by a pediatrician. Supplementation with 400 IU/d of vitamin E has been found to accelerate the progression of retinitis pigmentosa, which is not associated with vitamin E deficiency.

Drug interactions

Use of vitamin E supplements in doses higher than 800 IU may increase the risk of bleeding in individuals taking:

  • Anticoagulant drugs: such as warfarin (Coumadin®) Heparin or heparin-like products, including dalteparin (Fragmin®), enoxaparin (Lovenox®) or tinzaparin (Innohep®).

  • Antiplatelet drugs: such as aspirin, clopidogrel (Plavix®), ticlopidine (Ticlid®), cilostazole (Pletal®), and dipyridamole (Persantine®).

  • Thrombolytics: alteplase (Activase®), reteplase (Retavase®), streptokinase (Streptase®) and tenecteplase (TNKase®).

  • Non-steroidal anti-inflammatory drugs (NSAIDs): such as aspirin, ibuprofen (Motrin®, Advil®, Nuprin®), naproxen (Naprosyn®) or naproxen sodium (Aleve®, Anaprox® and Naprelan®), ketoprofen (Orudis®, Actron® and Oruvail®), indomethacin (Indocin® and Indocin SR®), etc.

Drugs that can decrease the absorption of vitamin E include cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, the fat substitute, olestra and the fat blocker Alli®.

Drugs that may decrease plasma levels of vitamin E include anticonvulsant drugs such as phenobarbital, phenytoin and carbamazepine.

Those who are vitamin K deficient should not take alpha-tocopherol supplements without close medical supervision, because of the increased risk of hemorrhage.

Patients on kidney dialysis who are given injections of iron frequently experience oxidative stress." This is because iron is a pro-oxidant, meaning that it interacts with oxygen molecules in ways that may damage tissues. These adverse effects of iron therapy may be counteracted by supplementation with vitamin E.

Robin Koon, executive vice president at Best Formulations, has more than 25 years of pharmaceutical experience in clinical pharmacy, managed care, and as a retail drug chain executive overseeing operations.

For a list of references, email [email protected].

About the Author(s)

Robin Koon

Robin Koon is executive vice president at Best Formulations , and has more than 35 years of pharmaceutical experience in clinical pharmacy, as a retail drug chain executive, in managed-care and in manufacturing.


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