Tocopherols (; TCP) are a class of organic compounds comprising various methylated phenols, 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 and , that is 'to carry a pregnancy', with the ending -ol signifying its status as a chemical alcohol.

α-Tocopherol is the main source found in supplements and in the European diet, where the main dietary sources are olive and sunflower oils, while γ-tocopherol is the most common form in the American diet due to a higher intake of soybean and corn oil.

Forms Vitamin E exists in eight different forms, four tocopherols and four tocotrienols. All feature a chromane ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain that allows for penetration into biological membranes. 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. Form Structure5-position7-position α-Tocopherol methylmethyl β-Tocopherol methylH γ-Tocopherol Hmethyl δ-Tocopherol HH

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 bonds 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, only one of which occurs naturally).

Each form has a different biological activity. 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 numbers: E306 (tocopherol), E307 (α-tocopherol), E308 (γ-tocopherol), and E309 (δ-tocopherol). All of these are approved in the US, EU, and Australia and New Zealand for use as antioxidants.

α-Tocopherol

α-Tocopherol is the form of vitamin E that is preferentially absorbed and accumulated in humans. It is also the most bioactive form of tocopherol. The measurement of "vitamin E" activity in international units (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 stereocenters in α-tocopherol, so this is a chiral molecule. The eight 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.

1 IU of tocopherol is defined as milligrams of RRR-α-tocopherol (formerly named d-α-tocopherol or sometimes ddd-α-tocopherol). 1 IU is also defined as 1 milligram of an equal mix of the eight stereoisomers, which is a racemic mixture called all-rac-α-tocopheryl acetate. This mix of stereoisomers is often called dl-α-tocopheryl acetate, even though it is more precisely ). However, 1 IU of this racemic mixture is not now considered equivalent to 1 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 IU racemic mixture = 0.45 "milligrams α-tocopherol".

Tocotrienols

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.

Function and dietary recommendations

Mechanism of action Tocopherols are radical scavengers, delivering an H atom to quench free radicals. At 323 kJ/mol, the O–H bond in tocopherols is approximately 10% weaker than in most other phenols. This weak bond allows the vitamin to donate a hydrogen atom to the peroxyl radical and other 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. As they are fat-soluble, tocopherols are incorporated into cell membranes, which are thus protected from oxidative damage.

Tocopherols are chain-breaking antioxidants. That is, they do not slow down the initiation of lipid peroxidation chain reactions, but they interrupt it. In detail, the standard lipid peroxidation chain reaction goes like

Initiation: where RH stands for a lipid. Propagation: , . Termination: .

Tocopherols insert themselves into the propagation step:

Interrupted propagation: .

Because the phenoxyl radicals are resonance stabilized, they do not in general propagate. They simply stay around until are eventually terminated by .

In general, the higher the reaction rate is , the better it is an antioxidant. Its reaction rate is explained by stereoelectronic effect. This theory has allowed chemists to design chemicals that are even more bioactive than the most bioactive form of tocopherol.

Dietary considerations The U.S. Recommended Dietary Allowance (RDA) for adults is 15 mg/day. 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. The U.S. Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) per day, using rodent data, specifically based on the highest level to not cause issues with blood coagulation.

The European Food Safety Authority sets UL at 300 mg (all forms, measured by molar equivalent of α-tocopherol) per day. This is derived from a human experiment testing up to 800 IU of racemic α-tocopherol acetate with no adverse events, with the conversion to 300 mg (rather than a typical 540 mg α-tocopherol equivalent) reflecting an understanding of bleeding being caused by excess vitamin E interfering with the absorption of vitamin K, which has a similar structure, instead of any regular biological activity of the vitamin. The value was last reviewed in 2024; it was noted that newer data on all-cause mortality were not clear enough to be incorporated into the UL analysis.

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 mg (natural) d-α-tocopherol by the resorption-gestation bioassay, which measures the ability to prevent fetal resorption in rats.

Specifically, female rats on a diet free of vitamin E inevitably reabsorb their fetus, despite normal ability to conceive and despite no apparent developmental abnormality of the fetus. They resume the ability to carry a pregnancy to term upon a sufficient dietary supplement. This then allows establishing equivalents. For example, if, to allow 50% of pregnancy to be carried to term, one needs to either supplement X amount of the amount of α-Tocopherol, or Y amount of γ-Tocopherol, then 1 unit of α-Tocopherol is considered equivalent to Y/X unit of γ-Tocopherol.

Using this bioassay, it is known that among tocopherols, α > β ~ γ > δ. 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. The IU is converted to aTE by multiplying it with 0.67. These factors do not correlate with the antioxidant activity of vitamin E isomers, where tocotrienols show even much higher activity in vivo.

Sources

The U.S. Department of Agriculture (USDA), Agricultural Research Services, maintains a food composition database. The last major revision was Release 28, September 2015. In general, food sources with the highest concentrations of vitamin E are vegetable oils, followed by nuts and seeds. Adjusting for typical portion sizes, however, for many people in the United States the most important sources of vitamin E include fortified breakfast cereals.

Deficiency

Vitamin E deficiency is rare, and in almost all instances caused by an underlying disease rather than a diet low in vitamin E. Vitamin E deficiency causes neurological problems due to poor nerve conduction. These include neuromuscular problems such as spinocerebellar ataxia and myopathies. Deficiency also may cause anemia, due to oxidative damage to red blood cells.

Commercial versions

Commercial vitamin E sold as food, supplement, or cosmetic ingredient may be classified into several distinct categories. By the nature of the tocopherol part, they can be divided into: Fully synthetic racemic vitamin E, "dl-α-tocopherol", the most inexpensive, most commonly sold supplement form. "Natural mixed tocopherols", which is extracted from plant oil. Fractionated "natural" d-α-tocopherol, which is the form of α-tocopherol found in nature. They are often made by semi-synthesis in addition to fractionation, starting from natural mixed tocopherols and undergoing a methylation procedure to convert the gamma and beta d-tocopherol vitamers into the α form. Commonly used in medicine and supplements. Other fractions extracted from plant oil such as high d-γ-tocopherol fraction supplements.

They can also be divided into free tocophenol and ester (often acetate) forms.

Synthetic all-racemic and d-α-tocopherol 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).

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) . The present largest manufacturers of this type are DSM and BASF.