Almost a century has passed since Evans and Bishop (Evans & Bishop, 1922) first described a “substance X” (today known as vitamin E) as a critical factor for post-fertilization placental development in rats. Recently, the Center for Disease Control and Prevention (CDC) estimated that more than 10% of the U.S. population may have nutritional deficiencies, including vitamin E. These deficiencies may result from inadequate consumption of nutrient-rich foods; lack of absorption in the digestive tract; illness and disease; interactions among prescription medications, over-the-counter (OTC) medicine and dietary supplements; and following “fad” diets that limit the intake of a variety of foods.

Since its discovery, vitamin E has been extensively researched by a large number of investigators in an attempt to understand its role in a variety of pathophysiological contexts. However, several recent randomized controlled trials have generated negative images of this well-publicized vitamin.

Use of the term “vitamin E” is recommended as the generic descriptor for all tocopherol and tocotrienol derivatives. Together, these two groups are termed the tocochromanols. In essence, the tocopherols have a 20-carbon phytyl tail (including the pyranol ring) and the tocotrienols a 20-carbon geranylgeranyl tail with double bonds at the 3’, 7’ and 11’ positions, attached to the benzene ring. These compounds are only synthesized by plants and other oxygenic, photosynthetic organisms, but they are essential components of the diet of animals, and collectively they are termed “vitamin E.”

Evidence Evaluation
The vast majority of published work has focused on vitamin E’s antioxidant properties. However, conflicting results regarding the effects of vitamin E supplementation in reducing levels of free radical damage have been reported from randomized, controlled human trials. Supplementary vitamin E was reported to be effective in reducing atherosclerosis progression but again recent large interventional clinical trials had not shown cardiovascular benefits by vitamin E supplementation.

Another development in vitamin E research indicates that some members of the vitamin E family, particularly α-, γ- and δ-tocotrienol, have emerged as vitamin E molecules with functions clearly distinct from that of α-tocopherol in anti-cancer activity. Vitamin E, known to reach therapeutic levels in brains of Alzheimer’s disease (AD) patients, decreases lipid peroxidation susceptibility by 60% in patients as compared to controls. However, ingestion of combined tocopherol, incorporating all the forms as opposed to α-tocopherol alone, has been shown to generate the protective effect against AD normally associated with vitamin E.

Plasma concentration of vitamin E depends completely on the absorption, tissue delivery and excretion rate from different isomers. The estimated α-tocopherol half-life in plasma of healthy individuals is almost double the half-life of γ-tocopherol. These kinetic data (i.e., α-tocopherol levels are maintained, while the other forms of vitamin E are removed much more rapidly) should be taken into consideration when designing therapeutic antioxidant options.

High dose vitamin E supplements have become a preferred option, going up to 2000 IU per day. However, three recent meta-analyses, which did not consider dose–response relationships, reported no overall effect of vitamin E on survival. In addition, several trials of high-dosage vitamin E supplementation have reported non–statistically significant increases in total mortality.

Conclusion
It has been almost 90 years since the discovery of vitamin E, but its functional roles still require much more investigation. Isolation and identification of the various types of tocopherols and tocotrienols have been an enormous help to the field in establishing biological effects, and the evidence accumulated so far supports a primary role as antioxidant. However, several lines of investigation have recently revealed that vitamin E has biological roles unrelated to its antioxidant properties. Among these roles, vitamin E has been described as: a regulator of signal transduction and gene expression, redox sensor and modulator of specific cell functions via interaction with certain membrane domains. On the basis of this emerging work, it is clear that vitamin E is a complex molecule with varied and pleiotropic effects.

Considering these novel aspects of vitamin E biochemistry, including the biological properties of related congeners, it should not be surprising that many of the clinical studies, both epidemiological and interventional, which did not take into consideration those aspects, are inconclusive. More research aimed at defining the uses and the dosage of different tocopherols and tocotrienols in prospective interventional studies is warranted before a final conclusion can be reached.


Dilip Ghosh, PhD, FACN, is director of nutriConnect, based in Sydney, Australia. He can be reached at [email protected].au; www.nutriconnect.com.au.

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The ideas and opinions expressed in this article are those of the author and do not necessarily reflect views held by Nutraceuticals World.