Genetic and environmental factors are co-responsible for cardiovascular disease, cancers, and other major causes of mortality.  According to recent studies ¹ environmental factors are most significant. Genetic research on disease prevention was not fulfilling the benefit expectations. The way to go is to  integrate genetic information into epidemiologic studies in order to clarify causal relations between environmental and genetic factors. As an example of integration between these two different factors studies on vitamin E deficiency caused disease will be presented.  Vitamin E, currently employed in laboratory experiments, as well as in animal and human studies, comprises the classical tocopherols, the tocotrienols and some of their ester derivatives (as succinate and acetate).² Traditionally, the action of vitamin E has been ascribed to its ability to chemically act as a lipid based (lipoprotein and membranes) free radical chain breaking molecule and to exert its action protecting the organism against the attack of those radicals.^2-6

More recently, alternative functions of vitamin E have been proposed, and in particular that of acting as a "gene regulator", independent of its radical chain breaking function. Effects of vitamin E have been observed at the level of mRNA protein and could be consequent to regulation of gene transcription, mRNA stability, protein translation, protein stability and post-translational events.^{2, 4-6}

In the studies discussed here, care will be taken in understanding at what level the effect of vitamin E is exerted. The mechanism by which vitamin E produces cellular events could be in principle related to the known radical chain breaking properties of the molecule. This would imply that regulation of certain cellular functions is entrusted in a controlled production and elimination of lipid soluble free radicals and that vitamin E serves as a radical scavenger. The biological difficulty of controlling the propagation of radical chain reactions makes this mechanism improbable. Furthermore, if this were the mechanism of action of tocopherols, other similar radical chain braking molecules would act analogously: this is however not the case.

On the other hand, given the high priority functions assigned to vitamin E, it would be inefficient to consume it as a radical scavenger. Rather, it would be important to protect vitamin E through a network of cellular antioxidant defenses, such as catalases, superoxide dismutases, ascorbate, glutathione, a-lipoic acid etc., similar to what occurs with proteins, nucleic acids and lipids.

The proposal that vitamin E has, similarly to vitamin A and vitamin D derivatives, cell regulatory properties unrelated to its radical chain braking potential, is supported by a number experimental facts. In particular, there is no obvious correlation between radical chain breaking potency of tocopherols and tocotrienols and their in vivo effectiveness.^7,8 On the contrary, other radical chain breaking molecules are in most cases not effective.⁹ Furthermore, the most potent form of natural vitamin E, α-tocopherol, is taken up and retained by the body much more efficiently than g--tocopherol, and all the other natural or synthetic derivatives.^10-14

A specific protein, possibly with the role of selecting α-tocopherol out of other phenolic diet components, has been retained throughout evolution, the α- tocopherol transfer protein (α-TTP)¹⁰ that regulates the concentration of α -tocopherol in the body. Genetic defects in vitamin E absorption are associated with neurodegenerative disease on the one hand; on the other vitamin E in high doses, appears to prevent in some population studies, heart ischemic disease and some cancers. Work at a molecular basis is presented to understand mechanisms of protection and possible therapeutic interventions.

References

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