GAMMA-TOCOPHEROL TRAPS MUTAGENIC ELECTROPHILES SUCH AS NOX AND COMPLEMENTS ALPHA-TOCOPHEROL - PHYSIOLOGICAL IMPLICATIONS

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of . NO and O-2(.-) duri ng activation of phagocytes. Chronic inflammation induced by phagocyte s Is a major contributor to cancer and other degenerative diseases, We examined how gamma-tocopherol (gamma T), the principal form of vitami n E in the United States diet, and alpha-tocopherol (alpha T), the maj or form in supplements, protect against peroxynitrite-induced lipid ox idation, Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the . NO and O-2( .-) generator SIN-1 (3-morpholinosydnonimine) was inhibited more effec tively by gamma T than alpha T. More importantly, nitration of gamma T at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximate to 50% and app roximate to 75%, respectively, was not affected by the presence of alp ha T, These results suggest that despite alpha T's action as an antiox idant gamma T is required to effectively remove the peroxynitrite-deri ved nitrating species, We postulate that gamma T acts in vivo as a tra p for membrane-soluble electrophilic nitrogen oxides and other electro philic mutagens, forming stable carbon-centered adducts through the nu cleophilic 5-position, which is blocked in alpha T, Because large dose s of dietary alpha T displace gamma T in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alpha T sh ould be reconsidered.