γ-Tocopherol traps mutagenic electrophiles such as NO(x) and complements α-tocopherol: Physiological implications

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of ·NO and O(2⨪) during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how γ-tocopherol (γT), the principal form of vitamin E in the United States diet, and α-tocopherol (αT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. 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 effectively by γT than αT. More importantly, nitration of γT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of ≈50% and ≈75%, respectively, was not affected by the presence of αT. These results suggest that despite αT’s action as an antioxidant γT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that γT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in αT. Because large doses of dietary αT displace γT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily αT should be reconsidered.