gamma-tocopherol traps mutagenic electrophiles such as NO(X) 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 O2.- during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), 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 O2.- generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximately 50% and approximately 75%, respectively, was not affected by the presence of alphaT. These results suggest that despite alphaT's action as an antioxidant gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT 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 alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.
Christen
S
S
Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720, USA.
Woodall
A A
AA
Shigenaga
M K
MK
Southwell-Keely
P T
PT
Duncan
M W
MW
Ames
B N
BN
D000975:Antioxidants / Q000737:chemistry; D016166:Free Radical Scavengers; D006801:Humans; D007536:Isomerism; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000737:chemistry; D009153:Mutagens / Q000737:chemistry*; D009566:Nitrates / Q000737:chemistry*; D014810:Vitamin E / Q000737:chemistry*
D000975:Antioxidants; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D009153:Mutagens; D009566:Nitrates; D014810:Vitamin E; C039642:peroxynitric acid