title: Redox cycles of vitamin E: hydrolysis and ascorbic acid dependent reduction of 8a-(alkyldioxy)tocopherones.
abstract: Oxidation of the biological antioxidant alpha-tocopherol (vitamin E; TH) by peroxyl radicals yields 8a-(alkyldioxy)tocopherones, which either may hydrolyze to alpha-tocopheryl quinone (TQ) or may be reduced by ascorbic acid to regenerate TH. To define the chemistry of this putative two-electron TH redox cycle, we studied the hydrolysis and reduction of 8a-[(2,4-dimethyl-1-nitrilopent-2-yl)dioxy]tocopherone (1) in acetonitrile/buffer mixtures and in phospholipid liposomes. TQ formation in acetonitrile/buffer mixtures, which was monitored spectrophotometrically, declined with increasing pH and could not be detected above pH 4. The rate of TQ formation from 1 first increased with time and then decreased in a first-order terminal phase. Rearrangement of 8a-hydroxy-alpha-tocopherone (2) to TQ displayed first-order kinetics identical with the terminal phase for TQ formation from 1. Both rate constants increased with decreasing pH. Hydrolysis of 1 in acetonitrile/H2(18)O yielded [18O]TQ. These observations suggest that 1 loses the 8a-(alkyldioxy) moiety to produce the tocopherone cation (T+), which hydrolyzes to 2, the TQ-forming intermediate. Incubation of either 1 or 2 with ascorbic acid in acetonitrile/buffer yielded TH. Reduction of both 1 and 2 decreased with increasing pH. In phosphatidylcholine liposomes at pH 7, approximately 10% of the T+ generated from 1 was reduced to TH by 5 mM ascorbic acid. The results collectively demonstrate that T+ is the ascorbic acid reducible intermediate in a two-electron TH redox cycle, a process that probably would require biocatalysis to proceed in biological membranes.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
authors.forename: D C
authors.initials: DC
authors.lastname: Liebler
authors.forename: K L
authors.initials: KL
authors.lastname: Kaysen
authors.forename: T A
authors.initials: TA
authors.lastname: Kennedy
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D006868:Hydrolysis; D010084:Oxidation-Reduction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C062546:8-((2,4-dimethyl-1-nitrilopent-2-yl)dioxy)tocopherone; D014810:Vitamin E; D001205:Ascorbic Acid