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J Biol Chem, Vol. 275, Issue 15, 10812-10818, April 14, 2000

Nitric Oxide Reaction with Lipid Peroxyl Radicals Spares -Tocopherol during Lipid Peroxidation
GREATER OXIDANT PROTECTION FROM THE PAIR NITRIC OXIDE/-TOCOPHEROL THAN -TOCOPHEROL/ASCORBATE^*

Homero Rubbo^¶§, Rafael Radi^¶, Daniel Anselmi^¶, Marion Kirk^**, Stephen Barnes^§**, John Butler, Jason P. Eiserich^§, and Bruce A. Freeman^§§§

From the ^¶ Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay, Departments of  Anesthesiology, ^§§ Biochemistry and Molecular Genetics, ^** Pharmacology and Toxicology, and ^§ Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama 35233, and the  Department of Biological Sciences, Salford University, Salford, United Kingdom

The reactions of nitric oxide (^·NO) and -tocopherol (-TH) during membrane lipid oxidation were examined and compared with the pair -TH/ascorbate. Nitric oxide serves as a more potent inhibitor of lipid peroxidation propagation reactions than -TH and protects -TH from oxidation. Mass spectrometry, oxygen and ^·NO consumption, conjugated diene analyses, and -TH fluorescence determinations all demonstrated that ^·NO preferentially reacts with lipid radical species, with -TH consumption not occurring until ^·NO concentrations fell below a critical level. In addition, -TH and ^·NO cooperatively inhibit lipid peroxidation, exhibiting greater antioxidant capacity than the pair -TH/ascorbate. Pulse radiolysis analysis showed no direct reaction between ^·NO and -tocopheroxyl radical (-T^·), inferring that peroxyl radical termination reactions are the principal lipid-protective mechanism mediated by ^·NO. These observations support the concept that ^·NO is a potent chain breaking antioxidant toward peroxidizing lipids, due to facile radical-radical termination reactions with lipid radical species, thus preventing -TH loss. The reduction of -T^· by ascorbate was a comparatively less efficient mechanism for preserving -TH than ^·NO-mediated termination of peroxyl radicals, due to slower reaction kinetics and limited transfer of reducing equivalents from the aqueous phase. Thus, the high lipid/water partition coefficient of ^·NO, its capacity to diffuse and concentrate in lipophilic milieu, and a potent reactivity toward lipid radical species reveal how ^·NO can play a critical role in regulating membrane and lipoprotein lipid oxidation reactions.

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^* This work was supported by National Institutes of Health Grants RO3 TW00489 (to R. R. and B. A. F,), RO1-HL64937, RO1-HL 58115, and P6-HL58418 (to B. A. F.), Consejo Nacional de Investigaciones Cientificas y Técnias (to H. R.), International Centre for Genetic Engineering and Biotechnology, and Swedish Agency for Cooperation Research (to R. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. de Bioquímica, Facultad de Medicina, General Flores 2125, 11800 Montevideo, Uruguay. Tel.: 5982-924-9561; Fax: 5982-924-9563; E-mail: hrubbo@ fmed.edu.uy.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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