A solid research effort is now focused on the hepatic biochemistry and toxicity of oxygen radicals. Carbon radicals formed under physiologically relevant oxidative conditions, however, have received relatively little attention despite the fact that the biological fates of carbon and oxygen radicals are intimately linked and that carbon radicals are highly informative mechanistic probes. The present proposal, which stems from recent developments in my laboratory, capitalizes on our demonstration that spin trapped carbon radicals can be isolated and their precise structure unambiguously determined. The first goal of the project is to extend and improve spin trapping methodology with the particular intent of using it in physiological systems. The second goal is to define the nature and range of substrates that give rise to diffusible carbon radicals upon oxidative (as distinct from reductive) hepatic metabolism. The third goal is to measure the lifetime of carbon radicals in biological systems and to determine if they are able, either free or in a masked form, to reach targets removed from the site of drug oxidation. The fourth goal is to investigate the fate of carbon radicals, particularly their possible oxidation by metals and their reactions with membrane lipids. The final goal is to investigate the formation and properties of carbon radicals in the isolated perfused liver. These studies are intended to elucidate the basic biochemistry of carbon radicals and to initiate a definitive exploration of their in vivo toxicological potential.
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