Model studies in cytochrome P-450-mediated toxicity of halogenated compounds: radical processes involving iron porphyrins.

Abstract

Haloalkane toxicity originates from attack on biological targets by reactive intermediates derived from haloalkane metabolism by a hemoprotein, cytochrome P-450. Carbon-centered radicals and their peroxyl derivatives are most likely involved. The reactions of iron porphyrin--a model for cytochrome P-450--with various carbon-centered and peroxyl radicals generated by pulse radiolysis are examined. Competition between iron porphyrin and unsaturated fatty acids for attack by peroxyl radicals is pointed out. These kinetic data are used to derive a model for toxicity of haloalkanes with particular attention to carbon tetrachloride and halothane. The importance of local oxygen concentration and structural arrangement of fatty acids around cytochrome P-450 is emphasized.

Chemistry of Reactive Oxygen Species

“…This has come about because of an increasing awareness of the role of peroxyl radicals in physiological processes, including aging, radiation-induced damage, and ischemia. Because of the involvement of in the toxicity of (Brault, 1985;Cheeseman et al, 1985), much of the work has focused on this radical, but there has also been a significant amount of interest in the behavior of other peroxyl radicals.…”