Prostaglandin H synthase and xenobiotic oxidation

We have attempted in this article to summarize and review cooxidation reactions that occur during the metabolism of AA and potential roles that these reactions can play in the activation and detoxification of chemicals. This review summarizes approximately 15 years of intensive investigation by a number of laboratories, and as such not all studies are cited, and in some cases data are not discussed with the emphasis that the original investigators may have intended. The major focus of many of these studies has been toward carcinogenesis. In the future, emphasis may shift to the formation of metabolites that will lead to other toxic effects. The cooxidation reactions that occur during AA metabolism are dependent upon the peroxidase activity of PHS. For some chemicals that are not cosubstrates, the epoxidation reactions that occur are dependent upon the subsequent formation of peroxyl radicals. A large and diverse number of chemicals are metabolized by an equally large and diverse number of chemical reactions. The unifying theme is the free radical nature of these oxidations. The subsequent reactions that these chemicals undergo is dictated by the nature of the free radical and the environment in which it is generated. Ample evidence now exists for the contribution of these free radical-mediated reactions not only in the formation of toxic metabolites, but also in some cases in the detoxification of chemicals. The overriding factor for this type of metabolism to occur is the relative concentrations in the specific tissue of PHS and peroxyl radicals with respect to other activating systems, particularly the monooxygenase system. In vivo investigations support the importance of the peroxidase and peroxyl radical systems in both activation and detoxification of chemicals in extrahepatic tissues.