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.

The determination of protein nitrotyrosine content has become a frequently used technique for the detection of oxidative tissue damage. Protein nitration has been suggested to be a final product of the production of highly reactive nitrogen oxide intermediates (e.g. peroxynitrite) formed in reactions between nitric oxide (NO ⅐ ) and oxygen-derived species such as superoxide. The enzyme prostaglandin H synthase-2 (PHS-2) forms one or more tyrosyl radicals during its enzymatic catalysis of prostaglandin formation. In the presence of the NO ⅐ -generator diethylamine nonoate, the electron spin resonance spectrum of the PHS-2-derived tyrosyl radical is replaced by the spectrum of another free radical containing a nitrogen atom. The magnitude of the nitrogen hyperfine coupling constant in the latter species unambiguously identifies it as an iminoxyl radical, which is likely formed by the oxidation of nitrosotyrosine, a stable product of the addition of NO ⅐ to tyrosyl radical. Addition of superoxide dismutase did not alter the spectra, indicating that peroxynitrite was not involved. Western blot analysis of PHS-2 after exposure to the NO ⅐ -generator revealed nitrotyrosine formation. The results provide a mechanism for nitric oxide-dependent tyrosine nitration that does not require formation of more highly reactive nitrogen oxide intermediates such as peroxynitrite or nitrogen dioxide.

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