Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as reactive intermediates

Environmental Health Perspectives
L J Marnett

Abstract

Prostaglandin-H synthase is unique among enzymes of the plant and animal kingdom in its ability to biosynthesize and metabolize hydroperoxides. Its cyclooxygenase activity oxygenates polyunsaturated fatty acids to hydroperoxy endoperoxides, and its peroxidase activity reduces the hydroperoxy group to hydroxy groups. Higher oxidation states of the peroxidase oxidize reducing substrates to electron-deficient derivatives that react with macromolecular nucleophiles. In the case of aromatic amines, the electron-deficient derivatives are mutagenic to bacterial and mammalian cells. beta-Dicarbonyl compounds and retinoic acid are oxidized to carbon-centered radicals that react with O2 to form peroxyl free radicals. Peroxyl radicals are the most stable oxy radicals and are able to diffuse some distance from the site of their generation. Peroxyl radicals are also formed during lipid peroxidation and in the reaction of polyunsaturated fatty acid hydroperoxides with metal complexes and metalloproteins. Peroxyl radicals epoxidize isolated doubled bonds of compounds such as 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol); 3,4-dihydroxy-3,4-dihydrobenzo(a)anthracene; and aflatoxin B1. The epoxide products represent the ultimate carcinog...Continue Reading

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