Prostaglandin H Synthase and Xenobiotic Oxidation

Abstract

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.

Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:Cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid‐DNA adducts found in patients with urothelial cancer

“…29 The levels of 2 forms of human prostaglandin H synthase (prostaglandin H synthase-1 and prostaglandin H synthase-2) appear to be induced in response to a number of hormonal and membrane active agents. 50,51 Their levels in individuals can therefore differ significantly. Expression levels and activities of CYP1A1/2 and NADPH:CYP reductase in humans are influenced by several factors (smoking, drugs, environmental chemicals and genetic polymorphisms) and also differ considerably among individuals.…”

“…Because prostaglandin H synthase, another enzyme activating AAI, 29 is present in human renal tissue, 50,51 we investigated the effect of its cofactor, arachidonic acid, on AAI-DNA adduct formation in human renal microsomes. Adduct levels were significantly higher (2.6-fold) when arachidonic acid was added into the incubation mixture (Table II).…”

Peroxidative metabolism of carcinogenic N-arylhydroxamic acids: implications for tumorigenesis.

“…Oxidations of these compounds, termed cosubstrates, were catalyzed by the peroxidase activity of PHS. Investigations from several laboratories on activation of carcinogenic N-arylamines via PHS-mediated oxidations have recently been reviewed (2,3). PHS catalyzed one electron (le-)-oxidation of N-2-fluorenamine (2-FA) to nitrogen-centered free radicals, which yielded dimeric and polymeric products and 2-nitrofluorene (2-NO2F).…”

Reactions of Prostaglandin H Synthase with Monosubstituted Hydrazines and Diazenes

“…Addition of two molecules of 0, to the arachidonyl radical and abstraction of an hydrogen atom from Tyr385 would lead to PGG,. Both PGHS-(porphyrin-cation-radical) iron(1V)-oxo and PGHS-iron(1V)-oxo species can be reduced back to PGHS-iron(II1) by a number of reducing cosubstrates including phenols, aromatic amines, P-dicarbonyl-compounds (Dietz et al, 1988;Eling et al, 1990;Karthein et al, 1985;Lambeir et al, 1985;Markey et al, 1987) and sulfides (Egan et al, 1980;PI6 and Marnett, 1989).…”