Acetaminophen as a Cosubstrate and Inhibitor of Prostaglandin H Synthase
Recently, several reports (Marnett et al., 1983; Nordenskjöld et al., 1984) have implicated prostaglandin H synthase (PHS) in the bioactivation of xenobiotics to potentially toxic metabolites. Benzidine (Zenser et al., 1983), p-aminophenol (Josephy et al., 1983), and phenacetin (Andersson et al., 1982) are among the compounds known to undergo metabolic activation by PHS. Of particular interest to us is the fact that this enzyme can metabolize acetaminophen (APAP) to a reactive species that can bind to proteins or form a glutathione conjugate (Moldeus and Rahimtula, 1980; Boyd and Eling, 1981; Mohandas et al., 1981; Moldeus et al., 1982). In fact, it has been suggested (Boyd and Eling, 1981; Mohandas et al., 1981) that the nephrotoxicity sometimes associated with APAP overdosage may be due in part to its metabolism by PHS which is present in high levels in the renal inner medulla.
KeywordsElectron Spin Resonance Arachidonic Acid Glutathione Conjugate Prostaglandin Synthetase APAP Overdosage
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- Egan, R. W., Paxton, J., and Kuehl, F. A., Jr., 1976, Mechanism for irreversible self-deactivation of prostaglandin synthetase, J. Biol. Chem., 251: 7329.Google Scholar
- Egan, R. W., Gale, P. H., Beveridge, G. C., Marnett, L. J., and Kuehl, F. A., Jr., 1980, Direct and indirect involvement of radical scavengers during prostaglandin biosynthesis, in: “Advances in Prostaglandin andThromboxane Research, Vol. 6,” B. Samuelson, P. W. Ramwell, and R. Paoletti, eds., Raven Press, New York, p. 153.Google Scholar
- Fernando, C. R., Calder, I. C., and Ham, K. N., 1980, Studies on the mechanism of toxicity of acetaminophen: synthesis and reactions of N-acetyl2,6-di-methyl-and N-acetyl-3,5-dimethylbenzoquinone amines, i7 Med. Chem., 23: 1153.Google Scholar
- Marnett, L. J., Bienkowski, M. J., Pagels, W. R., and Reed, G. A., 1980, Mechanism of xenobiotic cooxygenation coupled to prostaglandin H2 biosynthesis, in: “Advances in Prostaglandin and Thromboxane Research,Vol. 6,” B. Samuelson, P. W. Ramwell, and R. Paoletti, eds., Raven Press, New York, p. 149.Google Scholar
- Marnett, L. J., Dix, T. A., Sacks, R. J., and Sieldlik, P. H., 1983, Oxidation by fatty acid hydroperoxides and prostaglandin synthase, in “Advances in Prostaglandin, Thromboxane, and Leukotriene Research, Vol. 11,” B. Samuelson, R. Paoletti, and P. Ramwell, eds., Raven Press, New York, p. 79.Google Scholar
- Mason, R. P., 1979, Free radical metabolites of foreign compounds and their toxicological significance, in: “Reviews in Biochemical Toxicology, Vol. 1,” E. Hodgson, J. R. Bend, and R. M. Philpot, eds., Elsevier North Holland, New York, p. 151.Google Scholar
- NordenskjÖld,N,Andorooon,B.,Bahimtula,A.,and Moldeus,P.1984.Prostalandin synthase-catalyzed metabolic activation of some aromatic amines to genotoxic products, Mutat. Res., 127:107.Potter, D. W., Miller, D. W., and Hinson, J. A., 1985, J. Biol. Chem., in press.Google Scholar
- Zenser, T. V., Mattammal, M. B., Herman, C. A., Joshi, S., and Davis, B. B., 1978, Effect of acetaminophen on prostaglandin E2 and prostaglandin F2a in the renal inner medulla of rat, Biochim. Biophys. Acta, 2a 542: 486.Google Scholar