Abstract
Acetaminophen (APAP, N-acetyl-p-aminophenol) is a widely used analgesic and antipyretic which, at high doses, causes acute hepatic centrilobular necrosis in man and a variety of laboratory animals (Proudfoot and Wright, 1970; Boyer and Rouff, 1971; Mitchell et al., 1973). In addition, acute renal proximal tubular necrosis following APAP has been reported in man (Kleinman et al., 1980; Cobden et al., 1982; Kher and Makker, 1987; Davenport and Finn, 1988). A similar lesion has been described in the Fischer rat (McMurtry et al., 1978; Newton et al., 1983) andthe CD-1 mouse (Placke et al, 1987) but the APAP metabolite responsible for the toxicity is different between species. In the rat, APAP is enzymatically deacetylated to paminophenol, a potent nephrotoxicant whose activation is independent of cytochrome P450 (Crowe et al., 1979; Calder et al., 1979; Newton et al., 1982; 1985a; 1985b). By contrast, enzymatic deacetylation of APAP is not required in the mouse but instead activation of intact APAP by cytochrome P450 appears to mediate nephrotoxicity (Bartolone et al, 1989; Emeigh Hart et al., 1989a; 1989b). Since hepatic metabolism of APAP is similarly dependent on cytochrome P450 (Mitchell et al, 1973), nephrotoxicity and renal adduct accumulation could arise from transport of a livergenerated metabolite or adduct to the kidney and not from in situ metabolism of APAP. The purpose of the present study was to determine, using renal proximal tubule (RPT) cell suspensions and immunohistochemistry, if the mouse kidney could generate such adducts in situ.
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© 1991 Plenum Press, New York
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Hart, S.G.E. et al. (1991). In Vivo and in Vitro Evidence for in Situ Activation and Selective Covalent Binding of Acetaminophen (APAP) in Mouse Kidney. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_92
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DOI: https://doi.org/10.1007/978-1-4684-5877-0_92
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