A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [3H]acetaminophen (750-900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.
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