PROTECTION BY CLOFIBRATE AGAINST ACETAMINOPHEN HEPATOTOXICITY IN MALECD-1 MICE IS ASSOCIATED WITH AN EARLY INCREASE IN BILIARY CONCENTRATION OF ACETAMINOPHEN-GLUTATHIONE ADDUCTS

Repeated treatment with clofibrate (CFB) significantly increased hepat ic glutathione (GSH) content and also diminished acetaminophen's (APAP ) selective protein arylation, GSH depletion, and severity of hepatoce llular necrosis, The present work was conducted to evaluate the role o f elevated GSH and APAP detoxifying pathways in the amelioration of AP AP's toxicity by CFB. Male CD-1 mice received 500 mg CFB/kg, ip, daily for 10 days, Controls were given corn oil vehicle, They were challeng ed with 700 mg APAP/kg in 50% propylene glyco/water after an overnight fast, Results indicate that CFB pretreatment had no effect on 24-hr u rinary excretion of APAP-glucuronide, sulfate, or GSH-derived conjugat es; however, there was 50% less unchanged APAP excreted in urine of CF B-pretreated mice. CFB also did not alter microsomal UDP-glucuronyl tr ansferase activity toward APAP in vitro, However, elimination of APAP from plasma and liver was much greater in CFB-pretreated mice, This wa s accompanied by elevated biliary APAP-GSH content in CFB-pretreated m ice at 2 hr after APAP dosing with diminished levels in bile at 12 hr, The CFB-induced increase in biliary excretion of APAP-GSH may mediate the protection against APAP-induced hepatotoxicity. (C) 1996 Academic Press, Inc.