PROTECTION AGAINST ACETAMINOPHEN HEPATOTOXICITY BY A SINGLE-DOSE OF CLOFIBRATE - EFFECTS ON SELECTIVE PROTEIN ARYLATION AND GLUTATHIONE DEPLETION

Previous reports demonstrated that repeated administration of peroxiso me proliferators protects against acetaminophen (APAP) hepatotoxicity in mice. This protection was associated with a decrease in APAP's sele ctive protein arylation and glutathione depletion. This study was cond ucted to determine if a single dose of clofibrate (CFB), rather than r epeated doses, would similarly prevent APAP toxicity. CD-1 male mice r eceived a single dose of 500 mg CFB/kg and controls were given corn oi l 24 hr prior to APAP challenge. After an 18-hr fast, mice were challe nged with 800 mg APAP/kg (in 50% propylene glycol) and killed at 4 or 12 hr. Other mice similarly pretreated were killed without APAP challe nge. The results showed that pretreatment with a single CFB dose signi ficantly decreased APAP-induced hepatotoxicity. At 12 hr after APAP pl asma sorbitol dehydrogenase activity and the severity of hepatocellula r necrosis were decreased in CFB pretreated mice. Surprisingly, no dif ferences in hepatic nonprotein sulfhydryl (NPSH) depletion or selectiv e arylation of target proteins in cytosol were observed at 4 hr after APAP challenge. Neither did a single dose of CFB significantly alter h epatic NPSH content prior to APAP challenge. These results indicate th at protection against APAP hepatotoxicity by CFB does not require repe ated administration, and the absence of significant alterations in APA P's selective protein arylation or glutathione depletion suggests that the protection against APAP hepatotoxicity after a single treatment w ith CFB may differ mechanistically from the protection observed after repeated CFB dosing. (C) 1996 Society of Toxicology