TEMPORAL VARIATION IN HEPATOTOXICITY AND METABOLISM OF ACETAMINOPHEN IN MICE

Temporal variation in metabolism and hepatotoxicity of acetaminophen ( APAP) was examined using male ICR mice. Animals were injected with a s ingle dose of APAP (400 mg/kg, i.p.) at 08:00, 14:00 or 20:00 h. APAP at this dose was markedly hepatotoxic to mice when administered at 20: 00 h as determined by increases in serum alanine aminotransferase (ALT ) and aspartate aminotransferase (AST) activities, and by decreases in hepatic glucose-6-phosphatase (G-6-Pase) activity. However, mice appe ared to be entirely insensitive to an identical dose of APAP given eit her at 08:00 or 14:00 h. Hepatic glutathione (GSH) level was significa ntly higher at 08:00, but no difference in GSH levels between 14:00 an d 20:00 h was observed in normal mice. APAP and its metabolites in blo od were monitored using HPLC for 3 h following the treatment. There we re no significant differences in the plasma concentrations of APAP, AP AP-glucuronide, APAP-sulfate, or APAP-mercapturate among the mice trea ted with this drug at 08:00, 14:00 or 20:00 h. However, the APAP-cyste ine and APAP-GSH levels measured at 1 h following the APAP treatment w ere significantly lower in mice treated with this analgesic either at 14:00 or 20:00 h. In vitro hepatic microsomal p-nitrophenol hydroxylas e activities were not different between 08:00, 14:00 and 20:00 h. But ethoxyresorufin O-deethylase and aminopyrine N-demethylase activities measured at 14:00 h were significantly lower than those of 08:00 or 20 :00 h. Thus, the greater hepatotoxicity of APAP administered at 20:00 h appears to be related to the marked decrease in hepatic GSH at this time period, whereas the simultaneous reduction in APAP activation may be responsible for the lack of hepatotoxicity in mice treated with th is analgesic at 14:00 h. These results suggest that the temporal varia tion in hepatotoxicity and metabolism of APAP is determined by interac tions of multiple factors including the hepatic GSH level and drug met abolizing activities. (C) 1998 Elsevier Science Ireland Ltd. All right s reserved.