Acetaminophen toxicity in fed and fasted mice

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.