In a rat model, halothane causes liver injury by reductive interaction with microsomal cytochrome P-450 (P-450) and /or by a hepatotoxic effect mediated by halothane-derived free radicals. Rats that were pretreated with phenobarbital (0.1% in drinking water for 6 days) and fasted for the last day, then exposed to halothane (1.0%) under reduced oxygen tension (14%) for 2 horus developed hepatic centrilobular necrosis with marked elevation in serum GPT (GPT) 24 h after exposure. Pretreatment with a 5 mg/kg dose of zinc (Zn) 24 h prior to the exposure had no effect on GPT and liver necrosis. However, 10mg/kg and 20 mg/kg of Zn significantly decreased GPT and liver necrosis. Zn-pretreatment (5-20 mg/kg) significantly depleted hepatic microsomal P-450 before exposure in a dose dependent manner. Hepatic metallothionein (MT)-1 and MT-2 induced by Zn in a dose dependent manner and the levels did not significanlty differ prior to and after exposure to halothane under hypoxic conditions in all Zn-pretreated groups of rats. These results indicated that Zn-pretreatment has some protective effect against halothane-induced liver injury and suggested that this protective effect of Zn involves the depletion of P-450 which results in reduced interacton between P-450 and halothane in the microsomes and is not the result of MTs acting as free radical scavengers.