In a rat model, halothane causes liver injury by interaction with microsomal cytohrome P450 (P450) under a hypoxic condition. Rats that were pretreated with phenobarbital and exposed to halothane under reduced oxygen tension for 2 hours developed hepatic centrilobular necrosis with marked elevation of serum alanine aminotransferase (ALT) 24h after exposure. The elevation of ALT was significantly suppressed in the rats pretreated with a 10mg/kg dose of zinc (Zn) 24h prior to the exposure in comparison with the rats pretreated with saline (control rats). The region of necrosis was also significantly reduced in Zn-pretreated rats. The P450 content of the hepatic microsomes was slightly decreased before the exposure in Zn-pretreated rats in comparison with that in the control rats. It was noteworthy that the aminopyrine demethylation (AD) activity of hepatic microsomal after the exposure in Zn-pretreated rats. These findings indicate that Zn-pratreatment has some protective effect against halothane-induced liver injury and suggest that this protective effect of Zn involcves not only the decrease of P450 before exposure but also the preservation of AD activity during exposure, which result in reduced interaction between P450 and halothane in the microsomes.