This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with a-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in uiuo. Control animals were time-matched sham-ischemic animds. After 1,5 or 24 h r of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 h r (5,242 -+ 682 U L ) and were significantly reduced by a-tocopherol pretreatment (1,854 2 229 UL, p < 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by a-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although a-tocopherol restored cy- tochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with a-tocopherol treatment (p < 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by a-tocopherol pretreatment. Our findings suggest that pretreatment with a-tocopherol reduces hepatocellular damage as indicated by abnormalities in microsomal drugmetabolizing function during ischemia/reperfusion and that this protection is, in major part, caused by decreased lipid peroxidation. (HEPATOLOGY 1992; 15: 276-281.) Ischemialreperfusion (IIR) injury is responsible for organ damage in a variety of pathological events such as myocardial infarction, stroke and graft failure after organ transplantation (1,2). Although the nature of this