Effect of α‐tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion

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 α‐tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no‐flow hepatic ischemia in vivo. Control animals were time‐matched sham‐ischemic animals. After 1, 5 or 24 hr 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 hr (5,242 ± 682 U/L) and were significantly reduced by α‐tocopherol pretreatment (1,854 ± 229 U/L, p < 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle‐treated ischemic group, but this elevation was prevented by α‐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 α‐tocopherol restored cytochrome P‐450 content to the level of sham‐ischemic control rats, aminopyrine‐ N ‐demethylase activity remained at 76% of control with α‐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 α‐tocopherol pretreatment. Our findings suggest that pretreatment with α‐tocopherol reduces hepatocellular damage as indicated by abnormalities in microsomal drug‐metabolizing function during ischemia/reperfusion and that this protection is, in major part, caused by decreased lipid peroxidation. (H EPATOLOGY 1992;15:276–281).