Effects of ethanol on hepatic microsomal drug-metabolizing enzymes in the rat

Abstract

The activities of several hepatic microsomal drug-metabolizing enzymes were determined in male and female rats after administration of 20% ethanol or an isocaloric amount of glucose in drinking water for 10–49 days. The aniline hydroxylase activity increased, whereas the activities of both pentobarbital hydroxylase and benzphetamine N-demethylase were decreased in male rats given ethanol and killed without ethanol withdrawal. Twenty-four hr after removal of ethanol, the aniline hydroxylase remained elevated but a striking increase of both pentobarbital hydroxylase and benzphetamine N-demethylase above control values occurred. Six days later, all three of these microsomal enzymes returned to normal control values. The reduction in pentobarbital hydroxylase and benzphetamine N-demethylase could not be attributed simply to high endogenous ethanol levels since: (1) addition of high concentrations of ethanol in vitro inhibited microsomal aniline hydroxylase and pentobarbital hydroxylase but did not reduce benzphetamine N-demethylase; and (2) acute administration of ethanol by gastric tube, which markedly elevated the blood ethanol level, did not result in a decline in the enzyme activities. These two findings suggest that the observed decrease in microsomal enzymes in male rats required persistent ethanol exposure. In contrast to male rats, female rats given ethanol for 28 days showed a significant increase in aniline hydroxylase activity, but the activities of pentobarbital hydroxylase and benzphetamine N-demethylase were not decreased. Moreover, administration of ethanol for 28 days to female rats did not reduce the response of these three enzyme activities to pentobarbital administration. It is concluded that the effects of chronic ethanol ingestion on the hepatic microsomal drug-metabolizing enzymes are complex and depend on sex, exposure to other agents and, most importantly, on the duration and proximity of ethanol intake.