Metabolism of drugs by subfractions of hepatic microsomes from prolonged ethanol-treated rats.

Abstract

In a previous paper, it was reported that in rats treated chronically with ethanol, the side-chain oxidation of hexobarbital, N-demethylation of aminopyrine and p-hydroxylation of aniline in vitro from either 9, 000 g supernatant; fraction of liver homogenates or washed microsomes was identical with that of control rats when ethanol was withdrawn and substituted for tap water 24 hr prior to sacrifice. In contrast, the activity of aniline hydroxylase of the rats which continued to ingest ethanol ad libitum up to the time of sacrifice was approx. 1.5-fold increased, compated with that of controls, in spite of no change being detected in hexobarbital oxidase and aminopyrine demethylase activities (1, 2). It is known that pretreatment of rats with phenobarbital markedly increases the activities of several hepatic drug-metabolizing enzymes in smooth-surfaced microsomes relative to rough-surfaced ones. The ratio of enzyme activity in smooth microsomes to that in rough microsomes increases in the liver from the phenobarbital-treated animal as compared with that from the control animal (3, 4). Fouts and Gram (5) reported that ratios of smoothversus rough-surfaced microsomal aminopyrine N-demethylase and hexobarbital oxidase of rabbits decreased after 3-methylcholanthrene treatment. The present experiments were conducted to determine the intramicrosomal distribution of drug-metabolizing enzyme activity in the rats treated chronically with ethanol. Parallel experiments were done to determine the intramicrosomal distributions of cytochrome P-450, protein and phospholipid phosphorous contents of the liver from the rats treated chronically with ethanol.