Effect of ethanol administration on hepatic ethanol and drug-metabolizing enzymes and on rates of ethanol degradation.

Abstract

Abstract Ethanol administration was recently shown to enhance the activities of microsomal enzyme systems which metabolize ethanol and other drugs. The present study was designed to establish the time sequence and the mechanism that may account for the increases in enzyme levels, and to determine whether the increases in microsomal ethanol-oxidizing activity are accompanied by comparable changes in the rates of ethanol degradation in vivo. Male rats were fed ethanol for periods of 24, 48, and 72 hours, 7, and 14 days. Whereas liver weights and the cytosol enzymes alcohol dehydrogenase and lactate dehydrogenase were not changed, significant increases were obtained as early as 24 hours after ethanol administration for microsomal ethanol-oxidizing activity and at 48 hours for aniline hydroxylase and cytochrome P-450. Microsomal protein concentration was increased only at 14 days. Protein turnover studies demonstrated no changes in the rate of incorporation of 1- 14 C-l-leucine into microsomal protein, but significant decreases in the rate of degradation of 1- 14 C-l-leucine from microsomal protein were found at 14 days. The rates of ethanol disappearance from the blood were increased; however, the calculated mean increase of the microsomal ethanol-oxidizing activity accounted for only 13.8 per cent of the mean increase in the rate of in vivo ethanol disappearance at 7 days. The findings suggest that the mechanism of induction by ethanol is different from that of other known inducers, and that in vivo factors beside the absolute increase in microsomal enzyme activity must account for the observed changes in the rates of ethanol degradation.