Differences in the duration of the enhancement of liver mixed-function oxidase activities in ethanol-fed rats after withdrawal

Abstract

Liver microsomal mixed-function oxidase activities were determined in female Sprague-Dawley rats after 3 weeks of ethanol feeding and for up to 10 days after withdrawal. Ethanol (36% of total calories) was administered in a high fat liquid diet and was replaced isocalorically by carbohydrates in controls. Chronic ethanol feeding similarly enhanced both microsomal cytochrome P-450 content and benzphetamine N-demethylase activity, per mg of protein, and resulted in a disproportionate increase in both aniline hydroxylase and 7-ethoxycoumarin O-deethylase activities. A 6- to 7-day withdrawal period was apparently necessary for the overall disappearance of these effects of ethanol. Marked differences, however, were seen in the time courses of return of these variables to control levels, as also indicated by changes, during this period and specially during the first 24 hr after withdrawal, in the apparent molar activity of the microsomal fraction with the three substrates tested. The results were interpreted as indicating that the distinct ethanol-inducible cytochrome P-450 isozyme, with a high specific activity toward aniline, undergoes a very rapid turnover in liver microsomes. Induction of another form of cytochrome P-450, differing from the former by its slower turnover rate, would explain the induction by ethanol of 7-ethoxycoumarin O-deethylase activity. The withdrawal of ethanol was followed by a rapid but transient increase in benzphetamine N-demethylase activity above the ethanol-induced level, at a time when other activities were rapidly declining. This could suggest that the microsomal content of other cytochrome P-450 isozyme(s), with high specific activity toward this substrate, would also be temporarily altered during ethanol withdrawal. Important alterations in microsomal cytochrome P-450-dependent mixed-function oxidase activities occurred during the initial 24-hr period of withdrawal, even in the absence of a change in microsomal cytochrome P-450 content, indicating that the effects of chronic ethanol ingestion on hepatic drug-metabolizing enzyme activities may also be highly dependent on the proximity of ethanol intake.