Effects of Age, Sex, and Cimetidine on Acute Ethanol‐Induced Inhibition of the Hepatic Monooxygenase Systems

Abstract

Our aim was to investigate the possible interaction of acute ethanol (E) with the metabolism of other drugs by microsomes isolated from immature and mature rat livers and placenta. The effects of acute in vitro E exposure on the N-demethylation of [14C]aminopyrine and [1-14C]methylcaffeine by these tissues were determined. In addition, the effects of ethanol on these two enzyme systems from male and female livers were compared along with an analysis of ethanol and cimetidine inhibitory interactions. The degree (percentage) of inhibition by acute E (1-3 mg/ml) varied with both age and sex. Aminopyrine demethylase activity was inhibited by E to a greater degree (p less than 0.05) in the adult female than the male. However, when inhibition was expressed in absolute terms (control minus inhibited activity), these inhibitory values varied in direct proportion to initial (control) enzyme activity. Thus, E reduced aminopyrine demethylase from adult male microsomes by 4 times that in the female and in excess of 1000 times the absolute inhibition observed in fetal liver regardless of E concentration. A similar pattern of sex and age differences in caffeine demethylase response to E was observed except that absolute differences in inhibition were less due to smaller variation in control values. In addition, placental caffeine demethylase was highly sensitive to E inhibition (51% at 3 mg/nl) but not to the extent of caffeine demethylase from fetal liver (75% at 3 mg/nl). Finally, it was demonstrated that E interacts with cimetidine in a manner that may be additive.