Effects of food deprivation and adrenalectomy on CYP3A induction by RU486 in female rats

We have studied the effects of food deprivation and adrenalectomy on the induction by RU486 of female rat liver microsomal CYP3A apoprotein, erythromycin N-demethylase and diazepam C-3-hydroxylase activities. RU486 was a potent inducer of CYP3A apoprotein in intact animals and food deprivation enhanced this response. Food deprivation alone caused only weak CYP3A apoprotein induction suggesting a synergistic interaction in the regulation of protein expression. These results were reflected in the measurements of diazepam C-3-hydroxylase activity. This confirms diazepam C-3-hydroxylase as a useful and easily measured index of CYP3A monooxygenase content in female rat liver microsomes. Erythromycin N-demethylase did not show concordance with this pattern; this monooxygenase was much more strongly induced by food deprivation alone than by RU486 administration and, in addition, adrenalectomy abolished the induction response to food deprivation. The lack of correspondence between the apoprotein and erythromycin N-demethylase results suggests that non-CYP3A or novel, hitherto uncharacterized CYP3A isoforms may contribute to erythromycin N-demethylation in female rats. The close agreement between the results for CYP3A apoprotein and diazepam C-3-hydroxylase indicates that although RU486 possesses a terminal acetylenic moeity it does not, at the dosages used here, cause mechanism-based inactivation of the CYP3A monooxygenase protein it induces. Current studies are directed to characterizing the particular CYP3A isoform(s) whose production is stimulated by RU486. Copyright (C) 1996 Elsevier Science Ltd.