Effect of spironolactone on hepatic microsomal monooxygenase and azoreductase activities

Spironolactone pretreatment (10mg/100g, twice daily for 4 days, orally) caused a significant decrease in cytochrome P-450 levels in the liver microsomes in female rats but male rats were unaffected. NADH oxidase activity was significantly decreased in both sexes by this pretreatment but NADPH oxidase and NADH cytochrome C reductase activities were not altered. NADPH cytochrome c reductase activity was increased more markedly in female rats. Despite the decrease in P-450 levels, aminopyrine N-demethylase activity was increased in female rats, while it remained unchanged in males. 7-Ethoxycoumarin O-deethylase activity was markedly increased in male and slightly decreased in female rats. The azoreductase activity was slightly reduced in treated male rats and remained unaltered in female rats when it was expressed in activity per mg microsomal protein, but the activity did show a significant increase in female rats when it was expressed as a P-450 specific rate. Sex associated differences in the effect of spironolactone on the rat liver microsomal drug metabolizing enzyme system demonstrated in the present study cannot be simply explained by the previously reported effect on adrenal and testicular steroids in male rats. It also seems unlikely that these effects were caused by an alteration in P-450 quality by selective destruction of certain species of P-450.