Interactions of spironolactone with hepatic microsomal drug-metabolizing enzyme systems

Abstract

The nature of the stimulation of hepatic microsomal drug-metabolizing enzymes by spironolactone was studied in male mice. Mice given spironolactone (100 mg/kg, i.p.) twice daily for 3 consecutive days exhibited increased liver weight and mierosomal protein content. The administration of spironolactone also stimulated the microsomal metabolism of hexobarbital in vitro, the disappearance of hexobarbital from the whole body of mice in vivo and reduced hexobarbital sleeping time. Increases were noted in the microsomal N-demethylation of ethylmorphine, oxidation of hexobarbital and hydroxylation of aniline. Moreover, prior treatment with spironolactone increased the levels of several components of the microsomal electron transport system which included NADPH-oxidase, NADPH-cytochrome c reductase, cytochrome P-450 and NADPH-cytochrome P-450 reductase. In addition, the stimulatory effects of ethylmorphine or hexobarbital on the rate of cytochrome P-450 reduction by NADPH were greater in microsomes from spironolactone-treated animals. In other studies, it was found that the addition of spironolactone to liver microsomes (1) inhibited the N-demethylation of ethylmorphine and (2) blocked the stimulatory effect of ethylmorphine on the reduction of cytochrome P-450. The results indicate that spironolactone is an inducer of hepatic microsomal drug-metabolizing enzymes in male mice. A proposed mechanism for spironolactone's interaction with these enzyme systems is discussed.