Effects of Spironolactone, Canrenone and Canrenoate-K on Cytochrome P450, and 11β- and 18-Hydroxylation in Bovine and Human Adrenal Cortical Mitochondria11

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Abstract
Effects of spironolactone, canrenone and canrenoate-K were examined on adrenal cytochrome P450 (P450) and corticosteroid biosynthesis by studying difference spectra, P450 reduction and corticoid hydroxylation in mitochondrial preparations isolated from zona fasciculata and zona glomerulosa of bovine adrenals and from adrenal adenoma and hyperplastic adrenal cortex removed from patients with hyperaldosteronism. All 3 agents bound to P450 producing type I difference spectra and underwent hydroxylation. They all in inhibited 11.beta.-hydroxylation in bovine adrenal at 30 .mu.M and higher concentrations. Canrenone, the most potent inhibitor, blocked enzyme activity by 60% at a concentration of 60 .mu.M. Spironolactone stimulated P450 reduction. The order of potency of inhibition correlated with the order of affinity of these agents for P450. 11.beta.-Hydroxylase in human adrenal appeared to be less sensitive to canrenone. All 3 agents or their hydroxylated metabolites blocked 18-hydroxylation in bovine adrenal at lower concentrations. Canrenoate-K, being the most effective, inhibited 52% at 20 .mu.M. Low concentrations of canrenone (2.5-5.0 .mu.M) were without effect on 11.beta.-hydroxylase but markedly inhibited 18-hydroxylation (62-76%) in hyperplastic human adrenals. The inhibitors produced mixed type inhibition of 11.beta.-hydroxylation and competitive type inhibition of 18-hydroxylation. At low concentrations spironolactone and its major metabolites, canrenone and canrenoate-K, or their hydroxylated metabolites, can directly interfere with the biosynthesis of aldosterone in bovine and certain human adrenal cortical tissue.