Kinetic analysis of inhibition of human adrenal steroidogenesis by ketoconazole.
The kinetics of the inhibitory effects of the imidazole antimicrobial ketoconazole on the activities of the steroidogenic enzymes distal to cholesterol side-chain cleavage were studied in human adrenal microsomal and mitochondrial suspensions. Although ketoconazole was a competitive inhibitor of all five enzyme reactions, the effects on 17-hydroxylase, 17,20-desmolase, and 11-hydroxylase activities (Ki = 10(-8) M) were considerably greater than those on 21-hydroxylase and 3 beta-hydroxysteroid dehydrogenase/isomerase activities (Ki = 10(-4) M). These findings explain the clinical endocrine effects of ketoconazole in the usual therapeutic doses, which include inhibition of cortisol and androgen secretion, compensatory ACTH-mediated secretion of 17-desoxysteroids such as progesterone and aldosterone, and suppression of PRA.
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000311:Adrenal Glands / Q000201:enzymology / Q000378:metabolism*; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors; D000728:Androgens / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D006728:Hormones / Q000096:biosynthesis*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013255:Steroid 21-Hydroxylase / Q000037:antagonists & inhibitors
D000728:Androgens; D065607:Cytochrome P-450 Enzyme Inhibitors; D006728:Hormones; D015096:3-Hydroxysteroid Dehydrogenases; D013255:Steroid 21-Hydroxylase; D013254:Steroid 17-alpha-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D000446:Aldehyde-Lyases; D007654:Ketoconazole; D006854:Hydrocortisone