title: Kinetic analysis of inhibition of human adrenal steroidogenesis by ketoconazole.
abstract: 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.
mesh_terms: 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
chemical_list: 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