title: Inhibition of testicular 17 alpha-hydroxylase and 17,20-lyase but not 3 beta-hydroxysteroid dehydrogenase-isomerase or 17 beta-hydroxysteroid oxidoreductase by ketoconazole and other imidazole drugs.
abstract: Ketoconazole, an orally active antifungal drug, is known to inhibit testicular androgen production both in vitro and in vivo. The aim of the present study was to examine the effect of ketoconazole and 13 other imidazole drugs on rat testicular microsomal 17 alpha-hydroxylase, 17,20-lyase, 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). The order of decreasing inhibitory effect (determined from Ki values) on 17 alpha-hydroxylase (substrate [3H]progesterone; Km = 89 +/- 0.65 nmol/l; SEM, n = 8) was bifonazole (Ki = 86 +/- 3.3 nmol/l; SEM, n = 4) greater than ketoconazole (160 +/- 4.92) greater than clotrimazole (170 +/- 5.81) greater than miconazole (599 +/- 7.22) greater than econazole (688 +/- 6.98) greater than tioconazole (901 +/- 1.71) greater than isoconazole (1090 +/- 6.96) and on 17,20-lyase (substrate, [3H]17 alpha-hydroxyprogesterone; Km = 250 +/- 0.75 nmol/l; SEM, n = 8) was bifonazole (56.5 +/- 3.4) greater than clotrimazole (81.5 +/- 3.1) greater than ketoconazole (84 +/- 3.5) greater than miconazole (243 +/- 6.3) greater than econazole (325 +/- 5.1) greater than tioconazole (505 +/- 5.2) greater than isoconazole (610 +/- 6.34). However, these imidazole drugs did not inhibit the 3 beta-HSD-I or 17 beta-HSOR activities. A common structural feature of the imidazole drugs having an inhibitory effect was the presence of one or more aromatic rings on the imidazole side chain. In contrast, the imidazole drugs having the imidazole ring fused to a benezene ring, i.e. benzimidazoles (astemizole, mebendazole, thiabendazole) and those having an aliphatic side chain on the N-1 of the imidazole ring (carbimazole, metronidazole, nimorazole, tinidazole) did not inhibit 17 alpha-hydroxylase, 3 beta-HSD-I or 17 beta-HSOR enzyme activities. However some did inhibit 17,20-lyase activity but only at high concentrations. The results of the present study suggest that some imidazole drugs may be useful in clinical situations requiring the suppression of androgen production, for example in the treatment of hormone-dependent prostatic cancer.
authors.affiliation: Department of Chemical Pathology, University of Leeds, England.
authors.forename: M
authors.initials: M
authors.lastname: Ayub
authors.forename: M J
authors.initials: MJ
authors.lastname: Levell
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles / Q000494:pharmacology*; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011375:Progesterone Reductase / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology*
chemical_list: C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D000890:Anti-Infective Agents; D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009097:Multienzyme Complexes; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase; C045840:testosterone 17 beta-dehydrogenase (NADP+); D013250:Steroid Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D007535:Isomerases; D013251:Steroid Isomerases; D007654:Ketoconazole