Inhibition of testicular 17α-hydroxylase and 17,20-lyase but not 3β-hydroxysteroid dehydrogenase-isomerase or 17β-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 17α-hydroxylase, 17,20-lyase, 3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD-I) and 17β-hydroxysteroid oxidoreductase (17β-HSOR). The order of decreasing inhibitory effect (determined from K i values) on 17α-hydroxylase (substrate [ 3H]progesterone; K m = 89 ± 0.65 nmol/1; SEM, n = 8) was bifonazole ( K i = 86 ± 3.3 nmol/1; SEM, n = 4) > ketoconazole (160 ± 4.92) > clotrimazole (170 +- 5.81) > miconazole (599 ± 7.22) > econazole (688 ± 6.98) > tioconazole (901 ± 1.71) > isoconazole (1090 ± 6.96) and on 17,20-lyase (substrate, [ 3H]17α-hydroxyprogesterone; K m = 250 ± 0.75 nmol/1; SEM, n = 8) was bifonazole (56.5 ± 3.4) > clotrimazole (81.5 ± 3.1) > ketoconazole (84 ± 3.5) > miconazole (243 ± 6.3) > econazole (325 ± 5.1) > tioconazole (505 ± 5.2) > isoconazole (610 ± 6.34). However, these imidazole drugs did not inhibit the 3β-HSD-I or 17β-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 17α-hydroxylase, 3β-HSD-I or 17β-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.