酮康唑及其他咪唑类药物对睾丸17α-羟化酶和17,20-裂解酶有抑制作用，但对3β-羟类固醇脱氢酶异构酶或17β-羟类固醇氧化还原酶无抑制作用。

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.

作者信息

Ayub M, Levell M J

机构信息

Department of Chemical Pathology, University of Leeds, England.

出版信息

J Steroid Biochem. 1987 Nov;28(5):521-31. doi: 10.1016/0022-4731(87)90511-5.

DOI:10.1016/0022-4731(87)90511-5

PMID:2824931

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.

摘要

酮康唑是一种口服有效的抗真菌药物，已知其在体外和体内均可抑制睾丸雄激素的产生。本研究的目的是检测酮康唑及其他13种咪唑类药物对大鼠睾丸微粒体17α-羟化酶、17,20-裂解酶、3β-羟类固醇脱氢酶异构酶（3β-HSD-I）和17β-羟类固醇氧化还原酶（17β-HSOR）的影响。对17α-羟化酶（底物为[3H]孕酮；Km = 89±0.65 nmol/L；标准误，n = 8）抑制作用由强到弱（根据Ki值确定）的顺序为：联苯苄唑（Ki = 86±3.3 nmol/L；标准误，n = 4）＞酮康唑（160±4.92）＞克霉唑（170±5.81）＞咪康唑（599±7.22）＞益康唑（688±6.98）＞噻康唑（901±1.71）＞异康唑（1090±6.96）；对17,20-裂解酶（底物为[3H]17α-羟孕酮；Km = 250±0.75 nmol/L；标准误，n = 8）抑制作用由强到弱的顺序为：联苯苄唑（56.5±3.4）＞克霉唑（81.5±3.1）＞酮康唑（84±3.5）＞咪康唑（243±6.3）＞益康唑（325±5.1）＞噻康唑（505±5.2）＞异康唑（610±6.34）。然而，这些咪唑类药物并不抑制3β-HSD-I或17β-HSOR的活性。具有抑制作用的咪唑类药物的一个共同结构特征是咪唑侧链上存在一个或多个芳香环。相比之下，咪唑环与苯环稠合的咪唑类药物，即苯并咪唑类（阿司咪唑、甲苯达唑、噻苯达唑）以及咪唑环N-1位带有脂肪族侧链的药物（卡比马唑、甲硝唑、尼莫唑、替硝唑）并不抑制17α-羟化酶、3β-HSD-I或17β-HSOR的酶活性。不过，有些药物确实能抑制17,20-裂解酶的活性，但仅在高浓度时才会出现。本研究结果表明，某些咪唑类药物在需要抑制雄激素产生的临床情况下可能有用，例如在治疗激素依赖性前列腺癌时。