Eckhoff C, Oelkers W, Bähr V
Freie Universität Berlin, Institut für Toxikologie und Embryonalpharmakologie, F.R.G.
J Steroid Biochem. 1988 Nov;31(5):819-23. doi: 10.1016/0022-4731(88)90291-9.
Rat adrenal cells were incubated with various concentrations of two orally active azole antimycotics in order to evaluate the effects on steroidogenesis. The first compound was ketoconazole, a well-known inhibitor not only of fungal cytochrome P-450 but at higher concentrations also of mammalian cytochrome P-450 dependent enzymes. The second was fluconazole, a newly developed oral antimycotic with a triazole structure, which likewise inhibits fungal cytochrome P-450. The influence of both drugs on mammalian cytochrome P-450 dependent enzymes was investigated in this study. Ketoconazole inhibited ACTH-stimulated corticosterone (IC50 = 0.9 microM) and aldosterone secretion (IC50 = 1.4 microM) and enhanced 11-deoxycorticosterone output at low concentrations but reduced it at higher concentrations. Radiotracer experiments with [3H]pregnenolone or [3H]11-deoxycorticosterone as exogenous substrates revealed a 50% inhibition of the oxidative substrate metabolism at about 1 microM ketoconazole. These effects could also be observed with fluconazole but occurred at concentrations approximately two orders of magnitude higher as compared to ketoconazole. We conclude that fluconazole has a much higher selectivity for fungal cytochrome P-450 than ketoconazole. The order of sensitivity of the cytochrome P-450 dependent enzymes of rat adrenal steroidogenesis to ketoconazole was the 11 beta/18-hydroxylase, the cholesterol side chain cleavage enzyme and the 21-hydroxylase with decreasing sensitivities.
为了评估两种口服活性唑类抗真菌药对类固醇生成的影响，将大鼠肾上腺细胞与不同浓度的这两种药物进行孵育。第一种化合物是酮康唑，它不仅是一种众所周知的真菌细胞色素P - 450抑制剂，而且在较高浓度时也是哺乳动物细胞色素P - 450依赖性酶的抑制剂。第二种是氟康唑，一种新开发的具有三唑结构的口服抗真菌药，它同样抑制真菌细胞色素P - 450。本研究考察了这两种药物对哺乳动物细胞色素P - 450依赖性酶的影响。酮康唑抑制促肾上腺皮质激素刺激的皮质酮分泌（IC50 = 0.9微摩尔）和醛固酮分泌（IC50 = 1.4微摩尔），在低浓度时增强11 - 脱氧皮质酮的产量，但在高浓度时降低其产量。以[3H]孕烯醇酮或[3H]11 - 脱氧皮质酮作为外源性底物的放射性示踪实验表明，在约1微摩尔酮康唑时，氧化底物代谢受到50%的抑制。氟康唑也能观察到这些效应，但与酮康唑相比，其发生浓度大约高两个数量级。我们得出结论，氟康唑对真菌细胞色素P - 450的选择性比酮康唑高得多。大鼠肾上腺类固醇生成的细胞色素P - 450依赖性酶对酮康唑的敏感性顺序为11β/18 - 羟化酶、胆固醇侧链裂解酶和21 - 羟化酶，敏感性依次降低。
