Effects of ketoconazole on cholesterol synthesis.
Effects of ketoconazole on cholesterol synthesis.
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发表时间：
1986-09
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通讯作者：
F. Kraemer;S. Spilman
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作者：
F. Kraemer;S. Spilman
研究表明，酮康唑和相关咪唑类药物通过抑制几种细胞色素P-450依赖性酶，阻断人类性腺和肾上腺类固醇生成。此外，最近的证据表明，人体胆固醇的产生也受到酮康唑的影响。本实验采用体外培养的正常人成纤维细胞，研究了酮康唑对胆固醇合成的影响。酮康唑通过阻断甲基甾醇向胆固醇的转化，迅速抑制胆固醇合成（1小时内抑制率大于90%）。二氢羊毛甾醇是主要的甲基甾醇，与酮康唑一起积累。在高浓度的酮康唑下，角鲨烯向甲基甾醇的转化也受到抑制。胆固醇合成的抑制呈剂量依赖性，IC 50约为2.8 × 10（-8）M。与胆固醇合成的抑制平行，甲基甾醇的产生也相应增加。相关的咪唑类抗真菌药克霉唑也有类似的作用，而咪唑类麻醉剂依托咪酯对胆固醇合成几乎没有影响。接触酮康唑的融合细胞的3-羟基-3-甲基戊二酰辅酶A还原酶活性下降90%，T1/2下降约3.7小时。总之，酮康唑对胆固醇合成有多种影响，通过阻断甲基甾醇向胆固醇的转化直接抑制后期步骤，并通过3-羟基甾醇中间体的反馈抑制间接抑制总甾醇合成，羟基-3-甲基戊二酰辅酶A还原酶活性。
Studies have demonstrated that ketoconazole and related imidazoles block gonadal and adrenal steroidogenesis in humans by inhibiting several cytochrome P-450-dependent enzymes. Moreover, recent evidence suggests that cholesterol production in humans is also affected by ketoconazole. In the present experiments cultured normal human fibroblasts have been used to explore the effects of ketoconazole on cholesterol synthesis. Ketoconazole inhibited cholesterol synthesis (greater than 90% suppression in 1 hr) rapidly by blocking the conversion of methyl sterols to cholesterol. Dihydrolanosterol was the major methyl sterol which accumulated with ketoconazole. At high concentrations of ketoconazole, the conversion of squalene to methyl sterols was also inhibited. The inhibition of cholesterol synthesis was dose-dependent with an IC50 approximately 2.8 X 10(-8) M. In parallel to the inhibition of cholesterol synthesis, there was a reciprocal increase in methyl sterol production. The related imidazole antimycotic, clotrimazole, had similar effects, whereas the imidazole anesthetic, etomidate, had little effect on cholesterol synthesis. Confluent cells exposed to ketoconazole had a 90% fall in the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase that declined with a T1/2 approximately 3.7 hr. In conclusion, ketoconazole has multiple effects on cholesterol synthesis, directly inhibiting late steps by blocking the conversion of methyl sterols to cholesterol and indirectly suppressing total sterol synthesis via feedback inhibition by sterol intermediates of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.