Sikka S C, Swerdloff R S, Rajfer J
Endocrinology. 1985 May;116(5):1920-5. doi: 10.1210/endo-116-5-1920.
Oral ketoconazole has been demonstrated to lower plasma testosterone in man. Measurement of blood precursors of testosterone suggest that ketoconazole may have its effect inhibiting the 17,20-desmolase enzyme within the testis. To substantiate this, a series of in vitro experiments was conducted using the rat testis to determine where in the testosterone biosynthetic pathway ketoconazole has its effect. To accomplish this, an assay system to measure 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase activities involved in the delta 4-testosterone biosynthetic pathway was developed. It was demonstrated from dose-response and time-course experiments that a dose of approximately 10 micrograms/ml ketoconazole was sufficient to inhibit in vitro testicular steroidogenesis. Using dosages between 10 and 300 micrograms/ml ketoconazole, a marked inhibition of both the 17 alpha-hydroxylase and the 17,20-desmolase activities occurred. Ketoconazole under these conditions had no effect on 17 beta-hydroxysteroid dehydrogenase activity. Ketoconazole also inhibited the increased activity of these enzymes induced by hCG (1 IU). These data confirm the observation that in vitro ketoconazole has a direct inhibitory effect on 17,20-desmolase activity. These results further suggest that ketoconazole has more than one site of action in inhibiting testosterone biosynthesis in the testis and may indeed be a suitable agent for the treatment of patients with disseminated prostate cancer.
口服酮康唑已被证明可降低男性血浆睾酮水平。对睾酮血液前体物质的测量表明，酮康唑可能通过抑制睾丸内的17,20-裂解酶发挥作用。为证实这一点，使用大鼠睾丸进行了一系列体外实验，以确定酮康唑在睾酮生物合成途径中的作用位点。为此，开发了一种测定系统，用于测量参与Δ4-睾酮生物合成途径的17α-羟化酶、17,20-裂解酶和17β-羟类固醇脱氢酶的活性。剂量反应和时间进程实验表明，约10微克/毫升的酮康唑剂量足以抑制体外睾丸类固醇生成。使用10至300微克/毫升的酮康唑剂量，17α-羟化酶和17,20-裂解酶的活性均受到显著抑制。在这些条件下，酮康唑对17β-羟类固醇脱氢酶活性没有影响。酮康唑还抑制了由人绒毛膜促性腺激素（1国际单位）诱导的这些酶活性的增加。这些数据证实了体外酮康唑对17,20-裂解酶活性有直接抑制作用的观察结果。这些结果进一步表明，酮康唑在抑制睾丸睾酮生物合成方面有多个作用位点，可能确实是治疗播散性前列腺癌患者的合适药物。
