In VitroInhibition of Testosterone Biosynthesis by Ketoconazole

Abstract
Oral ketoconazole was 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 effects. 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 .apprx. 10 .mu.g/ml ketoconazole was sufficient to inhibit in vitro testicular steroidogenesis. Using dosages between 10 and 300 .mu.g/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 [human chorionic gonadotropin] (1 IU). Apparently, in vitro ketoconazole has a direct inhibitory effect on 17,20-desmolase activity. Evidently, ketoconazole has more than one site of action and inhibiting testosterone biosynthesis in the testis and may indeed be a suitable agent for the treatment of patients with disseminated prostate cancer.