BACKGROUND. The purpose of this study was to determine the effects of a nonsteroidal C17-20 lyase inhibitor, 2-(1H-imidazol-4-ylmethyl)-9H-carbazole (YM116), on serum concentrations of androgens and ventral prostatic weight in rats. METHODS. Serum concentrations of testosterone and of dehydroepiandrosterone sulfate and prostatic weights were measured in rats treated with YM116. RESULTS. YM116 inhibited testicular C17-20 lyase competitively (Ki, 0.38 nM), and decreased the serum testosterone concentration in gonadotropin-releasing hormone-treated rats (ED 50 , 0.7 mg/kg), indicating that YM116 was about 21-24 times more potent than other C17-20 lyase inhibitors such as ketoconazole and liarozole, and was twice as potent as CB7630. YM116 also reduced dehydroepiandrosterone sulfate levels in ACTH-treated castrated rats (ED 50 , 11 mg/kg). YM116 (40 mg/kg, p.o., for 2 weeks) was almost comparable to bilateral orchiectomy with respect to the time course and magnitude of the reduction in prostatic weight. Each of these two treatments decreased the prostatic weight 3 days following the treatment. Contrarily, leuprolide transiently increased the prostatic weight and then decreased it. YM116 (100 mg/kg) had no effect on the serum cortisol level in guinea pigs, and slightly decreased the serum aldosterone level in rats. CONCLUSIONS. YM116 is a selective C17-20 lyase inhibitor which decreases rat prostatic weight by reducing androgen production in the testes and adrenal glands.

Pages 5732 and 5733: Errors occurred in Tables II and IV. The corrected tables are shown below. TABLE IIKinetic parameters for ␤-lactams of the GC1 and P99 ␤-lactamases k cat and K m values were determined by the UV spectrophotometric method, and K i values were measured by the UV spectrophotometric method with cephalothin as the substrate.

The concentrations of androstenedione and dehydroepiandrosterone, products of C17-20 lyase, in the medium after a 6-hr incubation of NCI-H295 cells were decreased by YM116 (2-(1H-imidazol-4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17Alpha-hydroxyprogesterone, a product of 17alpha-hydroxylase, was increased by YM116 (1-30 nM) and by ketoconazole (10-300 nM) and then was decreased at higher concentrations of both agents (IC50: 180 nM for YM116, 906 nM for ketoconazole), indicating that YM116 and ketoconazole were 50- and 16.5-fold more specific inhibitors of C17-20 lyase, respectively, than 17alpha-hydroxylase. Compatible with these findings, progesterone, a substrate of 17alpha-hydroxylase, was increased by these agents. Cortisol production was inhibited by YM116 and ketoconazole (IC50: 50.4 and 80.9 nM, respectively). YM116 was a 14-fold more potent inhibitor of androstenedione production than cortisol production, whereas ketoconazole was a nonselective inhibitor of the production of both steroids. YM116 and ketoconazole inhibited the C17-20 lyase activity in human testicular microsomes (IC50: 4.2 and 17 nM, respectively). These results demonstrate that YM116 reduces the synthesis of adrenal androgens by preferentially inhibiting C17-20 lyase activity.

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