YM116, 2-(lH-Imidazol-4-ylmethyl)-9H-carbazole, Decreases Adrenal Androgen Synthesis by Inhibiting C17-20 Lyase Activity in NCI-H295 Human Adrenocortical Carcinoma Cells

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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-imidazol4-ylmethyl)-9H-carbazole) (IC50: 3.6 and 2.1 nM) and ketoconazole (IC50: 54.9 and 54.2 nM). 17αHydroxyprogesterone, a product of 17α-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 17α-hydroxylase. Compatible with these findings, progesterone, a substrate of 17α-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.
社団法人日本薬理学会の論文
1999-02-01