YM116, 2-(1H-Imidazol-4-ylmethyl)-9H-carbazole, Decreases Adrenal Androgen Synthesis by Inhibiting C17-20 Lyase Activity in NCI-H295 Human Adrenocortical Carcinoma Cells

The Japanese Journal of Pharmacology

Yoko Susaki¹  Hiroko Ishikawa¹  Takashi Fujikura¹  Takahito Nakahara¹  Kyoko Tanimoto¹  Masafumi Kudoh¹  Hideyuki Akaza²  Taiki Nanya¹  Yukitaka Ideyama¹  Hisataka Shikama¹ 

[1] Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.;Department of Urology, Institute of Clinical Medicine, University of Tsukuba

关键词: CYP17;    Adrenal androgen;    Ketoconazole;    Adrenocortical cell;    YM116;   

DOI  :  10.1254/jjp.79.213

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(37)Cited-By(9)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.

【 授权许可】

Unknown