Yukitaka Ideyama (1), Masafumi Kudoh (1), Kyoko Tanimoto (1), Yoko Susaki
(1), Taiki Nanya (1), Takahito Nakahara (1), Hiroko Ishikawa (1), Takashi
Fujikura (1), Hideyuki Akaza (2) and Hisataka Shikama (1,*)
(1) Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
(2) Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
(*) To whom correspondence should be addressed.
Abstract: 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.
Keywords: CYP17, Adrenal androgen, Ketoconazole, Adrenocortical cell, YM116