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 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.
Ideyama
Y
Y
Metabolic Diseases Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
Kudoh
M
M
Tanimoto
K
K
Susaki
Y
Y
Nanya
T
T
Nakahara
T
T
Ishikawa
H
H
Fujikura
T
T
Akaza
H
H
Shikama
H
H
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000096:biosynthesis; D002227:Carbazoles / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013737:Testis / Q000201:enzymology; D014407:Tumor Cells, Cultured
D000305:Adrenal Cortex Hormones; D000728:Androgens; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; C114168:YM 116; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole