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.
Jpn J Pharmacol
; 79(2): 213-20, 1999 Feb.
Article
in En
| MEDLINE
| ID: mdl-10202857
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbazoles
/
Steroid 17-alpha-Hydroxylase
/
Adrenocortical Carcinoma
/
Enzyme Inhibitors
/
Imidazoles
/
Androgens
/
Ketoconazole
Limits:
Humans
/
Male
Language:
En
Journal:
Jpn J Pharmacol
Year:
1999
Document type:
Article
Affiliation country:
Japan
Publication country:
JAPAN
/
JAPON
/
JAPÃO
/
JP