title: The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro.
abstract: CGS-16949A is a new orally active nonsteroidal aromatase inhibitor which is more than 100-fold more potent than aminoglutethimide. This compound is an imidazole derivative, and therefore, its possible effect on cytochrome P-450-dependent enzyme activities in the adrenal gland was evaluated. In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10(-7)-10(-6) M is a potent 11 beta-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concentration of metyrapone (IC50 for both compounds, 10(-7)-5 X 10(-7) M). Etomidate was a more potent 11 beta-hydroxylase inhibitor (IC50, approximately 10(-8) M), while 10(-7)-10(-6) M ketoconazole caused (via 17 alpha-hydroxylase inhibition) a similar inhibition of cortisol release as 10(-7) M CGS-16949A (IC50, 10(-7)-5 X 10(-7) M). The 11 beta-hydroxylase inhibition by CGS-16949A was accompanied by a dose-dependent increase in the release of precursor steroids by the adrenocortical cells in vitro, including deoxycortisol, 17-hydroxyprogesterone, and androstenedione. Aldosterone release was suppressed 50% by 10(-9) M CGS-16949A, while the IC50 for cortisol in the same cells was 10(-7) M. Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also significantly suppressed by CGS-16949A. We concluded that 1) the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11 beta-hydroxylase which is equipotent to metyrapone. At present it is unclear whether the compound at the dose that causes complete aromatase inhibition in vivo also affects stress-induced cortisol release in man. 2) CGS-16949A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10(-9) M) and on tumorous aldosterone secretion. CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.
authors.affiliation: Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
authors.forename: S W
authors.initials: SW
authors.lastname: Lamberts
authors.forename: H A
authors.initials: HA
authors.lastname: Bruining
authors.forename: H
authors.initials: H
authors.lastname: Marzouk
authors.forename: J
authors.initials: J
authors.lastname: Zuiderwijk
authors.forename: P
authors.initials: P
authors.lastname: Uitterlinden
authors.forename: J J
authors.initials: JJ
authors.lastname: Blijd
authors.forename: W H
authors.initials: WH
authors.lastname: Hackeng
authors.forename: F H
authors.initials: FH
authors.lastname: De Jong
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D047072:Aromatase Inhibitors; D002478:Cells, Cultured; D017316:Fadrozole; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009570:Nitriles / Q000494:pharmacology*
chemical_list: D000305:Adrenal Cortex Hormones; D047072:Aromatase Inhibitors; D007093:Imidazoles; D009570:Nitriles; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D017316:Fadrozole; D006854:Hydrocortisone