title: The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis.
abstract: The family of cytochrome P450 enzymes that mediates steroid hydroxylations are distinct but structurally related proteins. Inhibitors of these steroidogenic steps generally exhibit only relative and dose-related specificity. We evaluated an imidazole, cytochrome P450-related inhibitor, CGS 16949A, in postmenopausal patients with metastatic breast cancer. While a relatively specific aromatase inhibitor at daily dosages of 1-2 mg, CGS 16949A significantly blunted cortisol responses to ACTH at a dose of 16 mg daily. To further evaluate other inhibitory effects of this drug, we determined blood levels of aldosterone (ALDO) and 18-hydroxycorticosterone and their respective urinary metabolites, tetrahydroaldosterone and tetrahydro-18-hydroxy-11-dehydrocorticosterone in 16 postmenopausal women receiving CGS 16949A. At a dose of 16 mg/day, CGS 16949A produced significant (P less than 0.001) suppression of both basal and ACTH-stimulated ALDO production. This was accompanied by a significant rise in the blood 18-hydroxycorticosterone/ALDO ratio (11.4 +/- 0.19; normal, less than 2; P less than 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 +/- 1.2; normal, less than 5; P less than 0.001) in the urinary tetrahydro-18-hydroxy-11-dehydrocorticosterone/tetrahydroaldosterone ratio was also observed. These results suggest that CGS 16949A is a potent inhibitor of the corticosterone methyloxidase type II enzyme at a dose of 16 mg daily. At doses of 1-2 mg daily, CGS 16949A blocks aromatase without altering basal aldosterone production and, thus, exhibits dose-related specificity.
authors.affiliation: Department of Medicine and Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
authors.forename: L M
authors.initials: LM
authors.lastname: Demers
authors.forename: J C
authors.initials: JC
authors.lastname: Melby
authors.forename: T E
authors.initials: TE
authors.lastname: Wilson
authors.forename: A
authors.initials: A
authors.lastname: Lipton
authors.forename: H A
authors.initials: HA
authors.lastname: Harvey
authors.forename: R J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D015069:18-Hydroxycorticosterone / Q000032:analysis; D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone; D000368:Aged; D000450:Aldosterone / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis*; D047072:Aromatase Inhibitors; D001665:Binding Sites / Q000187:drug effects; D001943:Breast Neoplasms / Q000032:analysis / Q000201:enzymology / Q000556:secondary; D055598:Chemical Phenomena; D002621:Chemistry; D019405:Cytochrome P-450 CYP11B2; D065607:Cytochrome P-450 Enzyme Inhibitors; D004573:Electrolytes / Q000097:blood / Q000652:urine; D017316:Fadrozole; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008901:Mineralocorticoids / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004573:Electrolytes; D007093:Imidazoles; D008901:Mineralocorticoids; D009570:Nitriles; C013282:tetrahydroaldosterone; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D000324:Adrenocorticotropic Hormone; D006899:Mixed Function Oxygenases; D019405:Cytochrome P-450 CYP11B2; C025352:corticosterone methyl oxidase II; D017316:Fadrozole; D006854:Hydrocortisone