The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis

Laurence Demers, James C. Melby, Thomas E. Wilson, Allan Lipton, Harold Harvey, Richard J. Santen

Research output: Contribution to journalArticle

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Abstract

The family of cytochrome P450enzymes 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 < 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, <2; P < 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 ± 1.2; normal, <5; P < 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.

Original languageEnglish (US)
Pages (from-to)1162-1166
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume70
Issue number4
StatePublished - Apr 1990

Fingerprint

Fadrozole
Mineralocorticoids
Aromatase Inhibitors
Biosynthesis
Aldosterone
18-Hydroxycorticosterone
Corticosterone
Adrenocorticotropic Hormone
Blood
Hydroxylation
Aromatase
Cytochromes
Metabolites
Cytochrome P-450 Enzyme System
Hydrocortisone
Steroids
Breast Neoplasms
Enzymes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Demers, Laurence ; Melby, James C. ; Wilson, Thomas E. ; Lipton, Allan ; Harvey, Harold ; Santen, Richard J. / The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis. In: Journal of Clinical Endocrinology and Metabolism. 1990 ; Vol. 70, No. 4. pp. 1162-1166.
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abstract = "The family of cytochrome P450enzymes 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 < 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, <2; P < 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 ± 1.2; normal, <5; P < 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.",
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The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis. / Demers, Laurence; Melby, James C.; Wilson, Thomas E.; Lipton, Allan; Harvey, Harold; Santen, Richard J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 70, No. 4, 04.1990, p. 1162-1166.

Research output: Contribution to journalArticle

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T1 - The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis

AU - Demers, Laurence

AU - Melby, James C.

AU - Wilson, Thomas E.

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N2 - The family of cytochrome P450enzymes 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 < 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, <2; P < 0.001), consistent with a corticosterone methyloxidase type II inhibition. A similar significant elevation (7.5 ± 1.2; normal, <5; P < 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.

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