A second enzyme protecting mineralocorticoid receptors from glucocorticoid occupancy

Autor: Charles O. Watlington, John P. Johnson, Michael D. Rokaw, David J. Morris, Syed A. Latif
Rok vydání: 1998
Předmět:
medicine.medical_specialty
Physiology
medicine.drug_class
medicine.medical_treatment
Xenopus
Spironolactone
Biology
Kidney
Cell Line
Xenopus laevis
Receptors
Glucocorticoid
Mineralocorticoid receptor
Glucocorticoid receptor
Cytochrome P-450 Enzyme System
Internal medicine
medicine
Animals
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Receptor
Glucocorticoids
Mineralocorticoid Receptor Antagonists
Electric Conductivity
Hydroxysteroid Dehydrogenases
Oxidoreductases
N-Demethylating
Cell Biology
biology.organism_classification
Isoenzymes
Steroid hormone
Receptors
Mineralocorticoid
Endocrinology
Mechanism of action
Mineralocorticoid
Steroid Hydroxylases
11-beta-Hydroxysteroid Dehydrogenases
Aryl Hydrocarbon Hydroxylases
Macrolides
medicine.symptom
Corticosterone
Glucocorticoid
medicine.drug
Zdroj: American Journal of Physiology-Cell Physiology. 274:C1245-C1252
ISSN: 1522-1563
0363-6143
DOI: 10.1152/ajpcell.1998.274.5.c1245
Popis: We have confirmed that A6 cells (derived from kidney of Xenopus laevis), which contain both mineralocorticoid and glucocorticoid receptors, do not normally possess 11β-hydroxysteroid dehydroxgenase (11β-HSD1 or 11β-HSD2) enzymatic activity and so are without apparent “protective” enzymes. A6 cells do not convert the glucocorticoid corticosterone to 11-dehydrocorticosterone but do, however, possess steroid 6β-hydroxylase that transforms corticosterone to 6β-hydroxycorticosterone. This hydroxylase is cytochrome P-450 3A (CYP3A). We have now determined the effects of 3α,5β-tetrahydroprogesterone and chenodeoxycholic acid (both inhibitors of 11β-HSD1) and 11-dehydrocorticosterone and 11β-hydroxy-3α,5β-tetrahydroprogesterone (inhibitors of 11β-HSD2) and carbenoxalone, which inhibits both 11β-HSD1 and 11β-HSD2, on the actions and metabolism of corticosterone and active Na+transport [short-circuit current ( Isc)] in A6 cells. All of these 11β-HSD inhibitory substances induced a significant increment in corticosterone-induced Isc, which was detectable within 2 h. However, none of these agents caused an increase in Iscwhen incubated by themselves with A6 cells. In all cases, the additional Iscwas inhibited by the mineralocorticoid receptor (MR) antagonist, RU-28318, whereas the original Iscelicited by corticosterone alone was inhibited by the glucocorticoid receptor antagonist, RU-38486. In separate experiments, each agent was shown to significantly inhibit metabolism of corticosterone to 6β-hydroxycorticosterone in A6 cells, and a linear relationship existed between 6β-hydroxylase inhibition and the MR-mediated increase in Iscin the one inhibitor tested. Troleandomycin, a selective inhibitor of CYP3A, inhibited 6β-hydroxylase and also significantly enhanced corticosterone-induced Iscat 2 h. These experiments indicate that the enhanced MR-mediated Iscin A6 cells may be related to inhibition of 6β-hydroxylase activity in these cells and that this 6β-hydroxylase (CYP3A) may be protecting the expression of corticosterone-induced active Na+transport in A6 cells by MR-mediated mechanism(s).
Databáze: OpenAIRE
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