A second enzyme protecting mineralocorticoid receptors from glucocorticoid occupancy |
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Authors: | Morris, David J. Latif, Syed A. Rokaw, Michael D. Watlington, Charles O. Johnson, John P. |
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Abstract: | We have confirmed that A6 cells (derived fromkidney of Xenopus laevis), whichcontain both mineralocorticoid and glucocorticoid receptors, do notnormally possess 11-hydroxysteroid dehydroxgenase (11-HSD1 or11-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 6-hydroxylase that transforms corticosterone to6-hydroxycorticosterone. This hydroxylase is cytochromeP-450 3A (CYP3A). We have nowdetermined the effects of 3,5-tetrahydroprogesterone andchenodeoxycholic acid (both inhibitors of 11-HSD1) and11-dehydrocorticosterone and11-hydroxy-3,5-tetrahydroprogesterone (inhibitors of11-HSD2) and carbenoxalone, which inhibits both 11-HSD1 and11-HSD2, on the actions and metabolism of corticosterone and activeNa+ transport [short-circuitcurrent(Isc)] inA6 cells. All of these 11-HSD inhibitory substances induced asignificant increment in corticosterone-inducedIsc, which wasdetectable within 2 h. However, none of these agents caused an increasein Isc whenincubated by themselves with A6 cells. In all cases, the additionalIsc was inhibitedby the mineralocorticoid receptor (MR) antagonist, RU-28318, whereasthe original Iscelicited by corticosterone alone was inhibited by the glucocorticoidreceptor antagonist, RU-38486. In separate experiments, each agent wasshown to significantly inhibit metabolism of corticosterone to6-hydroxycorticosterone in A6 cells, and a linear relationshipexisted between 6-hydroxylase inhibition and the MR-mediatedincrease in Iscin the one inhibitor tested. Troleandomycin, a selective inhibitor ofCYP3A, inhibited 6-hydroxylase and also significantly enhancedcorticosterone-induced Isc at 2 h. Theseexperiments indicate that the enhanced MR-mediated Isc in A6 cellsmay be related to inhibition of 6-hydroxylase activity in thesecells and that this 6-hydroxylase (CYP3A) may be protecting theexpression of corticosterone-induced active Na+ transport in A6 cells byMR-mediated mechanism(s). |
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