Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone
We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11,1 9-...
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2000
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paper:paper_0026895X_v58_n1_p58_Galigniana2023-06-08T14:53:56Z Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone Vicent, Guillermo Pablo Burton, Gerardo aldosterone progesterone derivative tautomycin animal experiment article controlled study drug activity drug mechanism drug potency drug receptor binding hormone action intracellular transport male nonhuman priority journal protein transport rat sodium retention We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11,1 9-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19- oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19- oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone. Fil:Vicent, G.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2000 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v58_n1_p58_Galigniana http://hdl.handle.net/20.500.12110/paper_0026895X_v58_n1_p58_Galigniana |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
aldosterone progesterone derivative tautomycin animal experiment article controlled study drug activity drug mechanism drug potency drug receptor binding hormone action intracellular transport male nonhuman priority journal protein transport rat sodium retention |
| spellingShingle |
aldosterone progesterone derivative tautomycin animal experiment article controlled study drug activity drug mechanism drug potency drug receptor binding hormone action intracellular transport male nonhuman priority journal protein transport rat sodium retention Vicent, Guillermo Pablo Burton, Gerardo Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| topic_facet |
aldosterone progesterone derivative tautomycin animal experiment article controlled study drug activity drug mechanism drug potency drug receptor binding hormone action intracellular transport male nonhuman priority journal protein transport rat sodium retention |
| description |
We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11,1 9-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19- oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19- oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone. |
| author |
Vicent, Guillermo Pablo Burton, Gerardo |
| author_facet |
Vicent, Guillermo Pablo Burton, Gerardo |
| author_sort |
Vicent, Guillermo Pablo |
| title |
Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| title_short |
Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| title_full |
Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| title_fullStr |
Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| title_full_unstemmed |
Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| title_sort |
mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone |
| publishDate |
2000 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v58_n1_p58_Galigniana http://hdl.handle.net/20.500.12110/paper_0026895X_v58_n1_p58_Galigniana |
| work_keys_str_mv |
AT vicentguillermopablo mechanismofactionofthepotentsodiumretainingsteroid1119oxidoprogesterone AT burtongerardo mechanismofactionofthepotentsodiumretainingsteroid1119oxidoprogesterone |
| _version_ |
1768543644569042944 |