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Abstract:

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.

Registro:

Documento: Artículo
Título:Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone
Autor:Galigniana, M.D.; Vicent, G.P.; Piwien-Pilipuk, G.; Burton, G.; Lantos, C.P.
Filiación:Depto. de Quim. Biológica, Metabolica-Consejo Nac. Invest. C., Pabellón II, Buenos Aires, Argentina
Depto. de Quim. Orgánica, Fac. de Ciencias Exactas y Naturales, Pabellón II, Buenos Aires, Argentina
1301 Med. Science Research Bldg. III, Department of Pharmacology, Univ. of Michigan Medical School, Ann Arbor, MI 48109-0632, United States
Palabras clave: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
Año:2000
Volumen:58
Número:1
Página de inicio:58
Página de fin:70
DOI: http://dx.doi.org/10.1124/mol.58.1.58
Título revista:Molecular Pharmacology
Título revista abreviado:Mol. Pharmacol.
ISSN:0026895X
CODEN:MOPMA
CAS:aldosterone, 52-39-1, 6251-69-0; tautomycin, 109946-35-2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0026895X_v58_n1_p58_Galigniana

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Citas:

---------- APA ----------
Galigniana, M.D., Vicent, G.P., Piwien-Pilipuk, G., Burton, G. & Lantos, C.P. (2000) . Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone. Molecular Pharmacology, 58(1), 58-70.
http://dx.doi.org/10.1124/mol.58.1.58
---------- CHICAGO ----------
Galigniana, M.D., Vicent, G.P., Piwien-Pilipuk, G., Burton, G., Lantos, C.P. "Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone" . Molecular Pharmacology 58, no. 1 (2000) : 58-70.
http://dx.doi.org/10.1124/mol.58.1.58
---------- MLA ----------
Galigniana, M.D., Vicent, G.P., Piwien-Pilipuk, G., Burton, G., Lantos, C.P. "Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone" . Molecular Pharmacology, vol. 58, no. 1, 2000, pp. 58-70.
http://dx.doi.org/10.1124/mol.58.1.58
---------- VANCOUVER ----------
Galigniana, M.D., Vicent, G.P., Piwien-Pilipuk, G., Burton, G., Lantos, C.P. Mechanism of action of the potent sodium-retaining steroid 11,19- oxidoprogesterone. Mol. Pharmacol. 2000;58(1):58-70.
http://dx.doi.org/10.1124/mol.58.1.58