Mechanism of Action of the Potent Sodium-Retaining Steroid 11,19-Oxidoprogesterone
- Mario D. Galigniana1,
- Guillermo P. Vicent1,
- Graciela Piwien-Pilipuk1,
- Gerardo Burton2 and
- Carlos P. Lantos1
- 1Departamento de Quı́mica Biológica (M.D.G., G.P.V., G.P.-P, C.P.L.) and 2Departamento de Quı́mica Orgánica (G.B.), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, and Programa de Regulación Hormonal y Metabólica-Consejo Nacional de Investigaciones Cientı́ficas y Técnicas, Ciudad Universitaria, Pabellón II, Buenos Aires, Argentina
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 11,19-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.
Footnotes
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Send reprint requests to: Mario D. Galigniana, 1301 Medical Science Research Bldg. III, Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail:mgali{at}umich.edu
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Supported by the Universidad de Buenos Aires and Consejo Nacional de Investigaciones Cientı́ficas y Técnicas de la República Argentina.
- Abbreviations:
- 11-OP
- 11,19-oxidoprogesterone
- MR
- mineralocorticoid receptor
- GR
- glucocorticoid receptor
- hsp90
- 90-kDa heat shock protein
- RBA
- relative binding affinity
- ADX
- adrenalectomized
- CBG
- corticosterone-binding protein
- ALDO
- aldosterone
- CORT
- corticosterone
- PROG
- progesterone
- DOC
- 21-deoxycorticosterone
- SPO
- SC9420-spironolactone
- 6-OP
- 6,19-oxidoprogesterone
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- Received November 30, 1999.
- Accepted March 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
