11,19-oxidoprogesterone: A potent sodium retaining steroid binding to an alternative site in rat kidney type I receptor

GALIGNIANA MD, VICENT GP, LANTOS CP, BURTON G

EUROPEAN JOURNAL OF ENDOCRINOLOGY

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 1994 vol. 130 p. 260 - 262

0804-4643

We have demonstrated previously that a planar conformation ofthe molecular frame is required for steroids to acquire optimalsodium-retaining activity and binding properties to the mineralocorticoidreceptor (MR). One of the most active sodiumretainingcompounds tested in those studies was 11,19-oxidoprogesterone.Despite its biological potency, the relative affinityof 11,19-oxidoprogesterone for the MR is 5-fold lower than thatof 21-deoxycorticosterone and 10-fold lower than aldosterone.Such a discrepancy may be assigned to uncommon biopharmacologicalproperties of this synthetic steroid or an unusualmolecular mechanism of action. In this work, we studied thebiopharmacological and mechanistic features of 11,19-oxidoprogesterone.We show that both the pharmacokinetic propertiesof 11,19-oxidoprogesterone and its ability to transform andtranslocate the MR into the nucleus are undistinguishable fromaldosterone. However, the capability of the serine/threoninephosphatase inhibitor tautomycin to impair nuclear translocationof the aldosterone-MR complex is not observed for the11,19-oxidoprogesterone-MR complex. In addition, the bindingproperties of both steroids are differentially affected by modificationof crucial lysyl residues of the MR. Kinetic studiesperformed on the aldosterone-MR complex in the presence oflow concentrations of oxidopregnane suggest that 11,19-oxidoprogesteronemay bind to the MR in a different binding sitefrom the aldosterone binding pocket. Consistent with this postulate,a biologically inactive dose of 0.6 ng of oxidopregnane isable to potentiate the mineralocorticoid effect of a suboptimaldose of aldosterone.In contrast to glucocorticoids, which exhibit a slightly torsionedsteroid nucleus at the A/B-ring junction, mineralocorticoidsseem to require a flat conformation for optimal activity(Duax et al., 1978; Lantos et al., 1981; Yamakawa et al.,1986; Burton et al., 1995). Consistent with this structuralrequirement, we have reported previously (Burton et al.,1995) that the highly planar synthetic steroid 11,19-oxidoprogesterone(11-OP; see structure in Fig. 1) exhibits potentsodium-retaining activity. In this sense, 11-OP is equivalentto the biological activity measured with 21-deoxycorticosterone(DOC) and, at some doses, even approaches the effects ofaldosterone (