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 activit y and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11,19-o xidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycor ticosterone and 10-fold lower than aldosterone. Such a discrepancy may be a ssigned 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 an d its ability to transform and translocate the MR into the nucleus are undi stinguishable from aldosterone. However, the capability of the serine/threo nine phosphatase inhibitor tautomycin to impair nuclear translocation of th e aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differen tially affected by modification of crucial lysyl residues of the MR. Kineti c studies performed on the aldosterone-MR complex in the presence of low co ncentrations 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 subop timal dose of aldosterone.