Dihydrocortisol: A potential mineralocorticoid

Abstract

The finding of abnormal metabolism of cortisol in a low-renin, low-aldosterone, hypertensive child with the stigmata of hypermineralocorticoidism led us to examine the mineralocorticoid activity of several cortisol metabolites. Of these metabolites, dihydrocortisol (DHF) possessed mineralocorticoid activity as determined by several assays. In competition assays with [ 3H]-aldosterone or [ 3H]-dexa-methasone in rat kidney slices, the relative affinities for the respective cytoplasmic receptors were as follows: mineralocorticoid receptor-aldosterone (1.00) > cortisol (0.20) > 5α-DHF (0.083) > 5β-DHF (0.042) and glucocorticoid receptor-dexamethasone (1.00) > cortisol (0.10) > 5α-DHF (0.002) > 5β-DHF (0.001). On the basis of these receptor assays 5α-DHF and possibly 5β-DHF were potential mineralocorticoids but probably weak glucocorticoids. The free serum concentration probably determines the biologically-effective steroid concentration. Accordingly, the affinity of these cortisol metabolites for corticosteroid binding globulin (CBG) was determined as well. In competition assays with [ 3H]-cortisol for binding to purified human CBG, the relative affinities were: cortisol (1.00) > 5 α- DHF (0.083) = 5 β- DHF (0.083). The enhanced free concentration of both cortisol metabolites should allow greater access to cellular receptors. Since binding to receptors does not indicate whether the bound steroid will have agonist, antagonist, or mixed agonist-antagonist properties, the metabolites were further tested in two physiological assays. In the isolated toad bladder, at a concentration 500 × that of aldosterone, cortisol, 5α-DHF and 5β-DHF stimulated active Na + transport measured as the short-circuit current in the following order: aldosterone (1.00) > cortisol (0.80) > 5α-DHF (0.65) > 5β-DHF (none). Infusion of cortisol, 5α- and 5β-DHF into adrenalectomized rats at concentrations 100 × that of aldosterone, produced the following relative changes in K/Na urinary ratios: aldosterone (1.00) > cortisol (0.60) > 5α-DHF (0.38) > 5β-DHF (0.28). Of the observed changes, only the 5β-DHF value was not statistically significant. These results imply that 5α-DHF should be considered a potential mineralocorticoid.