Binding of Steroids to Mineralocorticoid Receptors: Implications for in Vivo Occupancy by Glucocorticoids*

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Abstract
The binding of a number of steroids to mineralocorticoidreceptors in rat kidney was studied by measuring theirability to inhibit competitively the binding of [3H]aldosterone.The calculated activities relative to cortisol (taken as 1) andthe equilibrium dissociation constants (K4 values), respectively,were: aldosterone, 51 and 0.86 nM; 11-deoxycorticosterone(DOC), 40 and 1.07 nM; 9α-iluorocortisol, 40.5 and1.03 nM; progesterone, 5.4 and 8.1 nM; β-methasone (9α-fluoro-11β,17α,21-trihydroxy-16β-methyl-pregna-l,4-diene,3,20-dione),4.5 and 9.8 nM; corticosterone, 3.8 and 11.5 nM; prednisolone(llβ,17α,21-trmydroxypregna-l,4-diene-3,20-dione), 1.8 and24.8 nM; dexamethasone (9α-fluoro-llβ,17α,21-trihydroxy-16amethyl-pregna-l,4-diene-3,20-dione), 1.8 and 23.9 nM; and cortisol,1 and 43.8 nM. For comparison, the Kd values for the bindingof some of these steroids to the renal glucocorticoid receptors(obtained by measuring their ability to inhibit [3H]dexamethasonebinding) were: aldosterone, 92 nM; DOC, 77 nM; cortisol, 61nM; prednisolone, 27 nM; β-methasone, 11 nM; and dexamethasone,9.8 nM. The relative binding affinities of aldosterone, 9α-fluorocortisol,and DOC for the mineralocorticoid receptor are consistent.with the relative sodium-retaining activities of these steroids;the high affinity of progesterone is consistent with its knownmineralocorticoid antagonist activity. Surprising was the findingthat cortisol, β-methasone, and prednisolone have approximatelythe same affinity for the mineralocorticoid receptor as for the glucocorticoid receptor, and that dexamethasone has 30% of theaffinity for the mineralocorticoid receptor that it has for theglucocorticoid receptor. These findings suggest that glucocorticoidshave the capacity to occupy the rat mineralocorticoidreceptor to a greater extent than has previously been appreciated. Such mineralocorticoid receptor-binding activities of theseglucocorticoids exceed their sodium-retaining activities as usuallyreported. However, both types of observations could beexplained if these steroids are mineralocorticoid antagonists orpartial agonists, or if their physiological effects on salt balancethrough glucocorticoid receptors mask their actions throughmineralocorticoid receptors. To examine whether glucocorticoid potency could be influentialin the sodium-retaining activity of a steroid, the ratios ofthe mineralocorticoid to the glucocorticoid receptor-binding potencieswere calculated. Relative to cortisol (1) these were:aldosterone, 89; DOC, 88; 9α-fluorocortisol, 7.1; corticosterone,1.0; prednisolone, 0.76; β-methasone, 0.63; and dexamethasone,0.20. These values provide a better index of the reported relativeeffectiveness of the steroids for lowering urinary sodium than does the sole estimate of affinity for the mineralocorticoid receptor.The reasons for this are not known, but the data could beexplained if the glucocorticoid actions of these steroids in someway effectively oppose their mineralocorticoid actions, as reflectedby overall measurements of salt balance.

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