16β-Hydroxydehydroepiandrosterone: the Dichotomy Between Renal Receptor Binding and Urinary Electrolyte Activity1

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Abstract
Excessive production of 16β-hydroxydehydroepiandrosterone (16β-OH-DHEA) has been suggested as a cause of low-renin essential hypertension. The mineralocorticoid effect of 16β-OH-DHEA was reported to be one-fortieth that of aldostereone in the rat bioassay. Using kidney slices from adrenalectomized rats, the affinity of 16β-OH-DHEA and a series of related compounds for mineralocorticoid receptors has been determined. In studies done at both 4 C and 37 C, the affinity of 16β-OH-DHEA for mineralocorticoid receptors was found to be less than 0.1% that of aldosterone (P < 0.01). Various related steroids and/or potential metabolites similarly showed negligible affinity for the aldosterone receptor. In addition, 16β-OH-DHEA showed no significant affinity for renal dexamethasone-binding sites (Type II glucocorticoid receptors), corticosterone-binding sites (Type III glucocorticoid receptors), dihydrotestosterone binding sites, or estradiol binding sites. In in vivo competition experiments, the concurrent administration of 50 μg deoxycorticosterone reduced [3H]aldosterone binding to 20-30% of control levels; 50 μg 16β-OH-DHEA did not compete for [3H]aldosterone binding sites. In in vivo bioassay experiments, the effect of 16β-OH-DHEA on patterns of urinary electrolyte excretion was found—in contrast to that of aldosterone—to be variable. Within a given group, certain rats reproducibly responded to 16β-OH-DHEA by sodium retention and kaliuresis; in others no response was observed. In vitro binding studies comparing ‘responders’ with ‘non-responders’ demonstrated that in neither group did 16β-OH-DHEA have significant affinity for renal mineralocorticoid receptors. Accordingly, the mechanism whereby 16β-OH-DHEA produces changes in urinary electrolyte excretion appears independent of classical mineralocorticoid effector mechanisms. The conditions under which this effect is seen await eludication.

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