STUDIES ON THE MECHANISM OF ANTIGLUCOCORTICOID ACTION OF 7-ALPHA-HYDROXYDEHYDROEPIANDROSTERONE

The literature reports that 7 alpha-hydroxydehydroepiandrosterone (7 a lpha-OH-DHEA), a metabolite of dehydroepiandrosterone (DHEA), displays numerous anti-aging properties (such as immunostimulation and anti-ap optotic effects) which may result from an apparent antiglucocorticoid activity. However, the molecular mechanism(s) of this effect remain to be elucidated. In the present work, we attempted to unravel some aspe cts of this mechanism in vitro, in adrenalectomized rats. No specific binding of [H-3]-7 alpha-OH-DHEA occurred with the hepatic cytosolic f raction, and the binding of [H-3]-dexamethasone ([H-3]-DEX) to the cyt osolic glucocorticoid receptor complex (GCRC) was unaffected by increa sing concentrations of either DHEA or 7 alpha-OH-DHEA. In marked contr ast, in isolated hepatic nuclei, the retention of partially purified [ H-3]-DEX-labelled cytosolic GCRC was significantly decreased after nuc lei preincubation with 7 alpha-OH-DHEA, DHEA or 7 alpha-hydroxypregnen olone. How ever, further experiments using isolated cytosolic fraction preactivated with [H-3]-DEX and then filtered on DNA-cellulose column s in the presence or in the absence of 7 alpha-hydroxy steroids unequi vocally demonstrated that 7 alpha-OH-DHEA neither competed with the ac tivation of the GCRC, nor inhibited the binding of this complex to DNA -cellulose in the cell-free system. The effect of 7 alpha-OH-DHEA on m embrane fluidity of brain cell membranes was observed only at concentr ations higher that that of the parent substance DHEA. Thus, the effect of 7 alpha-OH-DHEA does not seem to be mediated by the influence of t he accessibility of the hormone to intracellular receptors. While the GCRC binding to DNA is apparently unaffected by 7 alpha-OH-DHEA, and c annot therefore explain the lesser retention of DEX-activated GCRC in isolated nuclei, other mechanisms, possibly extranuclear, such as modi fication of the conformation of GCRC may be involved. The GCRC in the presence of 7 alpha-OH-DHEA, may account for the antiglucocorticoid pr operties of this steroid which are currently under investigation.