Progesterone Enhances Glucocorticoid Dissociation from the AtT-20 Cell Glucocorticoid Receptor*

Publisher Website
Google Scholar
Abstract
The dissociation rates of triamcinolone acetonide (9α-fluoro-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione-16,17-acetal with acetone), dexamethasone, and corticosterone from the AtT-20 cytosol receptor were measured after the addition of a 1000-fold excess of unlabeled homologous glucocorticoid. The simultaneous addition of unlabeled progesterone increased the rate of dissociation in a dose-dependent manner. The effect of progesterone was reversible. 17β-Estradiol, aldosterone, or additional amounts of glucocorticoids did not increase the dissociation rate. Steroids which were found to increase the dissociation rate were: R-5020 (dimethyl-19-norpregna- 4,9-diene-3,20-dione,17α,21-[17α-methyl]) > progesterone > desoxycorticosterone > medroxyprogesterone (17α-hydroxy-6α-methyl-Δ4-pregnen-3,20-dione) > cortexolone > testosterone > methyltestosterone (4-androsten-17α-methyl-17β-01-3- trione). Experiments were also performed using intact AtT-20 cells. Cells which had been incubated to equilibrium with tritiated glucocorticoids were further incubated with a large excess of either nonradioactive progesterone or glucocorticoid, and the rate at which the tritiated steroid dissociated from the cellular binding sites was determined. The studies showed that progesterone significantly enhanced the rate at which tritiated corticosterone or dexamethasone dissociated from intact cell glucocorticoid binding is qualitatively similar to that observed in cytosol preparations. Since this effect on binding was produced in vitro and in vivo by progestins and several other glucocorticoid antagonists, but not by glucocorticoids, it suggests the existence of a progestin-specific site capable of allosteric effects on the glucocorticoid-binding site. Effective interaction with this site may lead to reduced glucocorticoid-receptor affinity by changes in the dissociation rate. It is possible that this effect represents a mechanism by which antiglucocorticoid action is mediated.