Differences in the interaction of RU 486 and ketoconazole with the second binding site of the glucocorticoid receptor.
Ketoconazole and RU 486 are both antagonists of glucocorticoid hormone action at the target cell level. Both inhibit the binding of agonists to the receptor, although RU 486 is many-fold more potent. As reported here, ketoconazole, like all naturally occurring steroidal antiglucocorticoids, enhances the rate at which agonists dissociate from the glucocorticoid receptor. This indicates that this antiglucocorticoid interacts with the receptor at a site other than the agonist-binding site. RU 486, on the other hand, does not accelerate dissociation, suggesting that it does not interact with the putative allosteric regulatory site on the glucocorticoid receptor. Combining these findings with previous reports leads to the hypothesis that glucocorticoid antagonists can be divided into two classes: those that act through a second regulatory site on the glucocorticoid receptor and those that act by direct competition with agonists at the agonist-binding site.
Department of Medicine, Louisiana State University Medical Center, New Orleans 70112.
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D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D015735:Mifepristone; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D012016:Reference Values
D004963:Estrenes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D007654:Ketoconazole