RU 38486: a potent antiglucocorticoid in vitro and in vivo.
The antiglucocorticoid activity of RU 38486, was studied both in vitro and in vivo. In vitro studies, RU 38486 was characterized by a high affinity (3 times higher than that of dexamethasone) for the cytosolic glucocorticoid receptor in rat hepatoma tissue culture (HTC) cells. This high affinity was due to a very low dissociation rate of the complexes formed with the receptor. In whole cells it was a potent full antagonist of dexamethasone-induced tyrosine aminotransferase (TAT) activity: the IC50 was 6-7 times lower than the concentration of the dexamethasone used. It was devoid of any glucocorticoid activity up to a concentration of 10 microM. In in vivo studies using adrenalectomized rats, RU 38486 totally inhibited dexamethasone-induced hepatic tryptophan oxygenase (TO) activity. It is also the first pure antagonist of dexamethasone-induced hepatic TAT. However, doses as high as 5 mg/kg of body weight were required for a 50% inhibition of the effect of dexamethasone at 0.01 mg/kg. RU 38486 did not display any glucocorticoid effect on these two responses up to 50 mg/kg.
Gagne
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Philibert
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D000818:Animals; D001667:Binding, Competitive; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D004963:Estrenes / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D015735:Mifepristone; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors
D004963:Estrenes; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D014366:Tryptophan Oxygenase; D014444:Tyrosine Transaminase