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.