Analysis of the relation between receptor binding affinity and antagonist efficacy of antiglucocorticoids.

Abstract

The biological potencies of four antiglucocorticoids, RU486 (RU), dexamethasone-oxetanone (DOX), R5020, and progesterone have been studied with respect to dexamethasone induction of tyrosine aminotransferase (TAT) in rat hepatoma tissue culture (HTC) cells. Their inhibitory effects in whole-cell competition binding studies (at 37 degrees C) and in TAT induction studies were analyzed by Dixon plots and Schild plots, respectively. We show that: In both cases, there is an actual competition of each antiglucocorticoid with the agonist dexamethasone for the same binding site; the two Kd values derived from the two plots are almost identical for each antiglucocorticoid; RU486 can be distinguished from the three other antiglucocorticoids by its high biological efficacy and its high affinity for the glucocorticoid receptor in whole cells at 37 degrees C (identical to its affinity in cytosol at 0 degree C). These results imply that: There is a linear correlation between the antagonist efficacies of antiglucocorticoids and their affinities for the glucocorticoid receptor in whole cells at 37 degrees C; the antagonistic action is solely mediated by competition with the agonist for the receptor binding site; this is verified by the fact that in all cases, in the presence or absence of antiglucocorticoids, a specific TAT induction level was always related to the same level of receptor saturation by the agonist in whole cells; the phenomena responsible for the high antagonist efficacy of RU486 are also responsible for its high affinity in whole cells at 37 degrees C.

• Authors: D Gagne, M Pons, A Crastes de Paulet
• Journal: Journal of steroid biochemistry (J Steroid Biochem) Vol. 25 Issue 3 Pg. 315-22 (Sep 1986) ISSN: 0022-4731 [Print] England
• PMID: 2877119 (Publication Type: Journal Article)

Chemical References

• Estrenes
• Glucocorticoids
• Receptors, Glucocorticoid
• Mifepristone
• dexamethasone oxetanone
• Progesterone
• Dexamethasone
• Promegestone
• Tyrosine Transaminase

Topics

• Animals
• Binding, Competitive
• Cell Line
• Dexamethasone (analogs & derivatives, pharmacology)
• Estrenes (pharmacology)
• Glucocorticoids (antagonists & inhibitors)
• Kinetics
• Liver Neoplasms, Experimental (enzymology)
• Mathematics
• Mifepristone
• Progesterone (pharmacology)
• Promegestone (pharmacology)
• Rats
• Receptors, Glucocorticoid (drug effects, metabolism)
• Tyrosine Transaminase (metabolism)