Enhancement of affinity to receptors in the esterified glucocorticoid, hydrocortisone 17-butyrate 21-propionate (HBP), in the rat liver.
To investigate the affinity of glucocorticoid (GC) to its receptor, the binding of [3H]hydrocortisone 17-butyrate 21-propionate ([3H]HBP) and [3H]dexamethasone ([3H]DEX) in rat liver was analyzed kinetically. Scatchard analysis of [3H]hydrocortisone ([3H]HC) binding yielded a curvilinear plot with upward concavity with high and low affinities. The dissociation constant (Kd) value of high affinity was 1.9 nM and of low affinity 68.7 nM. A Scatchard plot of [3H]HBP binding showed a straight line with high affinity. The Kd value was 9.8 nM. The Kd values for the low affinity site of HC were in good agreement with the Ki values obtained from displacement experiments of [3H]DEX and [3H]HBP binding. The Ki values of HC for [3H]DEX and [3H]HBP were 51.9 and 42.3 nM respectively. The association rate constant for HBP to the GC receptor was 2.9 times lower than that for HC. The dissociation rate constant for HBP was 6.1 to 8.3 times lower than that for HC. The Kd values for [3H]HBP (9.5 nM) and [3H]HC (30.0 nM) obtained from the above two rate constants were approximately the same as the Ki and Kd values (in the case of HC, the value of the low affinity site). These results suggest that esterification of the hydroxyl group(s) in the side chain of GC by butyrate and propionate increased the affinity to the GC receptor, and that a decrease in the dissociation rate from the receptor caused the increase in the affinity to the GC receptor.
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism; D004951:Esterification; D005938:Glucocorticoids / Q000494:pharmacology; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014316:Tritium
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014316:Tritium; C033014:hydrocortisone 17-butyrate 21-propionate; D003907:Dexamethasone; D006854:Hydrocortisone