The glucocorticoid properties of the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (Delta HOP) are not entirely correlated with the steroid binding to the glucocorticoid receptor

The natural steroid 11 beta-hydroxyprogesterone is not only a modulator of 11 beta-hydroxy-steroid dehydrogenase activity, but also an efficient induc er of tyrosine aminotransferase activity in hepatocytes. In contrast with t he low affinity for the mineralocorticoid receptor, 11 beta-hydroxyprogeste rone binds well to both the glucocorticoid receptor and the carrier protein transcortin. It is accepted that the introduction of a 1:ene double bond i nto 3-keto 4:ene steroids increases the glucocorticoid potency, so that 3-k eto-1,4:diene steroids show improved chemical stability and are more potent glucocorticoids than their respective 4:ene analogs. The steroid pregna-1, 4-diene-11 beta-ol-3,20-dione (Delta HOP) had previously been described as an anti-inflamatory compound and an inhibitor of macromolecular biosynthesi s in thymocytes and lymphocytes. In such studies, Delta HOP also exhibited some particular glucocorticoid properties which made it attractive as a too l for the study of the mechanism of action of glucocorticoids. In the prese nt paper we show that Delta HOP possesses some classical biological actions of glucocorticoids such as deposition of glycogen in rat liver, induction of TAT activity in hepatocytes, and inhibition of the uptake of leucine and thymidine by thymocytes. It also exhibits minimal sodium-retaining propert ies. Consistent with these biological effects, Delta HOP shows a 70 times l ower relative binding affinity for the mineralocortioid receptor than aldos terone, but a reasonable affinity for the glucocorticoid receptor, and is a s efficient as dexamethasone in dissociating the 90 kDa heat shock protein from the glucocorticoid receptor heterocomplex. However, the inhibition of the uptake of amino acids and nucleotides observed in the presence of Delta HOP is not efficiently blocked when thymocytes are coincubated in the pres ence of steroids with known antiglucocorticoid activity. Delta HOP is simil arly inefficient in inducing chloramphenicol-acetyl transferase activity in cells transfected with a plasmid that possesses two canonical glucocortico id-responsive elements. Unlike most glucocorticoids, Delta HOP does not ind uce the fragmentation of DNA in a regular pattern characteristic of apoptos is and it does not reduce thymus weight. This unusual dissociation of gluco corticoid parameters makes Delta HOP a useful tool to discriminate between mechanisms of action by which steroids can exert their biological effects. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.