NATURE OF STEROID-RECEPTOR INTERACTIONS

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The object is to define the initial, intracellular events of steroid hormone action. These events include steroid binding to the intracellular receptor molecule, "activation" of the receptor-steroid complex to a DNA-binding and nuclear-binding species, and binding of the activated complex to those nuclear acceptor sites involved in the regulation of transcription of specific genes. One approach that has been used to examine these steps is to compare the properties of agonist and antagonist receptor-steroid complexes. Detailed studies of the amount of induction of tyrosine aminotransferase (TAT) by several antiglucocorticoids in two rat hepatoma tissue culture lines (HTC and Fu5-5) revealed that each antiglucocorticoid displayed about 2-fold more agonist activity in Fu5-5 cells than in HTC cells. At the same time, it was noted that the concentration of several glucocorticoids required for 50% of maximal TAT induction (i.e., EC50) in Fu5-5 cells were about 6-fold lower than in HTC cells. The values of both parameters varied over time. A retrospective analysis revealed an excellent linear, reciprocal relationship between the amount of agonist activity for the irreversible antiglucocorticoid dexamethasone 21-mesylate and the EC50 of the glucocorticoid dexamethasone (R=-0.896[n=46]). These changes in TAT enzyme activity were paralleled by changes in the amount of TAT mRNA sequences but were not observed with another glucocorticoid inducible enzyme, glutamine synthetase. Thus we have documented a novel modulation of glucocorticoid induction of TAT transcripts. Such modulation has not been observed for the control of gene transcripts by any other steroid hormones but may be related to the known variation in agonist activity seen for most antisteroids in vivo in different systems.