Tripartite Steroid Hormone Receptor Pharmacology: Interaction with Multiple Effector Sites as a Basis for the Cell- and Promoter-Specific Action of These Hormones John A. Katzenellenbogen, Bert W. O’Malley, and Benita S. Katzenellenbogen Department of Chemistry (J.A.K.) Departments of Molecular and integrative Physiology, and Cell and Structural Biology (B.S.K.) University of Illinois Urbana, Illinois 61801 Department of Cell Biology (B.W.O.) Baylor College of Medicine Houston. Texas 77030 INTRODUCTION The selective action that steroid hormones and the hormones for the other nuclear receptors have in dif- ferent tissues and on different responses is well known. In fact, this recognized selectivity forms the basis for major efforts, currently underway in the phar- maceutical industry and at universities, toward the development of new, synthetic hormones whose pro- file of desired activities is optimized for specific ther- apeutic and preventative applications. This commen- tary will examine the pharmacological mechanisms that underlie this selectivity. The study of steroid hormone pharmacology poses particular challenges. In viva, many steroids have pleiotropic activity, displaying a variety of effects in different tissues. Even in cell-based in vitro systems, attempts to investigate the molecular basis for steroid hormone action and the selectivity of this action are confounded by the fact that the genomic responses elicited by these ligands can be both primary and secondary (Le. cascade) responses. In the latter situ- ation, the correlation between molecular interaction and response is complex and indirect; this makes it difficult to clearly determine what interactions define the pharmacological parameters of potency and bio- 0888-8809/96/$3.00/O Molecular Endocrinology Copyright 0 1996 by The Endocrine Society character (biological character, i.e. agonist vs. antag- onist activity) of a specific hormone. Even the genomic actions vary: most involve direct receptor-DNA inter- action, but some appear to be mediated via interaction of receptor with other DNA-binding proteins. Steroid hormones may also exert nongenomic effects, some of which may still involve the receptor. In this com- mentary, we are focusing on the genomic action of steroid hormones that involves the regulation of gene transcription mediated by nuclear receptors. THREE MECHANISMS FOR STEROID HORMONE SELECTIVITY The selectivity that steroid and other hormones for nuclear receptors display at three different levels-the tissue, the cell, and the gene-may be mediated by three distinct mechanisms (Table 1): 1) ligand-based selectivity, 2) receptor-based selectivity, and 3) effec- tor site-based selectivity. Since the first two mecha- nisms are well recognized, they will be described only briefly; the third mechanism merits careful examina- tion and will be discussed in greater detail. Ligand-Based Selectivity By this mechanism, selectivity at the tissue or cell level may be achieved by differences in pharmacokinetics 119 Downloaded from https://academic.oup.com/mend/article-abstract/10/2/119/2713299 by guest on 12 March 2018