A MODEL FOR THE EFFECT OF ESTROGEN ANTAGONISTS ON COOPERATIVE ESTRADIOL BINDING

Partial agonists such as estriol and estrone have been reported to dim inish or even eliminate the upward convexity of the Scatchard plot of the binding of labeled estradiol to estrogen receptor. This has been i nterpreted as agonist interference with the receptor dimerization indu ced by estradiol. In order to investigate how a partial agonist or ant agonist might interfere with dimerization we have developed a theoreti cal mass-action law model, where soluble receptors can dimerize and bi nd to two different ligands. Special attention was devoted to manifest ations of positive cooperativity to determine whether they could be mo dified by competition with a second ligand. This was done using a comp uter program that evaluated a large set of combinations of affinity co nstants in an effort to explore all possible situations. The model cou ld reproduce the effect of a second ligand on the cooperative binding of estradiol to the estrogen receptor but only if the second ligand wa s anticooperative, which is not the case of estriol, estrone and tamox ifen. Furthermore, even when the Scatchard plot was linear, the model still required dimerization of the receptor in most of the cases, show ing that the addition of an antagonist may eliminate the upward curvat ure of the Scatchard without truly eliminating dimerization or coopera tivity. We conclude that the effect of a second ligand on the binding of labeled estradiol to estrogen receptor is not necessarily due to in terference with dimerization and/or cooperativity. The inability of th is model to fully explain the published data for estriol. estrone, clo miphene, and tamoxifen suggests that a more complex mechanism is invol ved.