Agonistic and synergistic activity of tamoxifen in a yeast model system

The background of agonist/antagonist behaviour of the non-steroidal antiest rogen tamoxifen is still not fully understood. Depending on cell type, its activities range from full agonistic to antagonistic in different tissues. We investigated the transactivational properties of tamoxifen in a basic ye ast model system which reconstitutes ligand-dependent human estrogen recept or-alpha (hER alpha) gene activation. Tamoxifen exerted low agonist activit y in this system compared to 17 beta-estradiol (E-2). Efficiencies and pote ncies of several isomers were calculated by fitting experimental data with a logistic dose-response function. Cis-, trans- and cis-trans-tamoxifen and trans-4-hydroxytamoxifen (4-OHT) showed comparable efficiencies and potenc ies in yeast. When subeffective doses of trans-, cis-/trans-, or trans-4-OH tamoxifen were combined with increasing 17 beta-estradiol concentrations, even a synergistic increase in efficiencies could be observed. interestingl y, the cis-isomer did nut show this synergistic effect. Mutation of the N-t erminus of the estrogen receptor changed the transactivational behaviour of tamoxifen and abolished the synergistic action with 17 beta-estradiol. Exc ept for 4-OHT, the potencies of the investigated isomers, defined as ligand concentrations with half-maximal response, highly correlated with the bind ing affinities to hERa. Therefore, cis-, trans-, and cis-/trans-tamoxifen c ould be regarded as full agonists in yeast, while 4-OHT was regarded as a p artial antagonist in yeast. Furthermore, these results indicate that the fu nctional difference between trans-tamoxifen and trans-4-OHT is not due to t heir different affinities for the receptor protein. BIOCHEM PHARMACOL 59;2: 177-185, 2000. (C) 1999 Elsevier Science Inc.