title: Agonistic and synergistic activity of tamoxifen in a yeast model system.
abstract: The background of agonist/antagonist behaviour of the non-steroidal antiestrogen 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 yeast model system which reconstitutes ligand-dependent human estrogen receptor-alpha (hER alpha) gene activation. Tamoxifen exerted low agonist activity in this system compared to 17 beta-estradiol (E2). Efficiencies and potencies of several isomers were calculated by fitting experimental data with a logistic dose-response function. Cis-, trans- and cis-transtamoxifen and trans-4-hydroxytamoxifen (4-OHT) showed comparable efficiencies and potencies 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. Interestingly, the cis-isomer did not show this synergistic effect. Mutation of the N-terminus of the estrogen receptor changed the transactivational behaviour of tamoxifen and abolished the synergistic action with 17 beta-estradiol. Except for 4-OHT, the potencies of the investigated isomers, defined as ligand concentrations with half-maximal response, highly correlated with the binding affinities to hER alpha. Therefore, cis-, trans-, and cis-/trans-tamoxifen could be regarded as full agonists in yeast, while 4-OHT was regarded as a partial antagonist in yeast. Furthermore, these results indicate that the functional difference between trans-tamoxifen and trans-4-OHT is not due to their different affinities for the receptor protein.
authors.affiliation: Institute for Applied Microbiology, University of the Agricultural Sciences, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Graumann
authors.forename: A
authors.initials: A
authors.lastname: Jungbauer
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001667:Binding, Competitive; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000819:agonists*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009154:Mutation; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D014452:Ubiquitins; D013629:Tamoxifen; D004958:Estradiol