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We examined the agonistic and antagonistic activities of three categories of pharmaceuticals, including selective estrogen receptor modulators (SERM), tamoxifen (Tam), raloxifene (Ral) and clomiphene citrate (CC); a ``pure'' ER antagonist, ICI 182,780 (ICI); and a subtype (ERa)-selective agonist, propyl pyrazole triol (PPT), using our newly established reporter yeast strains (Saccharomyces cerevisiae), which express human ERa or ERb. These strains also contain a reporter plasmid carrying one copy of estrogen responsive element (ERE) upstream of the bgalactosidase gene, and a plasmid expressing a steroid receptor coactivator, SRC-1e. In the ERa assay, none of the tested pharmaceuticals demonstrated antagonistic activity, whereas all showed weak agonistic activity at concentrations higher than 1×10-7 M. In the ERb assay, Tam, CC and ICI showed antagonistic activity, whereas only Ral showed agonistic activity at concentrations higher than 1×10-8 M. The distinct estrogenic response in the ERa and ERb assays was mainly due to their diŠerences in ligand a‹nity and interaction with coactivators. PPT showed an agonistic eŠect in the ERa assay, but not in the ERb assay. This study showed that our ERa and ERb reporter yeasts have diŠerent responses to the test pharmaceuticals and are able to distinguish subtype-selective ligands. These reporter yeasts are applicable for exploring ER subtype-speciˆc therapeutic agents and for detecting leaked pharmaceuticals that may act as environmental endocrine disruptors.

Differential Responses of Various Pharmaceuticals to Human Estrogen Receptors α and β in Newly-constructed Yeast Reporter Assays