title: Evaluation of clinical and environmental anti-estrogens with human estrogen receptor expressed in Saccharomyces cerevisiae: a novel role for ABC-cassette transporters in mediating anti-estrogenic activity.
abstract: The effectiveness of anti-estrogens in treating estrogen-dependent diseases is limited by the acquired resistance of some diseases to anti-estrogens. This effect could occur by the export of anti-estrogens by cell membrane transport proteins. To study this phenomenon we have expressed human estrogen receptor (hER) and an estrogen-sensitive reporter in wild-type yeast and two transport-defective strains. In the wild-type strain, the most effective anti-estrogen was nafoxidine. 4-Hydroxy tamoxifen and clomiphene were inactive whereas tamoxifen had significant inhibitory activity in the wild-type strain. Using a strain missing the ABC-cassette transporter Snq2, clomiphene had anti-estrogenic activity. 4-Hydroxy tamoxifen had anti-estrogenic activity only in yeast lacking the transporter Pdr5. Whole cell binding assays indicated that 4-hydroxy tamoxifen is exported by Pdr5. Environmental chemicals such as polychlorinated biphenyls function as partial estrogens and anti-estrogens in yeast. In the absence of Pdr5 or Snq2, the estrogenic activity of 4-hydroxy, 2',4',6'-trichloro biphenyl (3-PCB) was substantially reduced in comparison to its activity in the wild-type strain. Interestingly, the antiestrogenic activity of 3-PCB was equivalent in the wild-type and transporter-defective strains. Our results suggest a novel role for ABC-cassette transporters in regulating the activity of clinical and environmental anti-estrogens.
authors.affiliation: Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: D Q
authors.initials: DQ
authors.lastname: Tran
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: J A
authors.initials: JA
authors.lastname: McLachlan
authors.forename: S F
authors.initials: SF
authors.lastname: Arnold
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D002996:Clomiphene / Q000378:metabolism; D003001:Cloning, Molecular; D004964:Estriol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism; D017353:Gene Deletion; D017930:Genes, Reporter; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009256:Nafoxidine / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000378:metabolism* / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D018528:ATP-Binding Cassette Transporters; D004965:Estrogen Antagonists; D005656:Fungal Proteins; D008565:Membrane Proteins; C092438:PDR5 protein, S cerevisiae; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; C101797:SNQ2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013629:Tamoxifen; C016601:afimoxifene; D002996:Clomiphene; C015550:2,4',5-trichlorobiphenyl; D009256:Nafoxidine; D011078:Polychlorinated Biphenyls; D001616:beta-Galactosidase; D004964:Estriol