title: Differential biochemical and cellular actions of Premarin estrogens: distinct pharmacology of bazedoxifene-conjugated estrogens combination.
abstract: The use of estrogen-based therapies and the selective estrogen receptor (ER) modulator (SERM), raloxifene, which are approved for postmenopausal osteoporosis, is associated with side effects such as uterine/breast hyperproliferation, thromboembolism, and hot flashes. A combination of a new SERM, bazedoxifene (BZA), and Premarin (conjugated estrogens; CE) is under investigation to mitigate the estrogen/SERM side effects with promising results in Phase III clinical trials. To explore the mechanism of BZA/CE action, we investigated the recruitment of cofactor peptides to ERalpha by components of CE and a mixture containing the 10 major components of CE with or without three different SERMs. Here, we demonstrate differential recruitment of cofactor peptides to ERalpha by the individual CE components using a multiplex nuclear receptor-cofactor peptide interaction assay. We show that estrone and equilin are partial agonists in comparison with 17beta-estradiol in recruiting cofactor peptides to ERalpha. Further, CE was more potent than 17beta-estradiol in mediating ERalpha interaction with cofactor peptides. Interestingly, BZA was less potent than other SERMs in antagonizing the CE-mediated cofactor peptide recruitment to ERalpha. Finally, in accordance with these biochemical findings, 17beta-estradiol and CE, as well as SERM/CE combinations, showed differential gene regulation patterns in MCF-7 cells. In addition, BZA showed antagonism of a unique set of CE-regulated genes and did not down-regulate the expression of a number of CE-regulated genes, the expression of which was effectively antagonized by the other two SERMs. These results indicate that SERMs in combination with CE exhibit differential pharmacology, and therefore, combinations of other SERMs and estrogen preparations may not yield the same beneficial effects that are observed in clinic by pairing BZA with CE.
authors.affiliation: Nuclear Receptor Biology, Women's Health & Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Berrodin
authors.forename: Ken C N
authors.initials: KC
authors.lastname: Chang
authors.forename: Barry S
authors.initials: BS
authors.lastname: Komm
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D050071:Bone Density Conservation Agents; D047628:Estrogen Receptor alpha; D004966:Estrogens, Conjugated (USP); D007211:Indoles; D008024:Ligands; D010455:Peptides; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; C447119:bazedoxifene