title: Daidzein-sulfate metabolites affect transcriptional and antiproliferative activities of estrogen receptor-beta in cultured human cancer cells.
abstract: Daidzein (D), a soy isoflavone, is almost completely metabolized in the gut and liver. This biotransformation converts D to more water-soluble products and may affect its biological activity. The ability of daidzein metabolites to modulate 17beta-estradiol (E2)-sensitive gene transcription, cell growth, and a proapoptotic cascade was determined in human cancer cells devoid of any estrogen receptor (ER) and rendered E2 sensitive after transfection with ERbeta. The data show that D and some but not all of its metabolites 1) induce promoter activity, 2) reduce proliferation, 3) promote p38/mitogen-activated protein kinase (MAPK) phosphorylation, and 4) activate a proapoptotic cascade involving the cleavage of caspase-3 and its substrate poly(ADP-ribose)polymerase (PARP) in human cancer cells in an ERbeta-dependent manner. Pretreatment of cells with ICI 182,780, a pure antiestrogen, completely prevented the actions of D and its metabolites. These findings highlight the important and complex influence of metabolic transformation on key physiological effects of isoflavones and demonstrate the need to take biotransformation into account when assessing the potential health benefits of consuming soy isoflavones.
authors.affiliation: Department of Biology, University "Roma Tre," I-00146 Rome, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Totta
authors.forename: Filippo
authors.initials: F
authors.lastname: Acconcia
authors.forename: Fabio
authors.initials: F
authors.lastname: Virgili
authors.forename: Aedin
authors.initials: A
authors.lastname: Cassidy
authors.forename: Peter D
authors.initials: PD
authors.lastname: Weinberg
authors.forename: Gerald
authors.initials: G
authors.lastname: Rimbach
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
mesh_terms: D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000032:analysis / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000502:physiology*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007529:Isoflavones / Q000378:metabolism* / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013431:Sulfates / Q000378:metabolism* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D007529:Isoflavones; D013431:Sulfates; D004958:Estradiol; C004742:daidzein; D008156:Luciferases; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases