title: Genistein protects human mammary epithelial cells from benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide and 4-hydroxy-2-nonenal genotoxicity by modulating the glutathione/glutathione S-transferase system.
abstract: Epidemiological studies have shown that ingestion of isoflavone-rich soy products is associated with a reduced risk for the development of breast cancer. In the present study, we investigated the hypothesis that genistein modulates the expression of glutathione S-transferases (GSTs) in human breast cells, thus conferring protection towards genotoxic carcinogens which are GST substrates. Our approach was to use human mammary cell lines MCF-10A and MCF-7 as models for non-neoplastic and neoplastic epithelial breast cells, respectively. MCF-10A cells expressed hGSTA1/2, hGSTA4-4, hGSTM1-1 and hGSTP1-1 proteins, but not hGSTM2-2. In contrast, MCF-7 cells only marginally expressed hGSTA1/2, hGSTA4-4 and hGSTM1-1. Concordant to the protein expression, the hGSTA4 and hGSTP1 mRNA expression was higher in the non-neoplastic cell line. Exposure to genistein significantly increased hGSTP1 mRNA (2.3-fold), hGSTP1-1 protein levels (3.1-fold), GST catalytic activity (4.7-fold) and intracellular glutathione concentrations (1.4-fold) in MCF-10A cells, whereas no effects were observed on GST expression or glutathione concentrations in MCF-7 cells. Preincubation of MCF-10A cells with genistein decreased the extent of DNA damage by 4-hydroxy-2-nonenal (150 microM) and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (50 microM), compounds readily detoxified by hGSTA4-4 and hGSTP1-1. In conclusion, genistein pretreatment protects non-neoplastic mammary cells from certain carcinogens that are detoxified by GSTs, suggesting that dietary-mediated induction of GSTs may be a mechanism contributing to prevention against genotoxic injury in the aetiology of breast cancer.
authors.affiliation: Department of Nutritional Toxicology, Institute for Nutrition, Friedrich-Schiller University Jena, Dornburger Strasse 25, 07743 Jena, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Steiner
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
authors.forename: Evan P
authors.initials: EP
authors.lastname: Gallagher
authors.forename: Pamela
authors.initials: P
authors.lastname: Magee
authors.forename: Ian
authors.initials: I
authors.lastname: Rowland
authors.forename: Beatrice L
authors.initials: BL
authors.lastname: Pool-Zobel
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D000447:Aldehydes / Q000633:toxicity*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001940:Breast / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D001943:Breast Neoplasms; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000447:Aldehydes; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D017931:DNA Primers; D012333:RNA, Messenger; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019833:Genistein; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C027576:4-hydroxy-2-nonenal