Carcinogenesis Advance Access originally published online on October 25, 2006
Carcinogenesis 2007 28(3):738-748; doi:10.1093/carcin/bgl180
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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
Department of Nutritional Toxicology, Institute for Nutrition Friedrich-Schiller University Jena, Dornburger Straße 25, 07743 Jena, Germany
1 Department of Gastroenterology, St Radboud University Hospital Nijmegen, The Netherlands
2 Department of Environmental and Occupational Health Sciences, University of Washington 4225 Roosevelt Way NE, Suite 100, Seattle Washington, DC, USA
3 Northern Ireland Centre for Diet and Health, University of Ulster Coleraine, Northern Ireland BT52 1SA
*To whom correspondence should be addressed. Tel: +49 0 3641 949670; Fax: +49 0 3641 949672; Email: b8pobe{at}uni-jena.de
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 µM) and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (50 µM), 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.
Abbreviations: AP-1, activator protein-1; ARE, antioxidant response element; BPDE, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide; BSA, bovine serum albumin; CDNB, 1-chloro-2,4-dinitrobenzene; ER, estrogen receptor; ERE, estrogen responsive element; ERK1/2, extracellular regulated protein kinase 1/2; GSH, reduced glutathione; GST, glutathione S-transferase; 4-HNE, 4-hydroxy-2-nonenal; MAPK, mitogen-activated protein kinases; NQO1, ; NAD(P)H, quinone oxidoreductase; PAH, polycyclic aromatic hydrocarbon; ROS, reactive oxygen species.
Received December 15, 2005; revised August 30, 2006; accepted September 11, 2006.
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