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Carcinogenesis Advance Access published online on October 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl180
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received December 15, 2005
Revised August 30, 2006
Accepted September 11, 2006

CARCINOGENESIS

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

Claudia Steiner 1, Wilbert H. M. Peters 2, Evan P. Gallagher 3, Pamela Magee 4, Ian Rowland 4, and Beatrice L. Pool-Zobel 1 *

1 Department of Nutritional Toxicology, Institute for Nutrition, Friedrich-Schiller University Jena, Dornburger Straße 25, 07743 Jena, Germany
2 Department of Gastroenterology, St Radboud University Hospital, Nijmegen, The Netherlands
3 Department of Environmental and Occupational Health Sciences, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle Washington, United States of America
4 Northern Ireland Centre for Diet & Health, University of Ulster, Coleraine, Northern Ireland BT52 1SA

* To whom correspondence should be addressed.
Beatrice L. Pool-Zobel, E-mail: b8pobe{at}uni-jena.de


  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 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 etiology of breast cancer.

Keywords: breast cancer; isoflavones; genistein; glutathione S-transferases; glutathione; chemoprotection; 4-hydroxy-2-nonenal; benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide.
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