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.
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.
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DOI：
10.1093/carcin/bgl180
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发表时间：
2006-10
期刊：
影响因子：
4.7
通讯作者：
C. Steiner;W. Peters;E. Gallagher;P. Magee;I. Rowland;B. Pool-Zobel
中科院分区：
文献类型：
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作者：
C. Steiner;W. Peters;E. Gallagher;P. Magee;I. Rowland;B. Pool-Zobel
流行病学研究表明，摄入富含大豆酮的豆制品与降低患乳腺癌的风险有关。在本研究中，我们调查的假设，即染料木素调节谷胱甘肽S-转移酶（GST）在人类乳腺细胞的表达，从而赋予保护对遗传毒性致癌物的GST底物。我们的方法是使用人乳腺细胞系MCF-10A和MCF-7分别作为非肿瘤性和肿瘤性乳腺上皮细胞的模型。MCF-10A细胞表达hGSTA 1/2、hGSTA 4 -4、hGSTM 1 -1和hGSTP 1 -1蛋白，但不表达hGSTM 2 -2。相比之下，MCF-7细胞仅少量表达hGSTA 1/2、hGSTA 4 -4和hGSTM 1 -1。与蛋白表达一致，hGSTA 4和hGSTP 1 mRNA在非肿瘤细胞系中表达较高。暴露于genistein显着增加hGSTP 1 mRNA（2.3倍），hGSTP 1 -1蛋白水平（3.1倍），GST催化活性（4.7倍）和细胞内谷胱甘肽浓度（1.4倍）在MCF-10A细胞，而没有观察到影响GST表达或谷胱甘肽浓度在MCF-7细胞。用染料木黄酮预孵育MCF-10A细胞可降低4-羟基-2-壬烯醛（150 μ M）和苯并（a）芘-7，8-二氢二醇-9，10-环氧化物（50 μ M）对DNA的损伤程度，这些化合物易于被hGSTA 4 -4和hGSTP 1 -1解毒。总之，染料木素预处理保护非肿瘤性乳腺细胞免受某些致癌物的解毒GST，这表明饮食介导的诱导GST可能是一种机制，有助于预防遗传毒性损伤的乳腺癌病因。
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.