Carcinogenesis Advance Access originally published online on January 12, 2008
Carcinogenesis 2008 29(2):363-370; doi:10.1093/carcin/bgm235
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Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells
Institute of Applied Biosciences, Section of Food Chemistry, University of Karlsruhe, Kaiserstraße 12, D-76131 Karlsruhe, Germany
* To whom correspondence should be addressed. Tel: +49 721 608 4177; Fax: +49 721 608 7255; Email: leane.lehmann{at}lmc.uni-karlsruhe.de
The tissue concentrations of the female sex hormone 17β-estradiol (E2) and its reactive catechol metabolites such as 4-hydroxyestradiol (4-HO-E2) play important roles in hormonal carcinogenesis. They are influenced by the activity of local enzymes involved in the metabolic activation and inactivation of E2. In the mammary gland, catechol estrogens are predominately inactivated by catechol-O-methyltransferase (COMT). Food supplements containing the soy isoflavones genistein and daidzein are consumed because they are believed to protect from breast cancer; however, this proposed benefit is controversial. The aim of the present study was to investigate the influence of soy isoflavones on the gene expression and activity of COMT in cultured human mammary adenocarcinoma MCF-7 cells. Levels of COMT messenger RNA (mRNA) were determined by reverse transcription/competitive polymerase chain reaction and COMT activity was determined by high-performance liquid chromatography analysis of the methylation products of both the model substrate quercetin and the physiological relevant substrate 4-HO-E2. Our study demonstrates for the first time that soy isoflavones at hormonally active concentrations cause a significant reduction of both COMT mRNA levels and COMT activity as well as of the methylation of 4-HO-E2. Experiments using the estrogen receptor (ER) antagonist ICI 182,780 support a role of the ER in the isoflavone-induced down-regulation of COMT expression. Thus, this study not only demonstrates that hormonally active concentrations of soy isoflavones inhibit the detoxification of catechols in this human breast cancer cell line but also implies that diet might influence COMT activity to a greater extent than heretofore recognized.
Abbreviations: cDNA, complementary DNA; COMT, catechol-O-methyltransferase; CYP, cytochrome P450; DAI, daidzein; DMSO, dimethyl sulfoxide; E2, 17β-estradiol; ER, estrogen receptor; GC, gas chromatography; GEN, genistein; 4-HO-E2, 4-hydroxyestradiol; HPLC, high-performance liquid chromatography; HPRT, hypoxanthine-guanine phosphoribosyltransferase; ICI, ICI 182,780; MS, mass spectrometry; mRNA, messenger RNA; PCR, polymerase chain reaction
Received July 25, 2007; revised October 3, 2007; accepted October 18, 2007.
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