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Phytoestrogens Modulate the Expression of 17α-Estradiol Metabolizing Enzymes in Cultured MCF-7 Cells

  • Jörg Wagner
  • Ling Jiang
  • Leane Lehmann
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Summary

The activation of 17β-estradiol (E2) to 2-hydroxyestradiol (2-HO-E2), the more genotoxic 4-hydroxyestradiol (4-HO-E2), and the oxidation to the respective quinones constitutes a risk factor in hormonal carcinogenesis. 2-HO-E2 is formed by cytochrome P450 CYP1A1, and 4-HO-E2 is formed by CYP1B1. Both are detoxified by catechol-O-methyltransferase (COMT), whereas their quinones are inactivated by NADPH-quinone-oxidoreductase (QR). Since the soy isoflavones genistein (GEN) and daidzein (DAI) are widely consumed due to their putative protective function in breast carcinogenesis, we examined the influence of E2, GEN, and DAI on CYP1A1/1B1, COMT, and QR expression in MCF-7 cells by reverse transcription/competitive PCR. CYP1A1 and COMT enzyme activity were determined using ethoxyresorufin and quercetin as substrates. Furthermore, estrogen receptor (ER)-regulated cell proliferation was determined by E-screen. E2, GEN, and DAI inhibited the expression of CYP1A1, COMT, and QR. The maximum effect (reduction by 40–80%, depending on the gene product and compound) was obtained at 100pM E2,1 μM GEN, and 10μM DAI, which also induced the most pronounced cell proliferation in the E-screen. In contrast, expression of CYP1B1 was only slightly affected. CYP1A1 and COMT mRNA levels correlated with enzyme activities. The ER antagonist ICI 182,780 reversed the E2- and isoflavone-mediated effects. Thus, GEN and DAI at estrogen-active concentrations stimulate the formation of the more E2 genotoxic metabolites and inhibit the detoxification of catechol and quinone estrogens in estrogen-responsive tumor cells.

Keywords

Relative mRNA Level COMT Activity Catechol Estrogen Antioxidant Responsive Element Genotoxic Metabolite 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer 2008

Authors and Affiliations

  • Jörg Wagner
    • 1
  • Ling Jiang
  • Leane Lehmann
    • 2
  1. 1.Insitote of Applied Biosciences Section of Food Chemistry and ToxicologyUniversity of KarlsruheKarlsruheGermany
  2. 2.Institute of Applied BiosciencesUniversity of KarlsruheKarlsruheGermany

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