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

@inbook{citeulike:3392707, abstract = {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.}, address = {New York, NY}, author = {Wagner, J\"{o}rg and Jiang, Ling and Lehmann, Leane}, booktitle = {Advances in Experimental Medicine and Biology}, chapter = {Chapter 65}, citeulike-article-id = {3392707}, citeulike-linkout-0 = {http://dx.doi.org/10.1007/978-0-387-69080-3_65}, comment = {The main finding in this paper: Genistein and Daidzein - widely consumed soy isoflavones, 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. Catechol and Quinone Estrogens go on to form DNA adducts. These adducts are released from the DNA and leave behind an apurinic site on DNA. If the DNA repair mechanism is not effective or defective, these apurinic sites might form point mutations which pave the way toward the neoplastic transformation of the cells Should we really be automatically assuming in our hypotheses that all phytoestrogens are good interventions?? }, doi = {10.1007/978-0-387-69080-3_65}, editor = {Li, Jonathan J. and Li, Sara A. and Mohla, Suresh and Rochefort, Henri and Maudelonde, Thierry}, isbn = {978-0-387-69078-0}, journal = {Advances in Experimental Medicine and Biology}, keywords = {escreen, estrogen, future, metabolism, phytoestrogen, quinones}, pages = {625--632}, posted-at = {2008-10-10 10:08:16}, priority = {2}, publisher = {Springer New York}, title = {Phytoestrogens Modulate the Expression of 17α-Estradiol Metabolizing Enzymes in Cultured MCF-7 Cells}, url = {http://dx.doi.org/10.1007/978-0-387-69080-3_65}, volume = {617}, year = {2008} }

TY - CHAP ID - citeulike:3392707 L3 - citeulike-article-id:3392707 N2 - 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. JF - Advances in Experimental Medicine and Biology SN - 978-0-387-69078-0 AD - New York, NY EP - 632 TI - Phytoestrogens Modulate the Expression of 17α-Estradiol Metabolizing Enzymes in Cultured MCF-7 Cells PB - Springer New York VL - 617 T2 - Advances in Experimental Medicine and Biology SP - 625 KW - escreen KW - estrogen KW - future KW - metabolism KW - phytoestrogen KW - quinones N1 - The main finding in this paper: Genistein and Daidzein - widely consumed soy isoflavones, 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. Catechol and Quinone Estrogens go on to form DNA adducts. These adducts are released from the DNA and leave behind an apurinic site on DNA. If the DNA repair mechanism is not effective or defective, these apurinic sites might form point mutations which pave the way toward the neoplastic transformation of the cells Should we really be automatically assuming in our hypotheses that all phytoestrogens are good interventions?? AU - Wagner, Jörg AU - Jiang, Ling AU - Lehmann, Leane A2 - Li, Jonathan A2 - Li, Sara A2 - Mohla, Suresh A2 - Rochefort, Henri A2 - Maudelonde, Thierry PY - 2008/// UR - http://dx.doi.org/10.1007/978-0-387-69080-3_65 ER -