Catecholestrogens have been postulated to mediate the induction of kidney tumors by estradiol in male Syrian hamsters. In this study, we examined the mechanism of inhibition by quercetin of the catechol O-methyltransferase-catalyzed O-methylation of catecholestrogens as a basis for the previously reported enhancement of estradiol-induced tumorigenesis by this flavonoid. In hamsters treated with 50 µg of [6,7-H]estradiol, quercetin increased concentrations of 2- and 4-hydroxyestradiol in kidney by 80 and 59%, respectively. In animals treated with two 10-mg estradiol implants, quercetin also decreased by 63-65% the urinary excretion of 2- and 4-hydroxyestradiol monomethyl ethers. Taken together, these results demonstrate the in vivo inhibition of the O-methylation of catecholestrogens by quercetin. S-Adenosyl-L-homocysteine, produced by the methylation of catecholestrogens, noncompetitively inhibited the O-methylation of 2- and 4-hydroxyestradiol by hamster kidney cytosolic catechol O-methyltransferase (IC approximately 10-14 µM). Due to the rapid O-methylation of quercetin itself, quercetin decreased renal concentrations of S-adenosyl-L-methionine by approximately 25% in control or estradiol-treated hamsters and increased concentrations of S-adenosyl-L-homocysteine by 5-15 nmol/g of wet tissue, which was estimated to cause a 30-70% inhibition of the enzymatic O-methylation of catecholestrogens. Quercetin or fisetin (a structural analog) inhibited the O-methylation of 2- and 4-hydroxyestradiol by a competitive plus noncompetitive mechanism (IC approximately 2-5 µM). These results suggest that the in vivo O-methylation of catecholestrogens is inhibited more by S-adenosyl-L-homocysteine than by quercetin. The accumulation of 2- and 4-hydroxyestradiol during co-administration of estradiol and quercetin may enhance metabolic redox cycling of catecholestrogens and thus estradiol-induced kidney tumorigenesis.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				L. Lehmann, L. Jiang, and J. Wagner Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells Carcinogenesis, February 1, 2008; 29(2): 363 - 370. [Abstract] [Full Text] [PDF]

				M. Chang, K.-w. Peng, I. Kastrati, C. R. Overk, Z.-H. Qin, P. Yao, J. L. Bolton, and G. R. J. Thatcher Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells Endocrinology, October 1, 2007; 148(10): 4793 - 4802. [Abstract] [Full Text] [PDF]

				J. W. Erdman Jr., D. Balentine, L. Arab, G. Beecher, J. T. Dwyer, J. Folts, J. Harnly, P. Hollman, C. L. Keen, G. Mazza, et al. Flavonoids and Heart Health: Proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC J. Nutr., March 1, 2007; 137(3): 718S - 737S. [Abstract] [Full Text] [PDF]

				W. J. Lee and B. T. Zhu Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols Carcinogenesis, February 1, 2006; 27(2): 269 - 277. [Abstract] [Full Text] [PDF]

				W. J. Lee, J.-Y. Shim, and B. T. Zhu Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids Mol. Pharmacol., October 1, 2005; 68(4): 1018 - 1030. [Abstract] [Full Text] [PDF]

				J. A. Doherty, N. S. Weiss, R. J. Freeman, D. A. Dightman, P. J. Thornton, J. R. Houck, L. F. Voigt, M. A. Rossing, S. M. Schwartz, and C. Chen Genetic Factors in Catechol Estrogen Metabolism in Relation to the Risk of Endometrial Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 357 - 366. [Abstract] [Full Text] [PDF]

				L. I Mennen, R. Walker, C. Bennetau-Pelissero, and A. Scalbert Risks and safety of polyphenol consumption Am. J. Clinical Nutrition, January 1, 2005; 81(1): 326S - 329S. [Abstract] [Full Text] [PDF]

				M. B. M. van Duursen, J. T. Sanderson, P. Chr. de Jong, M. Kraaij, and M. van den Berg Phytochemicals Inhibit Catechol-O-Methyltransferase Activity in Cytosolic Fractions from Healthy Human Mammary Tissues: Implications for Catechol Estrogen-Induced DNA Damage Toxicol. Sci., October 1, 2004; 81(2): 316 - 324. [Abstract] [Full Text] [PDF]

				M. Nagai, A. H. Conney, and B. T. Zhu STRONG INHIBITORY EFFECTS OF COMMON TEA CATECHINS AND BIOFLAVONOIDS ON THE O-METHYLATION OF CATECHOL ESTROGENS CATALYZED BY HUMAN LIVER CYTOSOLIC CATECHOL-O-METHYLTRANSFERASE Drug Metab. Dispos., May 1, 2004; 32(5): 497 - 504. [Abstract] [Full Text] [PDF]

				Y. Duguay, M. McGrath, J. Lepine, J.-F. Gagne, S. E. Hankinson, G. A. Colditz, D. J. Hunter, M. Plante, B. Tetu, A. Belanger, et al. The Functional UGT1A1 Promoter Polymorphism Decreases Endometrial Cancer Risk Cancer Res., February 1, 2004; 64(3): 1202 - 1207. [Abstract] [Full Text] [PDF]

				M. Sasaki, M. Kaneuchi, N. Sakuragi, and R. Dahiya Multiple Promoters of Catechol-O-methyltransferase Gene Are Selectively Inactivated by CpG Hypermethylation in Endometrial Cancer Cancer Res., June 15, 2003; 63(12): 3101 - 3106. [Abstract] [Full Text] [PDF]

				B. T. Zhu, U. K. Patel, M. X. Cai, and A. H. Conney O-Methylation of Tea Polyphenols Catalyzed by Human Placental Cytosolic Catechol-O-Methyltransferase Drug Metab. Dispos., September 1, 2000; 28(9): 1024 - 1030. [Abstract] [Full Text]

				J. Russo, Y.-F. Hu, X. Yang, and I. H. Russo Chapter 1: Developmental, Cellular, and Molecular Basis of Human Breast Cancer J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 17 - 37. [Abstract] [Full Text] [PDF]

				J. D. Yager Chapter 3: Endogenous Estrogens as Carcinogens Through Metabolic Activation J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 67 - 73. [Abstract] [Full Text] [PDF]

				C. R. Jefcoate, J. G. Liehr, R. J. Santen, T. R. Sutter, J. D. Yager, W. Yue, S. J. Santner, R. Tekmal, L. Demers, R. Pauley, et al. Chapter 5: Tissue-Specific Synthesis and Oxidative Metabolism of Estrogens J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 95 - 112. [Abstract] [Full Text] [PDF]

				P. T. Mannisto and S. Kaakkola Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors Pharmacol. Rev., December 1, 1999; 51(4): 593 - 628. [Abstract] [Full Text] [PDF]