2003 Fiscal Year Final Research Report Summary
Modulating effects of halogenated compounds on the metabolic detoxification of catechol estrogens and mammary carcinogenesis
| Project/Area Number |
14580570
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | University of Shizuoka |
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Principal Investigator |
SHIMOI Kayoko University of Shizuoka, Institute for Environmental Sciences, Associate Professor, 環境科学研究所, 助教授 (10162728)
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| Co-Investigator(Kenkyū-buntansha) |
TERAO Yoshiyasu University of Shizuoka, Institute for Environmental Sciences, Professor, 環境科学研究所, 教授 (60046282)
TAKEMURA Hitomi School of Nursing, Research Associate, 看護学部, 助手 (60295558)
WAKABAYASHI Keiji National Cancer Center, Cancer Prevention Basic Research Project, Project Leader, がん予防研究部, 部長 (60158582)
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| Project Period (FY) |
2002 – 2003
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| Keywords | breast cancer / halogenated compounds / estrogen / bisphenol A / detoxification / conjugating enzyme / inflammation / uterus weight |
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| Research Abstract |
The estrogenic activity of bisphenol A (BPA) and its chlorinated derivatives, 2-(3-chloro-4-hydroxyphenyl) -2-(4-hydroxyphenyl) propane (3-ClBPA) and 2,2-bis(3-chloro-4-hydroxyphenyl)propane (3,3'-diClBPA) was assessed by determining their relative binding affinity for the human estrogen receptor-α and -β (ERα and ERβ) and also their uterotrophic activity in ovariectomized female rats. BPA and its chlorinated derivatives were active in competing with [^3H] 17β-estradiol for their binding to the human ERa and ERβ proteins. Treatment of animals with 50 and 100 mg/kg/day of BPA or its chlorinated derivatives caused a significant increase in the uterine wet weight and the endometrial area. The results of our present study demonstrated that the affinities of 3-ClBPA and 3,3'-diClBPA for ERα were higher than the affinity of BPA, although the in vivo estrogenic activity of the two chlorinated BPAs in ovariectomized female Sprague-Dawley rats appeared to be comparable to that of BPA.
17β-Estradiol (E_2) and estrone (E_1), two major endogenous estrogens, are metabolized to catechol estrogens (CEs, i.e., 2- and 4-hydroxy-F_2/E_1) in humans. CEs are effectively deactivated by the catechol-O-methyltransferase (COMT)-mediated O-methylation coupled with enzymatic glucuronidation and/or sulfation. We found that BPA and its chlorinated derivatives had little or no effect on the COMT-mediated O-methylation of CEs in vitro. However, 3-ClBPA inhibited the human UGT2B7-mediated glucuronidation of 4-hydroxy-E_1 in a concentration-dependent manner. The results of our study showed that 3-ClBPA, but not BPA or 3,3'-diClBPA, inhibited the human UGT2B7-mediated glucuronidation of 4-hydroxyestrogens in vitro, and it also inhibited the expression of this conjugating enzyme in cultured MCF-7 cells.
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Research Products
(3 results)
