Modulating effects of halogenated compounds on the metabolic detoxification of catechol estrogens and mammary carcinogenesis

卤代化合物对儿茶酚雌激素代谢解毒和乳腺癌发生的调节作用

• 批准号: 14580570
• 负责人: SHIMOI Kayoko
• 金额: $ 1.79万
• 依托单位: University of Shizuoka
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580570/
• 关键词: breast cancer; halogenated compounds; estrogen; bisphenol A; detoxification; conjugating enzyme; inflammation; uterus weight

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.

通过测定双酚A（BPA）及其氯代衍生物2-（3-氯-4-羟基苯基）-2-（4-羟基苯基）丙烷（3-ClBPA）和2，2-双（3-氯-4-羟基苯基）丙烷（3，3 '-diClBPA）与人雌激素受体-α和-β（ERα和ERβ）的相对结合亲和力，以及它们对去卵巢雌性大鼠子宫的促生长活性，评价了BPA及其氯代衍生物的雌激素活性。BPA及其氯化衍生物在与[^3H] 17β-雌二醇竞争结合人类ER α和ERβ蛋白时具有活性。用50和100 mg/kg/天的BPA或其氯化衍生物处理动物，导致子宫湿重和子宫内膜面积显著增加。我们的研究结果表明，3-ClBPA和3，3 '-diClBPA对ERα的亲和力高于BPA的亲和力，尽管这两种氯代BPA在去卵巢雌性Sprague-Dawley大鼠体内的雌激素活性似乎与BPA相当。17 β-雌二醇（E_2）和雌酮（E_1），两种主要的内源性雌激素，被代谢为儿茶酚雌激素（CEs，也就是说，2-和4-羟基-F_2/E_1）。通过儿茶酚-O-甲基转移酶（COMT）介导的O-甲基化结合酶促葡萄糖醛酸化和/或硫酸化，CE有效失活。我们发现BPA及其氯化衍生物对体外COMT介导的CE O-甲基化作用影响很小或没有影响。然而，3-ClBPA以浓度依赖性方式抑制人UGT 2B 7介导的4-羟基-E_1的葡萄糖醛酸化。我们的研究结果表明，3-ClBPA，而不是BPA或3，3 '-diClBPA，在体外抑制人UGT 2B 7介导的4-羟基雌激素的葡萄糖醛酸化，它也抑制这种结合酶在培养的MCF-7细胞中的表达。

项目成果

環境・健康科学辞典

环境与健康科学词典

• 发表时间: 2005
• 作者: 下位 香代子(分担執筆)