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

点击翻译按钮获取中文摘要

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.