Stimulation of 17 beta-estradiol metabolism in MCF-7 cells by bromochloro- and chloromethyl-substituted dibenzo-p-dioxins and dibenzofurans: correlations with antiestrogenic activity.
Stimulation of 17 beta-estradiol metabolism in MCF-7 cells by bromochloro- and chloromethyl-substituted dibenzo-p-dioxins and dibenzofurans: correlations with antiestrogenic activity.
复制标题
DOI：
10.1080/15287399409531856
复制
发表时间：
1994-04
期刊：
影响因子：
--
通讯作者：
D. Spink;J. Johnson;S. Connor;K. Aldous;J. Gierthy
中科院分区：
文献类型：
--
作者：
D. Spink;J. Johnson;S. Connor;K. Aldous;J. Gierthy
混合卤代和卤代烷基取代的二苯并对二恶英 (DD) 和二苯并呋喃 (DF) 是已知的环境污染物，尽管有关这些化合物对人体细胞的毒性作用的信息有限。在本研究中，使用一系列溴氯和氯甲基取代的 DD 和 DF 来研究抗雌激素性（2,3,7,8-Cl4-DD 的一种特性）。研究了这些化合物对 17 β-雌二醇 (E2) 代谢和 MCF-7 人乳腺细胞培养物中雌激素依赖性多细胞灶形成的影响。用 2,3,7,8-Cl4-DD 预处理 MCF-7 细胞诱导 E2 代谢途径，涉及细胞色素 P-450 催化的羟基化、儿茶酚雌激素的甲基化和结合。几种在 2、3、7 和 8 位被卤素取代的 Br-Cl3-DD 和 Br2-Cl2-DD 同系物也能刺激 E2 代谢，其效力与 2,3,7,8-Cl4-DD 相似。然而，在任何这些位置上用甲基取代卤素的化合物不会刺激E2的代谢。对于在 MCF-7 培养物中测试的一系列化合物，观察到抗雌激素性（通过抑制导致病灶形成的雌激素依赖性汇合后生长来测量）与化合物刺激 E2 代谢的功效之间存在密切相关性。在这些位置上具有一或两个溴原子的 2,3,7,8-TetrahaloDD 具有高度抗雌激素作用，这通过它们对雌激素依赖性病灶形成的抑制来确定，而所研究的甲基取代的多氯 DD 和 DF 不抑制病灶形成。这些结果表明，当考虑卤代 DD 和 DF 同系物的生物效应时，2,3,7,8-取代的混合卤代 DD 和 DF 非常重要，并为 E2 代谢增加在卤代 DD 和 DF 的抗雌激素作用中的作用提供了额外的证据。
Mixed halo- and haloalkyl-substituted dibenzo-p-dioxins (DD) and dibenzofurans (DF) are known environmental contaminants, although there is limited information on the toxic effects of these compounds in human cells. In this study antiestrogenicity, a property of 2,3,7,8-Cl4-DD, was investigated with a series of bromochloro- and chloromethyl-substituted DDs and DFs. The effects of these compounds on the metabolism of 17 beta-estradiol (E2) and on the estrogen-dependent formation of multicellular foci in cultures of MCF-7 human breast cells were examined. Pretreatment of MCF-7 cells with 2,3,7,8-Cl4-DD induced pathways of E2 metabolism involving cytochrome P-450-catalyzed hydroxylation, methylation of the catechol estrogens, and conjugation. Several Br-Cl3-DD and Br2-Cl2-DD congeners with halogen substitution at the 2, 3, 7, and 8 positions also stimulated E2 metabolism with similar potency to that of 2,3,7,8-Cl4-DD; however, compounds with substitution of a methyl group for a halogen at any of these positions did not stimulate the metabolism of E2. For the series of compounds tested in MCF-7 cultures, a close correlation was observed between the antiestrogenicity as measured by the inhibition of estrogen-dependent postconfluent growth that results in focus formation and the efficacy with which the compounds stimulated the metabolism of E2. 2,3,7,8-TetrahaloDDs with one or two bromine atoms at these positions were highly antiestrogenic as determined by their inhibition of estrogen-dependent focus formation, whereas the methyl-substituted polychlorinated DDs and DFs investigated did not inhibit focus formation. These results indicate that the 2,3,7,8-substituted mixed halo-substituted DDs and DFs are of importance when the biologic effects of halogenated DD and DF congeners are considered, and provide additional evidence for the role of increased metabolism of E2 in the antiestrogenic effects of halogenated DDs and DFs.