The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands
The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands
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DOI：
10.1093/toxsci/54.1.138
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发表时间：
2000-03-01
影响因子：
3.8
通讯作者：
Sheehan, DM
中科院分区：
文献类型：
--
作者：
Blair, RM;Fang, H;Sheehan, DM
我们使用了一种有效的(标准化的)雌激素受体(ER)竞争结合试验来确定一大类结构不同的化学物质的ER亲和力。去卵巢的SD大鼠子宫是竞争结合分析的内质网来源。最初，测试化学品在高浓度下进行筛选，以确定一种化学品是否与[H-3]-雌二醇竞争ER。随后使用广泛的浓度对第一层中表现出与ER亲和力的测试化学品进行分析，以表征结合曲线，并确定每种化学品的IC50和相对结合亲和力(RBA)值。总体而言，我们分析了188种化学品，涵盖了来自几个不同化学品或用途类别的1 x 10(6)倍范围的RBAs，包括类固醇雌激素、合成雌激素、抗雌激素、其他杂项类固醇、烷基酚、二苯衍生物、有机氯、杀虫剂、烷基羟基苯甲酸酯防腐剂(对羟基苯甲酸酯)、邻苯二甲酸酯、二苯甲酮化合物和一些其他杂项化学品。在接受测试的188种化学品中，100种与ER结合，88种是非粘结剂。与内质网结合的100种化学物质包括4-苄氧基苯酚、2，4-二羟基二苯甲酮和2，2‘-亚甲基双(4-氯苯酚)，这些化合物以前没有被证明与内质网结合。也很明显，某些结构特征，如整体的环结构，对于ER结合是重要的。目前的研究提供了结构最多样化的ER RBA数据集，提供了迄今为止公布的最广泛的RBA值范围。
We have utilized a validated (standardized) estrogen receptor (ER) competitive-binding assay to determine the ER affinity for a large, structurally diverse group of chemicals. Uteri from ovariectomized Sprague-Dawley rats were the ER source for the competitive-binding assay. Initially, test chemicals were screened at high concentrations to determine whether a chemical competed with [H-3]-estradiol for the ER. Test chemicals that exhibited affinity for the ER in the first tier were subsequently assayed using a wide range of concentrations to characterize the binding curve and to determine each chemical's IC50 and relative binding affinity (RBA) values. Overall, we assayed 188 chemicals, covering a 1 x 10(6)-fold range of RBAs from several different chemical or use categories, including steroidal estrogens, synthetic estrogens, antiestrogens, other miscellaneous steroids, alkylphenols, diphenyl derivatives, organochlorines, pesticides, alkylhydroxybenzoate preservatives (parabens), phthalates, benzophenone compounds, and a number of other miscellaneous chemicals. Of the 188 chemicals tested, 100 bound to the ER while 88 were non-binders. Included in the 100 chemicals that bound to the ER were 4-benzyloxyphenol, 2,4-dihydroxybenzophenone, and 2,2'-methylenebis(4-chlorophenol), compounds that have not been shown previously to bind the ER. It was also evident that certain structural features, such as an overall ring structure, were important for ER binding. The current study provides the most structurally diverse ER RBA data set with the widest range of RBA values published to date.