Fang Hong, Tong Weida, Branham William S, Moland Carrie L, Dial Stacy L, Hong Huixiao, Xie Qian, Perkins Roger, Owens William, Sheehan Daniel M
Northrop Grumman Information Technology, Jefferson, Arkansas 72079, USA.
Chem Res Toxicol. 2003 Oct;16(10):1338-58. doi: 10.1021/tx030011g.
A number of environmental and industrial chemicals are reported to possess androgenic or antiandrogenic activities. These androgenic endocrine disrupting chemicals may disrupt the endocrine system of humans and wildlife by mimicking or antagonizing the functions of natural hormones. The present study developed a low cost recombinant androgen receptor (AR) competitive binding assay that uses no animals. We validated the assay by comparing the protocols and results from other similar assays, such as the binding assay using prostate cytosol. We tested 202 natural, synthetic, and environmental chemicals that encompass a broad range of structural classes, including steroids, diethylstilbestrol and related chemicals, antiestrogens, flutamide derivatives, bisphenol A derivatives, alkylphenols, parabens, alkyloxyphenols, phthalates, siloxanes, phytoestrogens, DDTs, PCBs, pesticides, organophosphate insecticides, and other chemicals. Some of these chemicals are environmentally persistent and/or commercially important, but their AR binding affinities have not been previously reported. To the best of our knowledge, these results represent the largest and most diverse data set publicly available for chemical binding to the AR. Through a careful structure-activity relationship (SAR) examination of the data set in conjunction with knowledge of the recently reported ligand-AR crystal structures, we are able to define the general structural requirements for chemical binding to AR. Hydrophobic interactions are important for AR binding. The interaction between ligand and AR at the 3- and 17-positions of testosterone and R1881 found in other chemical classes are discussed in depth. The SAR studies of ligand binding characteristics for AR are compared to our previously reported results for estrogen receptor binding.
据报道，许多环境和工业化学品具有雄激素或抗雄激素活性。这些具有雄激素活性的内分泌干扰化学物质可能通过模拟或拮抗天然激素的功能来扰乱人类和野生动物的内分泌系统。本研究开发了一种低成本的重组雄激素受体（AR）竞争性结合试验，该试验不使用动物。我们通过比较其他类似试验（如使用前列腺胞质溶胶的结合试验）的方案和结果来验证该试验。我们测试了202种天然、合成和环境化学品，它们涵盖了广泛的结构类别，包括类固醇、己烯雌酚及相关化学品、抗雌激素、氟他胺衍生物、双酚A衍生物、烷基酚、对羟基苯甲酸酯、烷氧基酚、邻苯二甲酸酯、硅氧烷、植物雌激素、滴滴涕、多氯联苯、农药、有机磷杀虫剂和其他化学品。其中一些化学品在环境中具有持久性和/或具有商业重要性，但它们与AR的结合亲和力此前尚未见报道。据我们所知，这些结果代表了公开可得的关于化学品与AR结合的最大且最多样化的数据集。通过结合最近报道的配体-AR晶体结构知识对该数据集进行仔细的构效关系（SAR）研究，我们能够确定化学品与AR结合的一般结构要求。疏水相互作用对AR结合很重要。深入讨论了睾酮和R1881在3位和17位与配体和AR之间在其他化学类别中的相互作用。将AR配体结合特征的SAR研究与我们之前报道的雌激素受体结合结果进行了比较。
