Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor
Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor
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DOI：
10.1021/tx030011g
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发表时间：
2003-10-01
影响因子：
4.1
通讯作者：
Sheehan, DM
中科院分区：
文献类型：
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作者：
Fang, H;Tong, WD;Sheehan, DM
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。这些雄激素性内分泌干扰物可能通过模仿或拮抗天然激素的功能来干扰人类和野生动物的内分泌系统。本研究建立了一种低成本的重组雄激素受体（AR）竞争结合试验，不使用动物。我们通过比较其他类似试验的方案和结果来验证该试验，例如使用前列腺胞质溶胶的结合试验。我们测试了202种天然、合成和环境化学品，涵盖了广泛的结构类别，包括类固醇、己烯雌酚和相关化学品、抗雌激素、芴醇衍生物、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。其中一些化学品具有环境持久性和/或商业重要性，但它们的AR结合亲和力以前从未报道过。据我们所知，这些结果代表了公众可获得的与AR化学结合的最大和最多样化的数据集。通过仔细的构效关系（SAR）检查的数据集结合最近报道的配体AR晶体结构的知识，我们能够定义的一般结构要求的化学结合AR。疏水相互作用对于AR结合是重要的。配体和AR之间的相互作用在3-和17-位置的睾酮和R1881中发现的其他化学类进行了深入讨论。AR的配体结合特性的SAR研究进行了比较，我们以前报道的雌激素受体结合的结果。
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.