Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency
Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency
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DOI：
10.1006/taap.2000.9026
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发表时间：
2000-10-15
影响因子：
3.8
通讯作者：
Hahn, ME
中科院分区：
文献类型：
--
作者：
Hestermann, EV;Stegeman, JJ;Hahn, ME
受体作用模型对于描述配体-受体相互作用的性质是有价值的，从而有助于基于机制的受体介导的毒性作用的风险评估。为了建立芳烃受体（AHR）的模型，在PLHC-1细胞中测定了结合亲和力和CYP 1A诱导效力，并用于确定10种卤代芳烃（HAH）的内在效力：2，3，7，8-四氯二苯并-对-二恶英（TCDD），2，3，？，8-四氯二苯并呋喃（TCDF）和八种多氯联苯（PCB）。TCDD、TCDF和非邻位取代的PCBs 77、81、126和169表现为完全激动剂，并显示出高内在功效。相比之下，单-和二-邻位取代的PCB结合到AHR，但显示较低或没有内在功效。PCB 156是一种完全激动剂，但其内在功效比非邻位取代的PCB低10至50倍，PCB 118是一种非常弱的部分激动剂。PCBs 105和128在该体系中表现为竞争性拮抗剂。然后使用该模型预测二元混合物对CYP 1A的诱导作用。用PCB 126、128或156与TCDD的二元混合物对这些预测进行了测试。PCB 156（低内在效力激动剂）和PCB 128（竞争性拮抗剂）都抑制对TCDD的反应，而对TCDD和PCB 126的反应是相加的。这些数据支持以下结论：1）仅需要占据细胞中1-2%的受体就可以达到高内在功效激动剂之一的最大CYP 1A诱导的50%，表明在该系统中存在“备用”受体; 2）与非邻位取代的PCB相比，鱼类对邻位取代的PCB不敏感是由于亲和力降低和内在功效降低; 3）多氯联苯同系物具有明显的结构-亲和性和结构-功效关系。将AHR配体作用分离为亲和力和内在功效的性质允许改进配体的复杂混合物的行为的预测，以及跨物种和毒性终点的机制比较。(C)北京大学出版社.
Models of receptor action are valuable for describing properties of ligand-receptor interactions and thereby contribute to mechanism-based risk assessment of receptor-mediated toxic effects. In order to build such a model for the aryl hydrocarbon receptor (AHR), binding affinities and CYP1A induction potencies were measured in PLHC-1 cells and were used to determine intrinsic efficacies for 10 halogenated aromatic hydrocarbons (HAH): 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,?,8-tetrachlorodibenzofuran (TCDF), and eight polychlorinated biphenyls (PCB). TCDD, TCDF, and non-ortho-substituted PCBs 77, 81, 126, and 169 behaved as full agonists and displayed high-intrinsic efficacy. In contrast, the mono- and di-ortho-substituted PCBs bound to the AHR but displayed lower or no intrinsic efficacy. PCB 156 was a full agonist, but with an intrinsic efficacy 10- to 50-fold lower than non-ortho-substituted PCBs, PCB 118 was a very weak partial agonist. PCBs 105 and 128 were shown to be competitive antagonists in this system. The model was then used to predict CYP1A induction by binary mixtures. These predictions were tested with binary mixtures of PCB 126, 128, or 156 with TCDD, Both PCB 156 (a low-intrinsic efficacy agonist) and PCB 128 (a competitive antagonist) inhibited the response to TCDD, while the response to TCDD and PCB126 was additive. These data support the following conclusions: 1) only 1-2% of the receptors in the cell need be occupied to achieve 50% of maximal CYP1A induction by one of the high-intrinsic efficacy agonists, demonstrating the existence of "spare" receptors in this system; 2) the insensitivity of fish to ortho-substituted PCBs is due to both reduced affinity and reduced intrinsic efficacy compared to non-ortho-substituted PCBs; 3) PCB congeners exhibit distinct structure-affinity and structure-efficacy relationships. Separation of AHR ligand action into the properties of affinity and intrinsic efficacy allows for improved prediction of the behavior of complex mixtures of ligands, as web as mechanistic comparisons across species and toxic endpoints. (C) 2000 Academic Press.