Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathway
Interaction between halogenated aromatic compounds in the Ah receptor signal transduction pathway
复制标题
DOI：
10.1002/tox.20053
复制
发表时间：
2004-10-01
影响因子：
4.5
通讯作者：
Bunce, NJ
中科院分区：
文献类型：
--
作者：
Chen, GS;Bunce, NJ
卤代芳香族化合物（HACS），如多氯联苯（PCBs）和多氯二苯并二恶英（PCDDs）的许多毒性和生化反应是通过芳烃受体（AhR）介导的，这是一个细胞内的细胞溶质目标的HACS。在环境中暴露于HACs几乎总是涉及复杂的同系物混合物，其中一些可以拮抗强效HACs的作用，如2，3，7，8-四氯二苯并对二恶英（TCDD）。在这项工作中，我们研究了TCDD和代表性的PCB同系物，单独和混合物，其对原代大鼠肝细胞CYP 1A 1基因转录和蛋白水平的影响。连同我们以前的工作，我们的研究结果表明，形成的Ah受体配体DRE（二恶英反应元件）复合物是分歧的AhR激动剂和AhR拮抗剂之间的机制的主要点。共面PCBs 77和126以及单邻位PCBs 156对CYP 1A 1基因转录和CYP 1A蛋白水平是完全激动剂，与TCDD对靶分子AhR表现出典型的加和行为。相比之下，非平面PCB 153拮抗TCDD的作用，即使在浓度，占据了AhR分子的显着部分。竞争性抑制解释了通常报道的乙氧基试卤灵-O-脱乙基酶（EROD）活性降低时，多氯联苯是在高浓度和拮抗作用的多氯联苯的EROD活性的TCDD。结果是，蛋白质印迹法提供了一个更可靠的措施CYP 1A蛋白浓度比EROD测定，尽管后者更方便。(C)2004 Wiley Periodicals，Inc.
Many toxic and biochemical responses to halogenated aromatic compounds (HACS) such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDDs) are mediated through the aryl hydrocarbon receptor (AhR), which is an intracellular cytosolic target for HACs. Environmental exposure to HACs almost always involves complex mixtures of congeners, some of which can antagonize the action of potent HACs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this work we studied TCDD and representative PCB congeners, alone and in mixture, for their effect on CYP1A1 gene transcription and protein levels in primary rat hepatocytes. Together with our previous work, our results suggest that formation of the Ah receptor-ligand-DRE (dioxin response element) complex is the principal point of divergence in the mechanism between an AhR agonist and an AhR antagonist. The coplanar PCBs 77 and 126 and the mono-ortho PCB 156 were full agonists toward CYP1A1 gene transcription and CYP1A protein levels, showing typical additive behavior with TCDD to the target molecule AhR. In contrast, the nonplanar PCB 153 antagonized the action of TCDD, even at concentrations that occupied a significant fraction of AhR molecules. Competitive inhibition explains the commonly reported decrease of ethoxyresorufin-O-deethylase (EROD) activity when PCBs are present in high concentrations and the antagonism of PCBs to the EROD activity of TCDD. The result is that Western blotting offers a much more reliable measure of CYP1A protein concentration than does the EROD assay, despite the greater convenience of the latter. (C) 2004 Wiley Periodicals, Inc.