Synthesis of polybrominated diphenyl ethers and their capacity to induce CYP1A by the Ah receptor mediated pathway
Synthesis of polybrominated diphenyl ethers and their capacity to induce CYP1A by the Ah receptor mediated pathway
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DOI：
10.1021/es0107475
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发表时间：
2001-09-15
影响因子：
11.4
通讯作者：
Bunce, NJ
中科院分区：
文献类型：
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作者：
Chen, GS;Konstantinov, AD;Bunce, NJ
多溴联苯醚（PBDEs）由于用作阻燃剂，已成为广泛分布的环境污染物。它们与其他卤代芳香族污染物的结构相似性导致人们猜测它们可能具有共同的毒理学特性，如肝酶诱导。在这项工作中，我们合成了一些多溴联苯醚同系物，通过竞争性结合试验研究了它们对大鼠肝Ah受体的亲和力，并确定了它们诱导肝细胞色素P-450酶的能力，通过EROD（乙氧基试卤灵-O-脱乙基酶）在人类，大鼠，鸡，虹鳟鱼细胞测定。纯PBDE同系物和商用PBDE混合物的Ah受体结合亲和力都是2，3，7，8-四氯二苯并-对-二恶英的10（-2）-10（-5）倍。与多氯联苯相比，多溴二苯醚的Ah受体结合亲和力与分子的平面性无关，这可能是因为溴原子的大尺寸扩大了Ah受体的结合位点。在所有细胞中，多溴联苯醚同系物的EROD活性遵循类似的等级顺序。一些同系物，特别是PBDE 85，并没有遵循通常的趋势，即Ah受体结合亲和力的强度超过P-450的诱导效力。使用合成寡核苷酸的凝胶阻滞测定表明，在这些情况下，配体Ah受体未能结合到DNA识别序列。
Polybrominated diphenyl ethers (PBDEs) have become widely distributed as environmental contaminants due to their use as flame retardants. Their structural similarity to other halogenated aromatic pollutants has led to speculation that they might share toxicological properties such as hepatic enzyme induction. In this work we synthesized a number of PBDE congeners, studied their affinity for rat hepatic Ah receptor through competitive binding assays, and determined their ability to induce hepatic cytochrome P-450 enzymes by means of EROD (ethoxyresorufin-O-deethylase) assays in human, rat, chick, and rainbow trout cells. Both pure PBDE congeners and commercial PBDE mixtures had Ah receptor binding affinities 10(-2)-10(-5) times that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. In contrast with polychlorinated biphenyls, Ah receptor binding affinities of PBDEs could not be related to the planarity of the molecule, possibly because the large size of the bromine atoms expands the Ah receptor's binding site. EROD activities of the PBDE congeners followed a similar rank order in all cells. Some congeners, notably PBDE 85, did not follow the usual trend in which strength of Ah receptor binding affinity paralleled P-450 induction potency. Use of the gel retardation assay with a synthetic oligonucleotide indicated that in these cases the liganded Ah receptor failed to bind to the DNA recognition Sequence.