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首页> 外文期刊>Environmental Science & Technology >How PBDEs Are Transformed into Dihydroxylated and Dioxin Metabolites Catalyzed by the Active Center of Cytochrome P450s: A DFT Study
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How PBDEs Are Transformed into Dihydroxylated and Dioxin Metabolites Catalyzed by the Active Center of Cytochrome P450s: A DFT Study

机译：DFT研究如何通过细胞色素P450的活性中心将PBDEs转化为二羟基化和二恶英代谢产物

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摘要

Predicting metabolism of chemicals and potential toxicities of relevant metabolites remains a vital and difficult task in risk assessment. Recent findings suggested that polybrominated diphenyl ethers (PBDEs) can be transformed into dihydroxylated and dioxin metabolites catalyzed by cytochrome P450 enzymes (CYPs), whereas the mechanisms pertinent to these transformations remain largely unknown. Here, by means of density functional theory (DFT) calculations, we probed the metabolic pathways of 2,2',4,4'-tetraBDE (BDE-47) using the active center model of CYPs (Compound Ⅰ). Results show that BDE-47 is first oxidized to monohydroxylated products (HO-BDEs), wherein a keto-enol tautomerism is identified for rearrangement of the cyclohexenone intermediate. Dihydroxylation with HO-BDEs as precursors, has a unique phenolic H-abstraction and hydroxyl rebound pathway that is distinct from that for monohydroxylation, which accounts for the absence of epoxides in in vitro studies. Furthermore, we found only dihydroxylated PBDEs with heterophenyl -OH substituents ortho- and meta- to the ether bond serve as precursors for dioxins, which are evolved from aryl biradical coupling of diketone intermediates that are produced from dehydrogenation of the dihydroxylated PBDEs by Compound Ⅰ. This study may enlighten the development of computational models that afford mechanism-based prediction of the xenobiotic biotransformation catalyzed by CYPs.
机译：在风险评估中，预测化学物质的代谢以及相关代谢物的潜在毒性仍然是一项至关重要而又艰巨的任务。最近的发现表明，多溴联苯醚（PBDEs）可以被细胞色素P450酶（CYPs）催化转化为二羟基化和二恶英代谢物，而与这些转化有关的机制仍然未知。在这里，通过密度泛函理论（DFT）计算，我们使用CYPs（化合物Ⅰ）的活性中心模型探索了2,2'，4,4'-tetraBDE（BDE-47）的代谢途径。结果表明，BDE-47首先被氧化为单羟基化产物（HO-BDEs），其中确定了酮-烯醇互变异构现象，以重排环己烯酮中间体。以HO-BDEs为前体的二羟基化具有独特的酚H吸收和羟基回弹途径，这与单羟基化不同，后者说明了体外研究中不存在环氧化物。此外，我们发现只有带有杂苯基-OH取代基的邻位和间位醚键的二羟基化PBDEs才是二恶英的前体，二恶英是由二酮中间体的芳基双自由基偶联反应生成的，二酮中间体是由化合物Ⅰ对二羟基化PBDEs进行脱氢反应制得的。这项研究可能会启发计算模型的发展，这些模型提供了基于机制的对CYP催化的异源生物转化的预测。

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  • 来源
    《Environmental Science & Technology》 |2016年第15期|8155-8163|共9页
  • 作者

    Zhiqiang Fu; Yong Wang; Jingwen Chen; Zhongyu Wang; Xingbao Wang;

  • 作者单位

    Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China;

    State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China;

    Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China;

    Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China;

    State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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