Enantioselective induction of cytotoxicity by o,p'-DDD in PC12 cells: implications of chirality in risk assessment of POPs metabolites.
Enantioselective induction of cytotoxicity by o,p'-DDD in PC12 cells: implications of chirality in risk assessment of POPs metabolites.
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DOI：
10.1021/es3049306
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发表时间：
2013-04
影响因子：
11.4
通讯作者：
Cui Wang;Zhuoyu Li;Quan Zhang;Mei-rong Zhao;Weiping Liu
中科院分区：
文献类型：
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作者：
Cui Wang;Zhuoyu Li;Quan Zhang;Mei-rong Zhao;Weiping Liu
随着手性持久性有机污染物（POPs）向环境中释放量的增加，对映体选择性在这些化合物的归趋和生态毒理效应中的作用受到了越来越多的关注。虽然在以往的研究中已经考虑了手性持久性有机污染物的对映体选择性，但很少有人努力辨别手性持久性有机污染物代谢物的对映体特异性效应，这可能会阻碍对这些化学品进行全面的风险评估。本研究以o，p '-DDT的手性代谢产物o，p'-DDD作为模型手性代谢产物。首先，在100%乙醇中进行优先手性分离以获得纯的对映体。通过检测细胞凋亡和氧化应激系统的激活和芯片分析，评价o，p '-DDD在大鼠细胞（PC 12）中的对映体选择性细胞毒性。我们首次证明了R-（+）-o，p '-DDD通过选择性干扰氧化系统（酶和分子）和调节Aven、Bid、Cideb和Tp 53的转录来增加细胞凋亡。通过将本研究的数据与母体化合物的数据进行比较，我们得出结论，R-对映体是o，p '-DDT和o，p'-DDD的更有害的立体结构。这种观察到的立体结构效应与在其他结构水平上制定的结构-活性关系一致。手性持久性有机污染物及其代谢物在具有相似立体结构的条件下，其手性代谢物的生物活性可能发生在相同的绝对构型中。
The increased release of chiral persistent organic pollutants (POPs) into the environment has resulted in more attention to the role of enantioselectivity in the fate and ecotoxicological effects of these compounds. Although the enantioselectivity of chiral POPs has been considered in previous studies, little effort has been expended to discern the enantiospecific effects of chiral POPs metabolites, which may impede comprehensive risk assessments of these chemicals. In the present study, o,p'-DDD, the chiral metabolite of o,p'-DDT, was used as a model chiral metabolite. First, a preferential chiral separation at 100% ethanol was employed to obtain a pure enantiomer. The enantioselective cytotoxicity of o,p'-DDD in rat cells (PC12) was evaluated by detecting activation of the cellular apoptosis and oxidative stress systems and microarray analysis. We have documented for the first time that R-(+)-o,p'-DDD increases apoptosis by selectively disturbing the oxidative system (enzymes and molecules) and regulating the transcription of Aven, Bid, Cideb and Tp53. By comparing the data from the present study to data derived from the parent compound, we concluded that the R-enantiomer is the more detrimental stereostructure for both o,p'-DDT and o,p'-DDD. This observed stereostructural effect is in line with the structure-activity relationship formulated at other structural levels. Biological activities of the chiral metabolites are likely to occur in the same absolute configuration between chiral POPs and their metabolites provided that they have the similar stereostructures.