Polychlorinated biphenyls (PCBs) are persistent organic pollutants with human carcinogenicity. Many lower chlorinated and non-dioxin-like PCBs have been observed to be mutagenic following activation by human CYP2E1, while activation of dioxin-like (DL-) PCBs by this enzyme has never been evidenced. In this study, each DL-PCB was analyzed by molecular docking to human CYP2E1 protein for predicting a substrate interaction. All compounds demonstrated high affinities with the active site of human CYP2E1, binding energy being -8.7 ∼ -9.7 kcal/mol. However, most compounds demonstrated ligand-heme distances as ≥ 6.8 Å, while the values for 2,3,3',4,4'- (PCB 105) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118) were 5.3 and 5.4 Å, respectively (valid for electron transfer). Experimentally, both PCB 105 and 118 induced micronuclei in a V79-derived cell line engineered for expression of human CYP2E1 at low micromolar concentrations, while inactive or weakly positive in V79-Mz control cells; these effects were blocked or reduced by 1-aminobenzotriazole, a suicide CYP inhibitor. However, DL-PCBs 77, 81 and 126 were all negative in both cell lines. In a human hepatoma (C3A) cell line, PCB 105 and 118 induced micronuclei marginally, while with ethanol pretreatment (to stabilize CYP2E1) both compounds induced micronuclei efficiently, and co-exposure to trans-1,2-dichloroethylene (a selective CYP2E1 inhibitor) led to clearly negative results with both compounds. Finally, both PCB 105 and 118 induced PIG-A gene mutations in C3A cells, which was blocked by trans-1,2-dichloroethylene. In summary, in silico and experimental results consistently suggest that DL- PCBs 105 and 118 may be activated by human CYP2E1 for mutagenic activities.

中文翻译：

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人类CYP2E1激活的二恶英样PCB 105和118的致突变性-实验数据与分子对接结果一致。

多氯联苯（PCBs）是具有人类致癌性的持久性有机污染物。已观察到许多低级氯化和非二恶英样的多氯联苯在被人CYP2E1激活后具有致突变性，而这种酶对二恶英样（DL-）的多氯联苯的活化从未被证实。在这项研究中，通过分子对接至人CYP2E1蛋白来分析每个DL-PCB，以预测底物相互作用。所有化合物均与人CYP2E1的活性位点具有高亲和力，结合能为-8.7〜-9.7kcal / mol。但是，大多数化合物的配体-血红素距离为≥6.8Å，而2,3,3'，4,4'-（PCB 105）和2,3'，4,4'，5-五氯联苯（PCB 118）分别为5.3和5.4Å（对电子转移有效）。实验上，PCB 105和118在V79衍生的细胞系中诱导了微核，该细胞系经改造可在低微摩尔浓度下表达人CYP2E1，而在V79-Mz对照细胞中则无活性或弱阳性；这些作用被自杀性CYP抑制剂1-氨基苯并三唑阻断或减弱。然而，DL-PCB 77、81和126在两种细胞系中均为阴性。在人肝癌（C3A）细胞系中，PCB 105和118略微诱导微核，而用乙醇预处理（稳定CYP2E1），两种化合物均有效诱导微核，并共同暴露于反式1,2-二氯乙烯（选择性CYP2E1抑制剂） ）导致这两种化合物的结果明显为阴性。最后，PCB 105和118都诱导了C3A细胞中的PIG-A基因突变，该突变被反式1,2-二氯乙烯阻断。综上所述，