1. Human CYP2E1-activated mutagenicity of dioxin-like PCBs 105 and 118-Experimental data consistent with molecular docking results.
- Author
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Hu K, Yu H, Li Z, Jin G, Jia H, Song M, and Liu Y
- Subjects
- Activation, Metabolic, Animals, Carcinoma, Hepatocellular enzymology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Catalytic Domain, Cricetulus, Cytochrome P-450 CYP2E1 chemistry, Cytochrome P-450 CYP2E1 genetics, Fibroblasts drug effects, Fibroblasts enzymology, Fibroblasts pathology, Hep G2 Cells, Humans, Liver Neoplasms enzymology, Liver Neoplasms genetics, Liver Neoplasms pathology, Lung drug effects, Lung enzymology, Lung pathology, Polychlorinated Biphenyls chemistry, Polychlorinated Biphenyls metabolism, Protein Binding, Protein Conformation, Cytochrome P-450 CYP2E1 metabolism, Membrane Proteins genetics, Micronuclei, Chromosome-Defective chemically induced, Molecular Docking Simulation, Mutation, Polychlorinated Biphenyls toxicity
- Abstract
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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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