title: Human CYP2E1-dependent mutagenicity of mono- and dichlorobiphenyls in Chinese hamster (V79)-derived cells.
abstract: Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants with confirmed carcinogenicity to humans. Metabolic activation of lower chlorinated PCBs to genotoxic metabolites may involve hydroxylation and further oxidation, and some hydroxylated metabolites may be sulfo-conjugated. However, the genotoxicity of individual PCB compounds is largely unknown. In this study, 15 mono- and dichlorobiphenyls were investigated for genotoxicity using the micronucleus and Hprt mutagenicity assays in a Chinese hamster V79-derived cell line expressing both human cytochrome P450 (CYP) 2E1 and human sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1). All tested compounds were inactive in both assays in V79 control cells. However, eight dichlorobiphenyls strongly induced micronuclei and other congeners were weakly positive for this endpoint in V79-hCYP2E1-hSULT1A1 cells. The effects of each PCB in V79-hCYP2E1-hSULT1A1 cells were abolished or reduced in the presence of a CYP2E1 inhibitor (1-aminobenzotriazole), or enhanced by pretreatment of the cells with (CYP2E1-inducing) ethanol, while the genotoxicity was not significantly affected by a SULT1 inhibitor (pentachlorophenol). As representative dichlorobiphenyls, PCB 5, 10, 8 and 11 (2,3-, 2,5-, 2,4'- and 3,3'-dichlorobiphenyl, respectively) strongly induced Hprt gene mutations in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner. This is the first indication that human CYP2E1 is capable of converting a series of dichlorobiphenyls to strong mutagens.
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China.
authors.forename: Chiteng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert- Allee 114-116, D-14558 Nuthetal, Germany; Department of Food Safety, Federal Institute for Risk Assessment (BfR), Max-Hohrn-Straße 8-10, D-10589 Berlin, Germany.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China.
authors.forename: Qinzhi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China. Electronic address: yungliu@126.com.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000494:pharmacology; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004785:Environmental Pollutants; D009153:Mutagens; D014230:Triazoles; C033020:1-aminobenzotriazole; D011078:Polychlorinated Biphenyls; D019392:Cytochrome P-450 CYP2E1; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human
keywords: CYP2E1; Gene mutations; Micronuclei; Polychlorinated biphenyls; Sulfotransferase 1A1