title: Potent mutagenicity of some non-planar tri- and tetrachlorinated biphenyls in mammalian cells, human CYP2E1 being a major activating enzyme.
abstract: Polychlorinated biphenyls (PCBs) have been classified as human carcinogens. Mutagenicity of lower chlorinated biphenyls as well as activation of transcription factors by some other congeners may contribute to the carcinogenicity of PCBs. Recently, we reported that human CYP2E1 activates mono- and dichlorobiphenyls to mutagens. However, mutagenicity of other PCBs and the involvement of other CYPs remained unknown. In this study, Chinese hamster V79-derived cell lines genetically engineered for expression of individual human CYP enzymes and a human hepatocyte (L-02) line endogenously expressing various CYPs were used to determine the activities of several tri- and tetrachlorobiphenyls to induce micronuclei and gene mutations. 2,3,4'-Trichlorobiphenyl, 2,3,3'-trichlorobiphenyl, 2,4,4',5-tetrachlorobiphenyl and 2,2',5,5'-tetrachlorobiphenyl efficiently induced micronuclei and/or gene mutations in V79-derived cells at low micromolar concentrations, depending on human CYP2E1, while they were inactive in parental V79-Mz cells and weakly positive or inactive in V79-derived cells expressing human CYP1A1, 1A2, 1B1 or 3A4. The induction of gene mutations in human CYP2E1-expressing V79 cells by 2,3,4'-trichlorobiphenyl and 2,4,4',5-tetrachlorobiphenyl was more potent than that of N-nitrosodimethylamine, a strong carcinogen activated by CYP2E1. As representative PCB compounds, 2,3,3'-trichlorobiphenyl and 2,3,4'-trichlorobiphenyl induced micronuclei in L-02 cells, and this effect was blocked by specific CYP2E1 inhibition, wherein the effects of benzo[a]pyrene and aflatoxin B1(activated by some CYPs other than CYP2E1) were unaffected. This study demonstrates that some non-planar tri- and tetrachlorobiphenyls are potent mutagens in mammalian cells-more potent than previously tested mono- and dichlorobiphenyls-and that among several human CYP enzymes, CYP2E1 is most efficient in activating these environmental contaminants.
authors.affiliation: Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, 510515, Guangzhou, China. yungliu@126.com.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, 510515, Guangzhou, China.
authors.forename: Keqi
authors.initials: K
authors.lastname: Hu
authors.affiliation: Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, 510515, Guangzhou, China.
authors.forename: Hansi
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, 510515, Guangzhou, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Toxicology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.|Department of Food Safety, Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, 10589, Berlin, Germany.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.affiliation: Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, 510515, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008658:Inactivation, Metabolic / Q000187:drug effects; D015162:Micronucleus Tests; D009153:Mutagens / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D009154:Mutation; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D009153:Mutagens; D016604:Aflatoxin B1; D011078:Polychlorinated Biphenyls; D019392:Cytochrome P-450 CYP2E1; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: Cytochrome P450 (CYP); Gene mutations; Micronuclei; Polychlorinated biphenyls; Sulfotransferase (SULT) 1A1