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Genotoxic events are known to be crucial steps in the initiation of cancer. The genotoxic properties of TCE have been examined in many studies using a standard battery of genotoxicity tests both in vitro and in vivo. However, consistent results have not been obtained, and studies investigating the mechanism behind the genotoxicity of this compound are lacking. In the present study, we examined the genotoxicity of TCE by assessing phosphorylated histone H2AX (\u03b3\u2010H2AX), a new sensitive and reliable marker of DNA damage, in WRL\u201068 cells, cultured human hepatocytes and mouse livers. Our results showed that TCE exposure results in the generation of \u03b3\u2010H2AX, both in vitro and in vivo. By investigating the in vitro mechanism, we found that TCE increases the levels of intracellular reactive oxygen species (ROS) and that this increase in ROS levels is attenuated in the presence of disulfiram, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, \u03b3\u2010H2AX induced by TCE was also attenuated by CYP2E1 inhibitors and the antioxidant <jats:italic>N<\/jats:italic>\u2010acetylcysteine. These results suggested that ROS, produced via cytochrome P450 2E1\u2010mediated metabolic processing, is a major causal factor for \u03b3\u2010H2AX generation upon exposure to TCE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jat.3632","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T07:27:00Z","timestamp":1525332420000},"page":"1224-1232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Trichloroethylene exposure results in the phosphorylation of histone H2AX in a human hepatic cell line through cytochrome P450 2E1\u2010mediated oxidative stress"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2605-910X","authenticated-orcid":false,"given":"Tatsushi","family":"Toyooka","sequence":"first","affiliation":[{"name":"Industrial Toxicology and Health Effects Research Group National Institute of Occupational Safety and Health  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukie","family":"Yanagiba","sequence":"additional","affiliation":[{"name":"Industrial Toxicology and Health Effects Research Group National Institute of Occupational Safety and Health  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Ibuki","sequence":"additional","affiliation":[{"name":"Graduate Division of Nutritional and Environmental Sciences University of Shizuoka  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui\u2010Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Industrial Toxicology and Health Effects Research Group National Institute of Occupational Safety and Health  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,3]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"776","article-title":"Covalent binding of the carcinogen trichloroethylene to hepatic microsomal proteins and to exogenous DNA in vitro","volume":"38","author":"Banerjee S.","year":"1978","journal-title":"Cancer Research"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2523"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.10.854"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2003.12.074"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100466200"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gem034"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00412-009-0234-4"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.102.014845"},{"key":"e_1_2_10_10_1","unstructured":"ECHA. 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