https://scholars.lib.ntu.edu.tw/handle/123456789/630657
標題: | Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene in Cytochrome P450 2E1 Knockout and Humanized Transgenic Mice | 作者: | YU-SYUAN LUO Furuya, Shinji Soldatov, Valerie Y Kosyk, Oksana Yoo, Hong Sik Fukushima, Hisataka Lewis, Lauren Iwata, Yasuhiro Rusyn, Ivan |
關鍵字: | trichloroethylene; tetrachloroethylene; cytochrome P450 2E1; toxicokinetics; toxicodynamics; ACTIVATED-RECEPTOR-ALPHA; CONJUGATE BETA-LYASE; SEX-DEPENDENT REGULATION; TISSUE-SPECIFIC TOXICITY; PROXIMAL TUBULAR CELLS; PPAR-ALPHA; S-(1,2-DICHLOROVINYL)-L-CYSTEINE SULFOXIDE; REACTIVE METABOLITE; MEDIATED CLEAVAGE; MASS-SPECTROMETRY | 公開日期: | 1-八月-2018 | 出版社: | OXFORD UNIV PRESS | 卷: | 164 | 期: | 2 | 起(迄)頁: | 489 | 來源出版物: | Toxicological sciences : an official journal of the Society of Toxicology | 摘要: | Trichloroethylene (TCE) and tetrachloroethylene (PCE) are structurally similar olefins that can cause liver and kidney toxicity. Adverse effects of these chemicals are associated with metabolism to oxidative and glutathione conjugation moieties. It is thought that CYP2E1 is crucial to the oxidative metabolism of TCE and PCE, and may also play a role in formation of nephrotoxic metabolites; however, inter-species and inter-individual differences in contribution of CYP2E1 to metabolism and toxicity are not well understood. Therefore, the role of CYP2E1 in metabolism and toxic effects of TCE and PCE was investigated using male and female wild-type [129S1/SvlmJ], Cyp2e1(-/-), and humanized Cyp2e1 [hCYP2E1] mice. To fill in existing gaps in our knowledge, we conducted a toxicokinetic study of TCE (600 mg/kg, single dose, i.g.) and a subacute study of PCE (500 mg/kg/day, 5 days, i.g.) in 3 strains. Liver and kidney tissues were subject to profiling of oxidative and glutathione conjugation metabolites of TCE and PCE, as well as toxicity endpoints. The amounts of trichloroacetic acid formed in the liver was hCYP2E1≈ 129S1/SvlmJ > Cyp2e1(-/-) for both TCE and PCE; levels in males were about 2-fold higher than in females. Interestingly, 2- to 3-fold higher levels of conjugation metabolites were observed in TCE-treated Cyp2e1(-/-) mice. PCE induced lipid accumulation only in liver of 129S1/SvlmJ mice. In the kidney, PCE exposure resulted in acute proximal tubule injury in both sexes in all strains (hCYP2E1 ≈ 129S1/SvlmJ > Cyp2e1(-/-)). In conclusion, our results demonstrate that CYP2E1 is an important, but not exclusive actor in the oxidative metabolism and toxicity of TCE and PCE. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/630657 | ISSN: | 1096-6080 | DOI: | 10.1093/toxsci/kfy099 |
顯示於: | 食品安全與健康研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。