Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene in Cytochrome P450 2E1 Knockout and Humanized Transgenic Mice
Journal
Toxicological sciences : an official journal of the Society of Toxicology
Journal Volume
164
Journal Issue
2
Pages
489
Date Issued
2018-08-01
Author(s)
Furuya, Shinji
Soldatov, Valerie Y
Kosyk, Oksana
Yoo, Hong Sik
Fukushima, Hisataka
Lewis, Lauren
Iwata, Yasuhiro
Rusyn, Ivan
Abstract
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.
Subjects
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
Publisher
OXFORD UNIV PRESS
Type
journal article