Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene in Cytochrome P450 2E1 Knockout and Humanized Transgenic Mice.

Authors: Luo, Yu-Syuan; Furuya, Shinji; Soldatov, Valerie Y; Kosyk, Oksana; Yoo, Hong Sik; Fukushima, Hisataka; Lewis, Lauren; Iwata, Yasuhiro; Rusyn, Ivan

Published In Toxicol Sci, (2018 Aug 01)

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.

PubMed ID: 29897530 Exiting the NIEHS site

MeSH Terms: Animals; Cytochrome P-450 CYP2E1/deficiency; Cytochrome P-450 CYP2E1/genetics; Cytochrome P-450 CYP2E1/metabolism*; Cytochrome P450 Family 2/deficiency; Cytochrome P450 Family 2/genetics; Cytochrome P450 Family 2/metabolism*; Female; Glutathione/metabolism; Kidney/drug effects; Kidney/enzymology; Kidney/metabolism; Liver/drug effects; Liver/enzymology; Liver/metabolism; Male; Metabolic Networks and Pathways; Mice; Mice, Knockout; Mice, Transgenic; Tetrachloroethylene/metabolism*; Tetrachloroethylene/toxicity*; Trichloroacetic Acid/metabolism; Trichloroethylene/metabolism*; Trichloroethylene/toxicity*

Back
to Top