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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene

Joseph A Cichocki, Shinji Furuya, Kranti Konganti, Yu-Syuan Luo, Thomas J McDonald, Yasuhiro Iwata, Weihsueh A Chiu, David W Threadgill, Igor P Pogribny and Ivan Rusyn
Journal of Pharmacology and Experimental Therapeutics February 1, 2017, jpet.116.238790; DOI: https://doi.org/10.1124/jpet.116.238790
Joseph A Cichocki
1 Texas A&M University;
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Shinji Furuya
1 Texas A&M University;
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Kranti Konganti
1 Texas A&M University;
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Yu-Syuan Luo
1 Texas A&M University;
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Thomas J McDonald
1 Texas A&M University;
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Yasuhiro Iwata
1 Texas A&M University;
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Weihsueh A Chiu
1 Texas A&M University;
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David W Threadgill
1 Texas A&M University;
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Igor P Pogribny
2 National Center for Toxicological Research
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Ivan Rusyn
1 Texas A&M University;
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Abstract

Lifestyle factors and chronic pathological states are important contributors to inter-individual variability in susceptibility to xenobiotic-induced toxicity. Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that can dramatically affect chemical metabolism. We examined the effect of NAFLD on toxicokinetics of tetrachloroethylene (PERC), a ubiquitous environmental contaminant that requires metabolic activation to induce adverse health effects. Mice (C57Bl/6J, male) were fed a low-fat diet (LFD), high fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, steatosis, or nonalcoholic steatohepatitis (NASH), respectively. After 8 weeks, mice were orally administered a single dose of PERC (300 mg/kg) or vehicle (aqueous Alkamuls-EL620) and sacrificed at various time points (1-36 hours). Levels of PERC and its metabolites were measured in blood/serum, liver, and fat. Effects of diets on liver gene expression and tissue:air partition coefficients were evaluated. We found that hepatic levels of PERC were 6- and 7.6-fold higher in HFD- and MCD-fed mice compared to LFD-fed mice; this was associated with an increased PERC liver:blood partition coefficient. Liver and serum Cmax for trichloroacetate (TCA) was lower in MCD-fed mice, however hepatic clearance of TCA was profoundly reduced by HFD or MCD feeding, leading to TCA accumulation. Hepatic mRNA/protein expression and ex vivo activity assays revealed decreased xenobiotic metabolism in HFD- and MCD-, compared to LFD-fed, groups. In conclusion, experimental NAFLD was associated with modulation of xenobiotic disposition and metabolism, and increased hepatic exposure to PERC and TCA. Underlying NAFLD may be an important susceptibility factor for PERC-associated hepatotoxicity.

  • liver disease
  • toxicokinetics
  • toxicology
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene

Joseph A Cichocki, Shinji Furuya, Kranti Konganti, Yu-Syuan Luo, Thomas J McDonald, Yasuhiro Iwata, Weihsueh A Chiu, David W Threadgill, Igor P Pogribny and Ivan Rusyn
Journal of Pharmacology and Experimental Therapeutics February 1, 2017, jpet.116.238790; DOI: https://doi.org/10.1124/jpet.116.238790

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene

Joseph A Cichocki, Shinji Furuya, Kranti Konganti, Yu-Syuan Luo, Thomas J McDonald, Yasuhiro Iwata, Weihsueh A Chiu, David W Threadgill, Igor P Pogribny and Ivan Rusyn
Journal of Pharmacology and Experimental Therapeutics February 1, 2017, jpet.116.238790; DOI: https://doi.org/10.1124/jpet.116.238790
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