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      Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice.

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          Abstract

          Lifestyle factors and chronic pathologic states are important contributors to interindividual 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 euthanized 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 with 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 with 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.

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          Author and article information

          Journal
          J. Pharmacol. Exp. Ther.
          The Journal of pharmacology and experimental therapeutics
          American Society for Pharmacology & Experimental Therapeutics (ASPET)
          1521-0103
          0022-3565
          Apr 2017
          : 361
          : 1
          Affiliations
          [1 ] Department of Veterinary Integrative Biosciences (J.A.C; S.F; Y.S.L; Y.I; W.C; I.R), Texas A&M Institute for Genome Sciences and Society (K.K; D.W.T; I.R), Department of Environmental and Occupational Health (T.J.M), and Department of Molecular and Cellular Medicine (D.W.T), Texas A&M University, College Station, Texas; and National Center for Toxicological Research, US FDA, Jefferson, Arkansas (I.P).
          [2 ] Department of Veterinary Integrative Biosciences (J.A.C; S.F; Y.S.L; Y.I; W.C; I.R), Texas A&M Institute for Genome Sciences and Society (K.K; D.W.T; I.R), Department of Environmental and Occupational Health (T.J.M), and Department of Molecular and Cellular Medicine (D.W.T), Texas A&M University, College Station, Texas; and National Center for Toxicological Research, US FDA, Jefferson, Arkansas (I.P) irusyn@cvm.tamu.edu.
          Article
          jpet.116.238790
          10.1124/jpet.116.238790
          5363767
          28148637

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