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.
- Received November 8, 2016.
- Accepted January 30, 2017.
J.A.C. was a recipient of a National Research Service Award through the National Institutes of Health National Institute of Environmental Health Sciences [Grant F32 ES026005]. This work was supported, in part, by a cooperative agreement STAR [RD83561202] from U.S. EPA to Texas A&M University. The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the NIH, the U.S. EPA, or the U.S. Food and Drug Administration.
Part of this work was presented at the following meeting: Cichocki JA, Furuya S, Konganti K, Luo YS, McDonald TJ, Iwata Y, Chiu WA, Threadgill DW, Pogribny IP, Rusyn I (2016) Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene in mice. Lone Star Chapter of the Society of Toxicology Annual Meeting; 2016 Oct 21-22; Waco, TX.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics