PT  - JOURNAL ARTICLE
AU  - Joseph A Cichocki
AU  - Shinji Furuya
AU  - Kranti Konganti
AU  - Yu-Syuan Luo
AU  - Thomas J McDonald
AU  - Yasuhiro Iwata
AU  - Weihsueh A Chiu
AU  - David W Threadgill
AU  - Igor P Pogribny
AU  - Ivan Rusyn
TI  - Impact of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene
AID  - 10.1124/jpet.116.238790
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.116.238790
4099  - http://jpet.aspetjournals.org/content/early/2017/02/01/jpet.116.238790.short
4100  - http://jpet.aspetjournals.org/content/early/2017/02/01/jpet.116.238790.full
AB  - 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.