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

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 C_max 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.

SUBMITTER: Cichocki JA

PROVIDER: S-EPMC5363767 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Cichocki Joseph A JA Furuya Shinji S Konganti Kranti K Luo Yu-Syuan YS Luo Yu-Syuan YS McDonald Thomas J TJ Iwata Yasuhiro Y Chiu Weihsueh A WA Threadgill David W DW Pogribny Igor P IP Rusyn Ivan I

The Journal of pharmacology and experimental therapeutics 20170201 1

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) wer ...[more]

PMID: 28148637

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Project description:Accounting for genetic and other (eg, underlying disease states) factors that may lead to inter-individual variability in susceptibility to xenobiotic-induced injury is a challenge in human health assessments. A previous study demonstrated that nonalcoholic fatty liver disease (NAFLD), one of the common underlying disease states, enhances tetrachloroethylene (PERC)-associated hepatotoxicity in mice. Interestingly, NAFLD resulted in a decrease in metabolism of PERC to nephrotoxic glutathione conjugates; we therefore hypothesized that NAFLD would protect against PERC-associated nephrotoxicity. Male C57BL/6J mice were fed a low-fat (LFD), high-fat (31% fat, HFD), or high-fat methionine/choline/folate-deficient (31% fat, MCD) diets. After 8 weeks mice were administered either a single dose of PERC (300 mg/kg i.g.) and euthanized at 1-36 h post dose, or five daily doses of PERC (300 mg/kg/d i.g.) and euthanized 4 h after last dose. Relative to LFD-fed mice, HFD- or MCD-fed mice exhibited decreased PERC concentrations and increased trichloroacetate (TCA) in kidneys. S-(1,2,2-trichlorovinyl)glutathione (TCVG), S-(1,2,2-trichlorovinyl)-l-cysteine (TCVC), and N-acetyl-S-(1,2,2,-trichlorovinyl)-l-cysteine (NAcTCVC) were also significantly lower in kidney and urine of HFD- or MCD-fed mice compared with LFD-fed mice. Despite differences in levels of nephrotoxic PERC metabolites in kidney, LFD- and MCD-fed mice demonstrated similar degree of nephrotoxicity. However, HFD-fed mice were less sensitive to PERC-induced nephrotoxicity. Thus, whereas both MCD- and HFD-induced fatty liver reduced the delivered dose of nephrotoxic PERC metabolites to the kidney, only HFD was protective against PERC-induced nephrotoxicity, possibly due to greater toxicodynamic sensitivity induced by methyl and choline deficiency. These results therefore demonstrate that pre-existing disease conditions can lead to a complex interplay of toxicokinetic and toxicodynamic changes that modulate susceptibility to the toxicity of xenobiotics.

Dataset Information

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

Publications

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

Similar Datasets

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