Cichocki JA, Furuya S, Konganti K, Luo YS, McDonald TJ, Iwata Y, Chiu WA, Threadgill DW, Pogribny IP, Rusyn I. Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice.
J Pharmacol Exp Ther. 2017 Apr;361(1):17-28. doi: 10.1124/jpet.116.238790. Epub 2017 Feb 1.
Joseph A Cichocki Texas A&M University College Station, TX|
Ivan Rusyn Texas A&M University College Station, TX
With: Furuya S, Konganti K, Luo Y-S, McDonald TJ, Chiu WA, Threadgill DW, Pogribny IP
|Contact||Ivan Rusyn IRusyn@cvm.tamu.edu
|Acknowledgements||Funding provided by NIH ES026005; US EPA STAR RD83561202|
|MPD identifiers||Rusyn9 MPD:596|
|No updates/corrections. Initial release date: 05/2017.|
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Purpose: The effect of nonalcoholic fatty liver disease on toxicokinetics of tetrachloroethylene (PERC) was examined in C57BL/6/J males. Mice were fed control (base diet; BD), high fat (HFD), or methionine/folate/choline-deficient (MCD) diets to model a healthy liver, steatosis, or nonalcoholic steatohepatitis, respectively. After 8 wks on the diets, mice were orally administered a single dose of PERC or vehicle and sacrificed at various time points. Levels of PERC and its oxidative and conjugative metabolites were measured in blood, liver, and fat.
Methods: See Cichocki et al., 2017 for details.
Chemicals: Tetrachloroethylene (PERC; CAS 127-18-4) was purchased from Sigma Aldrich (#270393, batch #SHBD9374V, purity 99.3%), St. Louis MO USA.
Mice: Five-week old male C57BL/6J mice were obtained from The Jackson Laboratory, Bar Harbor ME USA. Mice were housed in polycarbonate cages with Sanichip hardwood chip bedding (PJ Murphy Forest Products Corp., Montville NJ USA). Mice were acclimatized for at least one week on a standard rodent chow containing 4% calories from fat (base diet (BD); Teklad Rodent Diet #8604, Harlan, Madison WI USA). Following acclimatization, mice were randomly assigned (5 mice per cage) into groups fed a control base diet (BD), a diet containing 31% fat (high-fat diet, HFD; Diet #519567; Dyets Inc., Bethlehem PA USA), or a diet containing 31% kcal from fat depleted in methionine and devoid of choline and folate (MCD; Diet #519541; Dyets Inc., Bethlehem PA USA) to model healthy liver, steatosis, or nonalcoholic steatohepatitis (NASH), respectively.
Study design: Following 8 wks of dietary treatments as described above, mice were administered a single intragastric dose of PERC (300 mg/kg in 5% Alkamuls-EL620 in saline). Mice were euthanized at 1, 2, 4, 12, 24, or 36h after gavage. At indicated timepoints, mice were deeply anesthetized with pentobarbital (50 mg/kg, i.p.) and sacrificed via exsanguination through the vena cava, which was the site of blood collection. Tissues were excised.
Analysis of PERC, trichloroacetate (TCA), S-(1,2-trichlorovinyl)-glutathione (TCGC), S-(1,2-trichlorovinyl)-L-cysteine (TCVC), and N-Acetyl-S-(1,2-trichlorovinyl)-L-cysteine (NAcTCVC): See Cichocki et al., 2017.
Per animal data: