title: Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J.
abstract: Mouse models of acetaminophen (APAP) hepatotoxicity are considered relevant for the human pathophysiology. The C57BL/6 strain is most popular because it is the background strain of gene knock-out mice. However, conflicting results in the literature may have been caused by sub-strain mismatches, e.g. C57BL/6J and C57BL/6N. This study was initiated to determine the mechanism behind the sub-strain susceptibility to APAP toxicity. C57BL/6N and C57BL/6J mice were dosed with 200 mg/kg APAP and sacrificed at different time points. C57BL/6N mice developed significantly more liver injury as measured by plasma ALT activities and histology. Although there was no difference in glutathione depletion or cytochrome P450 activity between groups, C57BL/6N had a higher glutathione disulfide-to-glutathione ratio and more APAP protein adducts. C57BL/6N showed more mitochondrial translocation of phospho-JNK and BAX, and more release of mitochondrial intermembrane proteins apoptosis-inducing factor (AIF), second mitochondria-derived activator of caspases (SMAC), which caused more DNA fragmentation. The increased mitochondrial dysfunction was confirmed in vitro as C57BL/6N hepatocytes had a more precipitous drop in JC-1 fluorescence after APAP exposure.
  
  
  CONCLUSIONS
  C57BL/6N mice are more susceptible to APAP-induced hepatotoxicity, likely due to increased formation of APAP-protein adducts and a subsequent enhancement of mitochondrial dysfunction associated with aggravated nuclear DNA fragmentation.
authors: Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, 66160, USA. Electronic address: lduan@kumc.edu.
authors: Luqi
authors: L
authors: Duan
authors: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20850, USA. Electronic address: John.Davis@nih.gov.
authors: John S
authors: JS
authors: Davis
authors: Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, 66160, USA. Electronic address: bwoolbright@kmc.edu.
authors: Benjamin L
authors: BL
authors: Woolbright
authors: Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, 66160, USA. Electronic address: kdu@kumc.edu.
authors: Kuo
authors: K
authors: Du
authors: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20850, USA. Electronic address: mala.cahkraborty@nih.gov.
authors: Mala
authors: M
authors: Cahkraborty
authors: Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, 66160, USA. Electronic address: jweemhoff@kumc.edu.
authors: James
authors: J
authors: Weemhoff
authors: Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, 66160, USA. Electronic address: hjaeschke@kumc.edu.
authors: Hartmut
authors: H
authors: Jaeschke
authors: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20850, USA. Electronic address: mohammed.bourdi@nih.gov.
authors: Mohammed
authors: M
authors: Bourdi
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D004198:Disease Susceptibility; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000082:Acetaminophen; D005978:Glutathione
keywords: Acetaminophen hepatotoxicity; C57BL/6 sub-strains; DNA fragmentation; Mitochondrial dysfunction; Protein adducts