Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J.

Journal Article (Journal Article)

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. CONCLUSION: 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.

Full Text

Duke Authors

Cited Authors

  • Duan, L; Davis, JS; Woolbright, BL; Du, K; Cahkraborty, M; Weemhoff, J; Jaeschke, H; Bourdi, M

Published Date

  • December 2016

Published In

Volume / Issue

  • 98 / Pt B

Start / End Page

  • 107 - 118

PubMed ID

  • 27773698

Pubmed Central ID

  • PMC5123947

Electronic International Standard Serial Number (EISSN)

  • 1873-6351

Digital Object Identifier (DOI)

  • 10.1016/j.fct.2016.10.021


  • eng

Conference Location

  • England