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. 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.

C57BL/6 Substrains Exhibit Different Responses to Acute Carbon Tetrachloride Exposure: Implications for Work Involving Transgenic Mice

“…Similarly, mice deficient in mitochondrial superoxide dismutase ( Sod2−/− ) exhibit enhanced tissue damage and increased lethality shortly after birth when they are on an Nnt mutant background compared to Sod2−/− mice on an Nnt wild-type background 5 . In contrast to what is observed after APAP overdose 17,53 or after CCl 4 in the present study, these studies show that a mutant Nnt leads to increased sensitivity to oxidative stress.…”

Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

“…We found that C57BL/6 mice from TAC are more susceptible to APAP-induced hepatotoxicity than those from JAX. Similar results were previously reported (47,48) although the underlying mechanisms remained unknown. Genetic drifts between C57BL/6 mice from JAX and TAC have been reported (37), including the deletion mutation in nicotinamide nucleotide transhydrogenase (Nnt) in JAX mice.…”

Early Detection of Acute Drug-Induced Liver Injury in Mice by Noninvasive Near-Infrared Fluorescence Imaging

“…C57BL/6 mice induced with APAP were fasted overnight (approximately 18 hours) prior to drug administration. For this particular treatment, the use of C57BL/6 mice was essential, as well as the use of males; female C57BL/6 mice and mice of other strains show low liver toxicity under the conditions explored in this research (Duan et al, 2016). For all other treatments, male BALB/c mice were used.…”

“…Acute overdoses are well known to cause rapid, potentially fatal, hepatocellular injury, which is the leading cause of acute liver failure in the Western world due to either deliberate overdose, accidental overdose, or other risk factors with therapeutic dosing (Maddox et al, 2010; Ging et al, 2016; Yoon et al, 2016). This drug induces marked hepatocellular toxicity in C57BL/6 mice with significant variations between mouse strains (McGill et al, 2012; Duan et al, 2016). …”