Acetaminophen-induced acute liver injury in HCV transgenic mice

作者：Uehara Takeki; Kosyk Oksana; Jeannot Emmanuelle; Bradford Blair U; Tech Katherine; Macdonald Jeffrey M; Boorman Gary A; Chatterjee Saurabh; Mason Ronald P; Melnyk Stepan B; Tryndyak Volodymyr P; Pogribny Igor P; Rusyn Ivan^*

来源：Toxicology and Applied Pharmacology, 2013, 266(2): 224-232.

DOI：10.1016/j.taap.2012.11.019

• Hepatitis C virus
• Acetaminophen
• Liver
• Mouse
• Mitochondria
• Oxidative stress

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility.

• 出版日期2013-1-15