Acetaminophen-induced acute liver injury in HCV transgenic mice.
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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 24h 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.
author list (cited authors)
Uehara, T., Kosyk, O., Jeannot, E., Bradford, B. U., Tech, K., Macdonald, J. M., ... Rusyn, I.
complete list of authors
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