title: Acetaminophen-induced acute liver injury in HCV transgenic mice.
abstract: 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.
authors.affiliation: Department of Environmental Sciences & Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jeannot
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Katherine
authors.initials: K
authors.lastname: Tech
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Macdonald
authors.forename: Gary A
authors.initials: GA
authors.lastname: Boorman
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.forename: Stepan B
authors.initials: SB
authors.lastname: Melnyk
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Tryndyak
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D006526:Hepatitis C / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen