Chronic hepatitis C virus (HCV)
infection predisposes patients to develop
liver failure after
acetaminophen (
APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural
proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg
body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular
necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver
glutathione levels, elevated mitochondrial oxidative stress and enhanced release of
apoptosis-inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver
glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in
glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against
APAP hepatotoxicity in these mice. These results demonstrate that while HCV
infection could exacerbate
APAP-induced liver injury due to induction and amplification of mitochondrial
oxidant stress, it could also protect against injury by activation of
APAP scavenging mechanisms.