Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity

Hepatitis C virus (HCV) core protein is a transcriptional modifier whose expression is associated with increased levels of prooxidants in hepatocytes in vivo and in vitro. We previously reported that HCV-infected liver biopsies and core protein-expressing hepatocytes show diminished levels of heme oxygenase-1 (HO-1), which is an important oxidative defense enzyme. The objective of these studies was to test the hypothesis that the expression of core protein sensitizes hepatocytes to toxic injury and inhibits the induction of HO-1 in response to stress. The effects of core protein were tested in two different human hepatocyte cell lines, HepG2 and Huh7, which show increased prooxidative activity and cytotoxicity after treatment with heme, heavy metals, and peroxides compared to control cells. HO-1 is upregulated in response to these treatments in control cells, while the induction is attenuated in core protein-expressing cells. The effects of core protein on HO-1 expression are not accounted for by differences in HO-1 mRNA turnover or by the known effects of core protein on cellular proliferation. Collectively, these data suggest that HCV core protein may contribute to hepatocellular injury by increasing both steady-state levels of prooxidants and the susceptibility of hepatocytes to damage by impairing their response to other sources of oxidative stress.