This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Substantial evidence suggests that oxidative stress plays an important role in the severity and progression of hepatitis C virus (HCV)-induced hepatic injury. That HCV itself causes oxidative stress is supported by its association with porphyria cutanea tarda (PCT), a model disorder of hepatic oxidative stress. Hepatic cytochromes P450 are likely to play an important role in determining the overall amount of hepatic oxidative stress. These enzymes are responsible for oxidative metabolism of endogenous and exogenous substrates, and there is a wide inter-individual variability in their activities. Interferon-alpha, widely used as therapy for HCV, is known to down-regulate P450s, which might explain part of its beneficial effects. These findings suggest that hepatic P450s might modulate injury from oxidative stress in HCV-infected individuals. This proposal will investigate the typothesis that increased activities of specific P450 isoforms (in particular CYPs 1A2, 2E1, and/or 3A4) contribute to hepatic injury via an oxidative mechanism in HCV infected patients. Patients with mild, moderate, and severe histologic activity and matched controls will be using the drug probes theophylline (CYP1A2), chlorzoxazone (CYP2E1), and midazolam (CYP3A4). Assessments of oxidative stress (urinary F2-isoprostanes, monocyte NFkB) and active fibrinogenesis (TGFb1, N-terminal procollagen peptide III) will be correlated with changes in oxidative stress and changes in P450 profiles. These studies will help define a potentially important role of P450s in enhancing HCV liver injury and might suggest P450 inhibitors as inexpensive therapies for HCV infected individuals.
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