Overexpression of CYP2E1 and Alcohol Liver Disease

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by applicant): CYP2E1 activate many hepatotoxins and is induced under a variety of physiological and pathophysiological conditions, hence, studies on the biochemical and toxicological properties of CYP2E1 are important. Induction of CYP2E1 by ethanol is believed to be 1 of the central pathways by which ethanol generates a state of oxidative stress and causes hepatotoxicity. However, some studies recently have suggested that CYP2E1 may not play a role in alcohol liver injury based upon studies with gadolinium chloride or CYP2E1 knockout mice. Therefore, further studies are necessary to resolve the discrepancies over the role of CYP2E1 in alcohol-induced liver injury. In order to evaluate the biochemical and toxicological actions of CYP2E1 and its role in alcohol liver injury, an adenovirus which can mediate overexpression of CYP2E1 was constructed in our laboratory. This virus could express catalytic CYP2E1 in HepG2 cells, and it increased the sensitivity to acetaminophen induced toxicity in HepG2 cells. By injecting this virus into mice, we found that CYP2E1 protein and activity were elevated in the liver of the mice, and preliminary studies showed that it induced liver toxicity. The overall goal of this application is to focus on the use of this adenovirus mediated CYP2E1 expression model to evaluate the biochemical and toxicological properties of CYP2E1 and its role in the liver injury induced by alcohol administration. Studies will be carried out to evaluate molecular and cellular mechanisms responsible for the liver toxicity induced by ethanol which relates to CYP2E1. We hope this study could make a significant contribution to the prevention and therapy for alcohol liver disease, benefiting millions of such patients worldwide.