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ToxSci Advance Access published online on March 20, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj165
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 18, 2006
Accepted March 13, 2006

Genetic Toxicology

Adenovirus-Mediated Expression of CYP2E1 Produces Liver Toxicity in Mice

Jingxiang Bai 1 * and Arthur I Cederbaum 1

1 Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029

* To whom correspondence should be addressed.
Jingxiang Bai, E-mail: Jingxiang.Bai{at}mssm.edu


  Abstract

Induction of cytochrome P450 2E1 by ethanol is believed to be one of the central pathways by which ethanol generates a state of oxidative stress and causes hepatotoxicity. In order to evaluate the biochemical and toxicological actions of CYP2E1 and its sensitization of hepatotoxin-induced injury, an adenovirus which can mediate overexpression of CYP2E1 was constructed. Injecting this virus into mice through the tail vein elevated CYP2E1 protein and activity 2 fold in the liver of the mice compared with the mice injected with Ad-LacZ or saline. Transaminase levels were dramatically increased in mice injected with the CYP2E1 adenovirus. Histological evaluation of liver specimens of mice injected with Ad-2E1 showed liver cell injury. TUNEL assay demonstrated that more cells were stained positively in the liver of the mice infected with Ad-2E1 than in the liver of the mice infected with Ad-LacZ. 3-Nitrotyrosine protein adducts and protein carbonyl adducts were increased in the liver of the mice infected with Ad-2E1 compared with Ad-LacZ. This potentiated toxicity most likely reflects interactions between CYP2E1-and adenovirus-mediated toxicity pathways. These results show that adenovirus mediated overexpression of CYP2E1 could induce liver toxicity in mice, and suggests a mechanism involving oxidative / nitrosative stress.

Keywords: Adenovirus; CYP2E1; Liver toxicity; Oxidative stress.
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