ToxSci Advance Access published online on October 16, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn205
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Coexposure of mice to trovafloxacin and lipopolysaccharide, a model of idiosyncratic hepatotoxicity, results in a unique gene expression profile and interferon gamma-dependent liver injury
1 Department of Pharmacology & Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA 2 Department of Cell and Molecular Toxicology, Abbott Laboratories, Abbott Park, IL, USA
Corresponding Author: Dr. Robert Roth, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824, Phone: (517) 353-9841, Fax: (517) 432-2310.
Received July 16, 2008; revision received September 12, 2008; accepted September 23, 2008
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Abstract |
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The antibiotic trovafloxacin (TVX) has caused severe idiosyncratic hepatotoxicity in people, whereas levofloxacin (LVX) has not. Mice cotreated with TVX and lipopolysaccharide (LPS), but not with LVX and LPS, develop severe hepatocellular necrosis. Mice were treated with TVX and/or LPS, and hepatic gene expression changes were measured before liver injury using gene array. Hepatic gene expression profiles from mice treated with TVX/LPS clustered differently from those treated with LPS or TVX alone. Several of the probesets expressed differently in TVX/LPS-treated mice were involved in interferon signaling and the JAK/STAT pathway. A timecourse of plasma concentrations of interferon gamma (IFN
) and interleukin-18 (IL-18), which directly induced IFN production, revealed that both cytokines were selectively increased in TVX/LPS-treated mice. Both IL-18-/- and IFN-/- mice were significantly protected from TVX/LPS-induced liver injury. In addition, IFN-/- mice had decreased plasma concentrations of TNF
, IL-18 and IL-1β when compared to wild-type mice. In conclusion, the altered expression of genes involved in type II interferon signaling in TVX/LPS-treated mice led to the finding that IL-18 and IFN play a critical role in TVX/LPS-induced liver injury.
Key Words: trovafloxacin; inflammation; hepatotoxicity; idiosyncratic toxicity; liver injury; interferon gamma.
shawpatr{at}msu.edu, amy.ditewig{at}abbott.com, jeff.waring{at}abbott.com, Michael.liguori{at}abbott.com, eric.blomme{at}abbott.com, ganey{at}msu.edu, rothr{at}msu.edu
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