ToxSci Advance Access originally published online on October 16, 2008
Toxicological Sciences 2009 107(1):270-280; 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
* Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
Department of Cell and Molecular Toxicology, Abbott Laboratories, Abbott Park, Illinois 60064
1 To whom correspondence should be addressed at 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 432-2310. E-mail: rothr{at}msu.edu.
Received July 16, 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 probe sets expressed differently in TVX/LPS–treated mice were involved in interferon (IFN) signaling and the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. A time course of plasma concentrations of IFN-
and interleukin (IL)-18, which directly induces 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 tumor necrosis factor-
, IL-18, and IL-1β when compared to wild-type mice. In conclusion, the altered expression of genes involved in IFN 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.
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