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ToxSci Advance Access originally published online on August 19, 2007
Toxicological Sciences 2007 100(1):259-266; doi:10.1093/toxsci/kfm218
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Lipopolysaccharide and Trovafloxacin Coexposure in Mice Causes Idiosyncrasy-Like Liver Injury Dependent on Tumor Necrosis Factor-Alpha

Patrick J. Shaw, Marie J. Hopfensperger, Patricia E. Ganey and Robert A. Roth1

Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824

1 To whom the correspondence should be addressed at the Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, 221, Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824. Fax: (517) 432-2310. E-mail: rothr{at}msu.edu.

Received May 22, 2007; accepted July 20, 2007


  Abstract

Idiosyncratic adverse drug reactions (IADRs) occur in a small subset of patients, are unrelated to the pharmacological action of the drug, and occur without an obvious relationship to dose or duration of drug exposure. The liver is often the target of these reactions. Why they occur is unknown. One possibility is that episodic inflammatory stress interacts with the drug to precipitate a toxic response. We set out to determine if lipopolysaccharide (LPS) renders mice sensitive to trovafloxacin (TVX), a fluoroquinolone antibiotic linked to idiosyncratic hepatotoxicity in humans and if the cytokine tumor necrosis factor-{alpha} (TNF{alpha}) is involved in the development of liver injury. Male mice were treated with a nontoxic dose of TVX followed 3 h later by a nonhepatotoxic dose of LPS. Coexposure to TVX and LPS led to a significant increase in liver injury as determined by plasma alanine aminotransferase activity and histopathological examination. In contrast, coexposure of mice to LPS and levofloxacin (LVX), a fluoroquinolone without liability for causing IADRs in humans, was not hepatotoxic. Measurements of TNF{alpha} concentration in the plasma revealed a significant, selective increase in TVX/LPS-treated mice at times prior to and at the onset of liver injury. Treatment with either pentoxifylline to inhibit TNF{alpha} transcription or etanercept to inhibit TNF{alpha} activity significantly reduced TVX/LPS-induced liver injury. The results suggest that the model in mice is able to distinguish between drugs with and without the propensity to cause idiosyncratic liver injury and that the hepatotoxicity is dependent on TNF{alpha}.

Key Words: trovafloxacin; inflammation; liver toxicology; adverse drug reactions; cytokines; mechanisms of systems toxicology; idiosyncratic reactions.


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