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Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
Department of Cellular, Molecular, & Exploratory Toxicology, Abbott Laboratories, IL 60064, USA
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, University; East Lansing, MI 48824, USA
Discovery Toxicology, Bristol-Myers Squibb; Princeton, NJ 08540, USA
The Beatson Institute for Cancer Research, Glasgow, UK
Current address: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, MS-1018, Kansas City, KS 66160, USA.
* Author to whom correspondence should be addressed.
Received: 12 September 2010; in revised form: 22 October 2010 / Accepted: 15 November 2010 / Published: 18 November 2010
Abstract: Idiosyncratic drug reactions (IDRs) are poorly understood, unpredictable, and not detected in preclinical studies. Although the cause of these reactions is likely multi-factorial, one hypothesis is that an underlying inflammatory state lowers the tolerance to a xenobiotic. Previously used in an inflammation IDR model, bacterial lipopolysaccharide (LPS) is heterogeneous in nature, making development of standardized testing protocols difficult. Here, the use of rat tumor necrosis factor-α (TNFα) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNFα, and hepatic transcriptomic effects were compared. TNFα showed enhanced consistency at the transcriptomic level compared to LPS. TNFα and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNFα. Rats were then codosed with TNFα and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNFα/TVX induced unique gene expression changes that clustered separately from TNFα/levofloxacin, a drug not associated with IDRs. TNFα/TVX cotreatment led to autoinduction of TNFα resulting in potentiation of underlying gene expression stress signals. Comparison of TNFα/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNFα could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs.
Keywords: idiosyncratic hepatotoxicity; liver; inflammation; rat; transcriptomics
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Liguori, M.J.; Ditewig, A.C.; Maddox, J.F.; Luyendyk, J.P.; Lehman-McKeeman, L.D.; Nelson, D.M.; Bhaskaran, V.M.; Waring, J.F.; Ganey, P.E.; Roth, R.A.; Blomme, E.A.G. Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example. Int. J. Mol. Sci. 2010, 11, 4697-4714.
Liguori MJ, Ditewig AC, Maddox JF, Luyendyk JP, Lehman-McKeeman LD, Nelson DM, Bhaskaran VM, Waring JF, Ganey PE, Roth RA, Blomme EAG. Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example. International Journal of Molecular Sciences. 2010; 11(11):4697-4714.
Liguori, Michael J.; Ditewig, Amy C.; Maddox, Jane F.; Luyendyk, James P.; Lehman-McKeeman, Lois D.; Nelson, David M.; Bhaskaran, Vasanthi M.; Waring, Jeffrey F.; Ganey, Patricia E.; Roth, Robert A.; Blomme, Eric A. G. 2010. "Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example." Int. J. Mol. Sci. 11, no. 11: 4697-4714.