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

Michael J. Liguori²  Amy C. Ditewig²  Jane F. Maddox¹  James P. Luyendyk¹  Lois D. Lehman-McKeeman³  David M. Nelson⁴  Vasanthi M. Bhaskaran³  Jeffrey F. Waring²  Patricia E. Ganey¹  Robert A. Roth¹ 

[1] Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University; East Lansing, MI 48824, USA; E-Mails:;Department of Cellular, Molecular, & Exploratory Toxicology, Abbott Laboratories; Abbott Park, IL 60064, USA; E-Mails:;Discovery Toxicology, Bristol-Myers Squibb; Princeton, NJ 08540, USA; E-Mail:;The Beatson Institute for Cancer Research, Glasgow, UK; E-Mail:

关键词: idiosyncratic hepatotoxicity;    liver;    inflammation;    rat;    transcriptomics;   

DOI  :  10.3390/ijms11114697

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.