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Comparison of TNF? to lipopolysaccharide as an inflammagen to characterize the idiosyncratic hepatotoxicity potential of drugs: Trovafloxacin as an example.

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-? (TNF?) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNF?, and hepatic transcriptomic effects were compared. TNF? showed enhanced consistency at the transcriptomic level compared to LPS. TNF? and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNF?. Rats were then codosed with TNF? and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNF?/TVX induced unique gene expression changes that clustered separately from TNF?/levofloxacin, a drug not associated with IDRs. TNF?/TVX cotreatment led to autoinduction of TNF? resulting in potentiation of underlying gene expression stress signals. Comparison of TNF?/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNF? could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs.

SUBMITTER: Liguori MJ

PROVIDER: S-EPMC3000109 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Comparison of TNFα to lipopolysaccharide as an inflammagen to characterize the idiosyncratic hepatotoxicity potential of drugs: Trovafloxacin as an example.

Liguori Michael J MJ Ditewig Amy C AC Maddox Jane F JF Luyendyk James P JP Lehman-McKeeman Lois D LD Nelson David M DM Bhaskaran Vasanthi M VM Waring Jeffrey F JF Ganey Patricia E PE Roth Robert A RA Blomme Eric A G EA

International journal of molecular sciences 20101118 11

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) t ...[more]

PMID: 21151465

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Dataset Information

Comparison of TNF? to lipopolysaccharide as an inflammagen to characterize the idiosyncratic hepatotoxicity potential of drugs: Trovafloxacin as an example.

Publications

Comparison of TNFα to lipopolysaccharide as an inflammagen to characterize the idiosyncratic hepatotoxicity potential of drugs: Trovafloxacin as an example.

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