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Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example

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 infl...

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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000109/
https://www.ncbi.nlm.nih.gov/pubmed/21151465
http://dx.doi.org/10.3390/ijms11114697
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author 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.
author_facet 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.
author_sort Liguori, Michael J.
collection PubMed
description 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.
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spelling pubmed-30001092010-12-10 Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example 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. Int J Mol Sci Article 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. Molecular Diversity Preservation International (MDPI) 2010-11-18 /pmc/articles/PMC3000109/ /pubmed/21151465 http://dx.doi.org/10.3390/ijms11114697 Text en © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
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.
Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title_full Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title_fullStr Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title_full_unstemmed Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title_short Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
title_sort comparison of tnfα to lipopolysaccharide as an inflammagen to characterize the idiosyncratic hepatotoxicity potential of drugs: trovafloxacin as an example
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000109/
https://www.ncbi.nlm.nih.gov/pubmed/21151465
http://dx.doi.org/10.3390/ijms11114697
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