Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1782193506308063232 |
---|---|
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. |
format | Text |
id | pubmed-3000109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Molecular Diversity Preservation International (MDPI) |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT liguorimichaelj comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT ditewigamyc comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT maddoxjanef comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT luyendykjamesp comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT lehmanmckeemanloisd comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT nelsondavidm comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT bhaskaranvasanthim comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT waringjeffreyf comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT ganeypatriciae comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT rothroberta comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample AT blommeericag comparisonoftnfatolipopolysaccharideasaninflammagentocharacterizetheidiosyncratichepatotoxicitypotentialofdrugstrovafloxacinasanexample |