JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 21, 2006; DOI: 10.1124/jpet.106.110247

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.106.110247v1
319/3/1191    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Deng, X.
Right arrow Articles by Roth, R. A
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Deng, X.
Right arrow Articles by Roth, R. A


Received for publication July 3, 2006.
Revised September 19, 2006.
Accepted for publication September 20, 2006.

Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacteria translocation

Xiaomin Deng 1, Robert F Stachlewitz 2, Michael J Liguori 3, Eric A.G Blomme 3, Jefferey F Waring 3, James P Luyendyk 4, Jane F Maddox 1, Patricia E Ganey 1, Robert A Roth 1*

1 Michigan State University 2 Boehringer-ingelheim Pharmaceuticals 3 Abbott Laboratories 4 Scripps Research Institute

* Address correspondence to: E-mail: rothr{at}msu.edu

Abstract

Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase (ALT) activity and liver histopathologic change 6 hours after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLF-cotreated group compared to groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large dose of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.


Key words: bacterial translocation, diclofenac, gene array, hepatotoxicity, idiosyncratic adverse drug reaction, neutrophils


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
X. Deng, M. J. Liguori, E. M. Sparkenbaugh, J. F. Waring, E. A. G. Blomme, P. E. Ganey, and R. A. Roth
Gene Expression Profiles in Livers from Diclofenac-Treated Rats Reveal Intestinal Bacteria-Dependent and -Independent Pathways Associated with Liver Injury
J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 634 - 644.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. H. Yang, Y. S. Jung, D. Y. Lee, J. H. Lee, Y. C. Kim, and M. G. Lee
Time-Dependent Effects of Klebsiella Pneumoniae Endotoxin (KPLPS) on the Pharmacokinetics of Theophylline in Rats: Return of the Parameters in 96-Hour KPLPS Rats to the Control Levels
Drug Metab. Dispos., May 1, 2008; 36(5): 811 - 815.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
P. J. Shaw, M. J. Hopfensperger, P. E. Ganey, and R. A. Roth
Lipopolysaccharide and Trovafloxacin Coexposure in Mice Causes Idiosyncrasy-Like Liver Injury Dependent on Tumor Necrosis Factor-Alpha
Toxicol. Sci., November 1, 2007; 100(1): 259 - 266.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.