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Title: Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide

Abstract

Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferasemore » and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure.« less

Authors:
 [1];  [2];  [3];  [4];  [4];  [5];  [6];  [2];  [3];  [3];  [7]
  1. Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States). E-mail: maddox@msu.edu
  2. Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States)
  3. Investigative Toxicology, Pharmacia Corporation, Kalamazoo, MI 49001 (United States)
  4. Pharmacia Corporation, Skokie, IL 60077 (United States)
  5. HTS Metabolic Profiling, Pharmacia Corporation, Chesterfield, MO 63198 (United States)
  6. School of Chemistry, The University of Manchester, Manchester, England, UK (United Kingdom)
  7. Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824 (United States). E-mail: rothr@msu.edu
Publication Date:
OSTI Identifier:
20783451
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 212; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2005.06.021; PII: S0041-008X(05)00384-4; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; BLOOD; DRUGS; HISTAMINE; INFLAMMATION; INJURIES; LIVER; MASS SPECTROSCOPY; NUCLEAR MAGNETIC RESONANCE; RATS; RECEPTORS; TOXICITY; URINE

Citation Formats

Maddox, Jane F., Luyendyk, James P., Cosma, Gregory N., Breau, Alan P., Bible, Roy H., Harrigan, George G., Goodacre, Royston, Ganey, Patricia E., Cantor, Glenn H., Cockerell, Gary L., and Roth, Robert A.. Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.06.021.
Maddox, Jane F., Luyendyk, James P., Cosma, Gregory N., Breau, Alan P., Bible, Roy H., Harrigan, George G., Goodacre, Royston, Ganey, Patricia E., Cantor, Glenn H., Cockerell, Gary L., & Roth, Robert A.. Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide. United States. doi:10.1016/j.taap.2005.06.021.
Maddox, Jane F., Luyendyk, James P., Cosma, Gregory N., Breau, Alan P., Bible, Roy H., Harrigan, George G., Goodacre, Royston, Ganey, Patricia E., Cantor, Glenn H., Cockerell, Gary L., and Roth, Robert A.. 2006. "Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide". United States. doi:10.1016/j.taap.2005.06.021.
@article{osti_20783451,
title = {Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide},
author = {Maddox, Jane F. and Luyendyk, James P. and Cosma, Gregory N. and Breau, Alan P. and Bible, Roy H. and Harrigan, George G. and Goodacre, Royston and Ganey, Patricia E. and Cantor, Glenn H. and Cockerell, Gary L. and Roth, Robert A.},
abstractNote = {Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferase and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure.},
doi = {10.1016/j.taap.2005.06.021},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 212,
place = {United States},
year = 2006,
month = 4
}
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