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Biomarkers for the Assessment of Acetaminophen Induced Liver Injury

Systems Toxicology

Metabolomic Technology

  1. Wimal Pathmasiri1,
  2. Rodney W. Snyder1,
  3. Jason P. Burgess1,
  4. James A. Popp2,
  5. Timothy R. Fennell1,
  6. Susan J. Sumner1

Published Online: 15 SEP 2011

DOI: 10.1002/9780470744307.gat219

General, Applied and Systems Toxicology

General, Applied and Systems Toxicology

How to Cite

Pathmasiri, W., Snyder, R. W., Burgess, J. P., Popp, J. A., Fennell, T. R. and Sumner, S. J. 2011. Biomarkers for the Assessment of Acetaminophen Induced Liver Injury. General, Applied and Systems Toxicology. .

Author Information

  1. 1

    Discovery and Analytical Sciences, RTI International, Research Triangle Park, NC, USA

  2. 2

    Stratoxon LLC, Lancaster, PA, USA

Publication History

  1. Published Online: 15 SEP 2011

Abstract

This chapter summarizes a selection of literature regarding the development of biomarkers of acetaminophen (APAP)–induced liver injury (AILI), and provides new data related to the use of metabolomics for the development of a noninvasive marker profile for AILI. Our research investigation used male rats dosed daily with APAP at 0, 10, or 1500 per kg per day for up to 9 days. Urine, blood, and liver were obtained following a day and nine. Metabolomics of urine and extracts of liver showed separation of groups based on dose and duration of dose. Serum transaminases were evaluated. Histopathological analysis revealed complex pathological incidences for three lobes of the liver (left, right, and median), where centrilobular hypertrophy, centrilobular necrosis, and centrilobular inflammation were prominent in all lobes. Subsets of metabolites were identified that correlated with presence of AILI, even in cases were clinically relevant serum enzymes were not consistently correlated with pathology findings. Metabolite changes consistent with the presence of liver damage correlated with interruptions in amino acid, histidine, purine and pyrimidine, and glutamate metabolism. This study reveals markers that could find pre-clinical and clinical use, and provides insights into mechanisms involved in AILI.

Keywords:

  • acetaminophen;
  • APAP;
  • liver injury;
  • NMR;
  • metabolomics