Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

Rachel P. L. van Swelm, Mackenzie Hadi, Coby M. M. Laarakkers, Rosalinde Masereeuw, Geny M. M. Groothuis, Frans G. M. Russel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker identification, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. PCLS were incubated with acetaminophen (APAP), 3-acetamidophenol, diclofenac and lipopolysaccharide for 24-48 h. PCLS medium from all species treated with APAP demonstrated similar changes in protein profiles, as previously found in mouse urine after APAP-induced liver injury, including the same key proteins: superoxide dismutase 1, carbonic anhydrase 3 and calmodulin. Further analysis showed that the concentration of hepcidin, a hepatic iron-regulating hormone peptide, was reduced in PCLS medium after APAP treatment, resembling the decreased mouse plasma concentrations of hepcidin observed after APAP treatment. Interestingly, comparable results were obtained after 3-acetamidophenol incubation in rat and human, but not mouse PCLS. Incubation with diclofenac, but not with lipopolysaccharide, resulted in the same toxicity parameters as observed for APAP, albeit to a lesser extent. In conclusion, proteomics can be applied to identify potential translational biomarkers using the PCLS system. Copyright (C) 2013 John Wiley & Sons, Ltd.

Original languageEnglish
Pages (from-to)993-1001
Number of pages9
JournalJournal of Applied Toxicology
Volume34
Issue number9
DOIs
Publication statusPublished - Sep-2014

Keywords

  • Precision-cut liver slices
  • drug-induced liver injury
  • hepcidin
  • proteomics profiling
  • acetaminophen
  • diclofenac
  • CARBONIC-ANHYDRASE-III
  • MASS-SPECTROMETRY
  • ACETAMINOPHEN
  • ACTIVATION
  • EXPRESSION
  • TOXICITY
  • CELLS
  • MODEL
  • HEPATOCYTE
  • PEROXIREDOXINS

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