Omics-based identification of the combined effects of idiosyncratic drugs and inflammatory cytokines on the development of drug-induced liver injury

J. Jiang*, K. Mathijs, L. Timmermans, S. M. Claessen, A. Hecka, J. Weusten, R. Peters, J. H. van Delft, J. C. S. Kleinjans, D. G. J. Jennen, T. M. de Kok

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

Abstract

The mechanisms of idiosyncratic drug-induced hepatotoxicity remain largely unclear. It has demonstrated that the drug idiosyncrasy is potentiated in the context of inflammation and intracellular ceramides may play a role in this process.

To study the mechanisms, HepG2 cells were co-treated with high and low doses of three idiosyncratic (I) and three non-idiosyncratic (N) compounds, with (I+ and N+) or without (I- and N-) a cytokine mix. Microarray, lipidomics and flow cytometry were performed to investigate the genome-wide expression patterns, the intracellular ceramide levels and the induction of apoptosis.

We found that all I + treatments significantly influenced the immune response- and response to stimulus-associated gene ontology (GO) terms, but the induction of apoptotic pathways, which was confirmed by flow cytometry, only appeared to be induced after the high-dose treatment. The ceramide signaling-, ER stress-, NF-kB activation- and mitochondrial activity-related pathways were biologically involved in apoptosis induced by the high-dose I+. Additionally, genes participating in ceramide metabolism were significantly altered resulting in a measurable increase in ceramide levels. The increases in ceramide concentrations may induce ER stress and activate the JNK pathway by affecting the expression of the related genes, and eventually trigger the mitochondria independent apoptosis in hepatocytes. Overall, our study provides a potential mechanism to explain the role of inflammation in idiosyncratic drug reactions. (C) 2017 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)100-108
Number of pages9
JournalToxicology and Applied Pharmacology
Volume332
DOIs
Publication statusPublished - 1 Oct 2017

Keywords

  • Drug-induced liver injury
  • Microarray
  • Toxicogenomics
  • Ceramide
  • ER stress
  • Apoptosis
  • NECROSIS-FACTOR-ALPHA
  • INDUCED CELL-DEATH
  • JNK ACTIVATION
  • HEPG2 CELLS
  • PROTEOMICS INVESTIGATIONS
  • INDUCED HEPATOTOXICITY
  • HUMAN HEPATOCYTES
  • PROTEIN-KINASES
  • CERAMIDE
  • APOPTOSIS

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