Precision cut intestinal slices are an appropriate ex vivo model to study NSAID-induced intestinal toxicity in rats

Xiaoyu Niu, Inge A. M. de Graaf*, Hendrik A. van der Bij, Geny M. M. Groothuis

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used therapeutic agents, however, they are associated with a high prevalence of intestinal side effects. In this investigation, rat precision cut intestinal slices (PCIS) were evaluated as an ex vivo model to study NSAID-induced intestinal toxicity. Firstly, PCIS were incubated with 0-200 μM diclofenac (DCF), one of the most intensively studied NSAIDs, to investigate whether they could correctly reflect the toxic mechanisms. DCF induced intestinal toxicity in PCIS was shown by morphological damage and ATP depletion. DCF induced endoplasmic-reticulum (ER) stress, mitochondrial injury and oxidative stress were reflected by up-regulated HSP-70 (heat shock protein 70) and BiP (binding immunoglobulin protein) gene expression, caspase 9 activation, GSH (glutathione) depletion and HO-1 (heme oxygenase 1) gene up-regulation respectively. Furthermore, DCF intestinal metabolites, which gave rise to protein adduct but not toxicity, were detected in PCIS. Secondly, PCIS were incubated with various concentrations of five NSAIDs. Typical NSAID-induced morphological changes were observed in PCIS. The ex vivo toxicity ranking (diflunisal> diclofenac = indomethacin > naproxen ≫ aspirin) showed good correlation with published in vitro and in vivo data, with diflunisal being the only exception. In conclusion, PCIS correctly reflect the various mechanisms of DCF-induced intestinal toxicity, and can serve as an ex vivo model for the prediction of NSAID-induced intestinal toxicity.

Original languageEnglish
Pages (from-to)1296-1305
Number of pages10
JournalToxicology in Vitro
Volume28
Issue number7
DOIs
Publication statusPublished - Oct-2014

Keywords

  • NSAID
  • Precision cut intestinal slices
  • Toxicity
  • Metabolism
  • Toxicity ranking
  • Diclofenac
  • NONSTEROIDAL ANTIINFLAMMATORY DRUGS
  • MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION
  • INDOMETHACIN-INDUCED APOPTOSIS
  • ENDOPLASMIC-RETICULUM STRESS
  • LIVER PROTEIN ADDUCTS
  • IN-VITRO
  • INDUCED ENTEROPATHY
  • ACYL GLUCURONIDE
  • CELL INJURY
  • MOUSE MODEL

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