title: Precision cut intestinal slices are an appropriate ex vivo model to study NSAID-induced intestinal toxicity in rats.
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.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Niu
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: i.a.m.de.graaf@rug.nl.
authors.forename: Inge A M
authors.initials: IA
authors.lastname: de Graaf
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Hendrik A
authors.initials: HA
authors.lastname: van der Bij
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Geny M M
authors.initials: GM
authors.lastname: Groothuis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001241:Aspirin / Q000633:toxicity; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004008:Diclofenac / Q000633:toxicity; D004061:Diflunisal / Q000633:toxicity; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D007213:Indomethacin / Q000633:toxicity; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009288:Naproxen / Q000633:toxicity; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000255:Adenosine Triphosphate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D053453:Caspase 9; D004008:Diclofenac; D004061:Diflunisal; D005978:Glutathione; D006360:Heat-Shock Proteins; D006419:Heme Oxygenase (Decyclizing); D007213:Indomethacin; D009288:Naproxen; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C491523:Hmox1 protein, rat; C506435:Casp9 protein, rat
keywords: Diclofenac; Metabolism; NSAID; Precision cut intestinal slices; Toxicity; Toxicity ranking