Titre
Differential involvement of mitochondrial dysfunction, cytochrome P450 activity, and active transport in the toxicity of structurally related NSAIDs.
Type
article
Institution
Externe
Périodique
Auteur(s)
van Leeuwen, J.S.
Auteure/Auteur
Unlü, B.
Auteure/Auteur
Vermeulen, N.P.
Auteure/Auteur
Vos, J.C.
Auteure/Auteur
Liens vers les personnes
ISSN
1879-3177
Statut éditorial
Publié
Date de publication
2012-03
Volume
26
Numéro
2
Première page
197
Dernière page/numéro d’article
205
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. However, this group of drugs is associated with serious adverse drug reactions. Previously, we studied the mechanisms underlying toxicity of the NSAID diclofenac using Saccharomycescerevisiae as model system. We identified the involvement of several mitochondrial proteins, a transporter and cytochrome P450 activity in diclofenac toxicity. In this study, we investigated if these processes are also involved in the toxicity of other NSAIDs. We divided the NSAIDs into three classes based on their toxicity mechanisms. Class I consists of diclofenac, indomethacin and ketoprofen. Mitochondrial respiration and reactive oxygen species (ROS) play a major role in the toxicity of this class. Metabolism by cytochrome P450s further increases their toxicity, while ABC-transporters decrease the toxicity. Mitochondria and oxidative metabolism also contribute to toxicity of class II drugs ibuprofen and naproxen, but another cellular target dominates their toxicity. Interestingly, ibuprofen was the only NSAID that was unable to induce upregulation of the multidrug resistance response. The class III NSAIDs sulindac, ketorolac and zomepirac were relatively non-toxic in yeast. In conclusion, we demonstrate the use of yeast to investigate the mechanisms underlying the toxicity of structurally related drugs.
Sujets
PID Serval
serval:BIB_058287FB6D38
PMID
Date de création
2019-01-22T15:11:31.827Z
Date de création dans IRIS
2025-05-20T15:16:44Z