title: Differential involvement of mitochondrial dysfunction, cytochrome P450 activity, and active transport in the toxicity of structurally related NSAIDs.
abstract: 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.
authors.affiliation: LACDR, Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Jolanda S
authors.initials: JS
authors.lastname: van Leeuwen
authors.forename: Betül
authors.initials: B
authors.lastname: Unlü
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
authors.forename: J Chris
authors.initials: JC
authors.lastname: Vos
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001693:Biological Transport, Active / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004008:Diclofenac / Q000633:toxicity; D004579:Electron Transport; D019450:Genes, MDR / Q000187:drug effects; D007052:Ibuprofen / Q000633:toxicity; D007213:Indomethacin / Q000633:toxicity; D007660:Ketoprofen / Q000633:toxicity; D020910:Ketorolac / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009288:Naproxen / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D013467:Sulindac / Q000633:toxicity; D014046:Tolmetin / Q000031:analogs & derivatives / Q000633:toxicity; D015003:Yeasts / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; D004008:Diclofenac; D013467:Sulindac; D009288:Naproxen; C020549:zomepirac; D003577:Cytochrome P-450 Enzyme System; D007660:Ketoprofen; D014046:Tolmetin; D007052:Ibuprofen; D007213:Indomethacin; D020910:Ketorolac