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Nimesulide interaction with membrane model systems : are membrane physical effects involved in nimesulide mitochondrial toxicity?
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Monteiro, João P., Martins, André F., Lúcio, Marlene, Reis, Salette, Pinheiro, Teresa J. T., Geraldes, Carlos F. G. C., Oliveira, Paulo J. and Jurado, Amália S. (2011) Nimesulide interaction with membrane model systems : are membrane physical effects involved in nimesulide mitochondrial toxicity? Toxicology in Vitro, Vol.25 (No.6). pp. 1215-1223. doi:10.1016/j.tiv.2011.05.014 ISSN 08872333.
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Official URL: http://dx.doi.org/10.1016/j.tiv.2011.05.014
Abstract
Nimesulide (NIM), a widely used nonsteroidal anti-inflammatory drug (NSAID), is known to interfere with mitochondrial physiology and to cause idiosyncratic hepatotoxicity. In this study, we characterized the effects of NIM on the physical properties of membrane models containing the main phospholipid classes of the inner mitochondrial membrane: phosphatidylcholine (PC), phosphatidylethanolamine (PE) and cardiolipin (CL). NIM binding/incorporation was observed with the mitochondrial membrane mimicking model composed of dioleoyl PC (DOPC), dioleoyl PE (DOPE) and tetraoleoyl CL (TOCL) at a 1:1:1 M ratio, as well as an increase of membrane permeability, monitored by calcein release, and an increase of lipid disorder, evaluated by fluorescence anisotropy of DPH-PA. Consistently, DSC thermograms of dipalmitoyl PC (DPPC) and a mixture of dipalmitoyl PE (DPPE) and TOCL (7:3 M ratio) showed a NIM-induced decrease of the cooperativity of the phase transition and a shift of the DPPC endotherm to lower temperatures. On the other hand, (31)P NMR studies with the ternary lipid model indicated a stabilizing effect of NIM on the lipid bilayer structure. Quenching of the fluorescent probes DPH and DPH-PA revealed a peripheral insertion of NIM in the hydrophobic portion of the bilayer. Our data indicate that NIM may influence mitochondria physiological processes by interfering with membrane structure and dynamics. The relevance of these findings will be discussed in terms of the reported NIM effects on mitochondria transmembrane potential, protonophoresis, and induction of the permeability transition pore.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QC Physics Q Science > QH Natural history > QH301 Biology R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Library of Congress Subject Headings (LCSH): | Nimesulide, Membranes (Biology) -- Fluidity, Calorimetry, Fluorescence spectroscopy, Nuclear magnetic resonance spectroscopy, Nonsteroidal anti-inflammatory agents, Mitochondrial membranes | ||||
| Journal or Publication Title: | Toxicology in Vitro | ||||
| Publisher: | Pergamon | ||||
| ISSN: | 08872333 | ||||
| Official Date: | September 2011 | ||||
| Dates: |
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| Volume: | Vol.25 | ||||
| Number: | No.6 | ||||
| Page Range: | pp. 1215-1223 | ||||
| DOI: | 10.1016/j.tiv.2011.05.014 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published |
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