Nimesulide interaction with membrane model systems: Are membrane physical effects involved in nimesulide mitochondrial toxicity?

• Tipo: Artigo em Revista Científica Internacional
• Data: 2011

Autores

Joao P Monteiro (Autor) Outra; Andre F Martins (Autor) Outra; Marlene Lucio (Autor) FEUP; Salette Reis (Autor) FFUP; Teresa J T Pinheiro (Autor) Outra; Carlos F G C Geraldes (Autor) Outra; Paulo J Oliveira (Autor) Outra; Amalia S Jurado (Autor) Outra

Revista

Título: Toxicology in Vitro

Vol. 25 Nº 6

Páginas: 1215-1223

ISSN: 0887-2333

Editora: Elsevier

Indexação

ISI Web of Knowledge - 17 Citações

Scopus - 19 Citações

Pubmed / Medline

Classificação Científica

FOS: Ciências médicas e da saúde > Medicina básica

CORDIS: Ciências Físicas > Química > Química analítica

Outras Informações

ID Authenticus: P-002-NBM

DOI: 10.1016/j.tiv.2011.05.014

Resumo (PT): 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, 31P 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. <br> <br> Keywords: Nimesulide; Membrane fluidity and permeability; Lamellar and inverted hexagonal phases; Differential scanning calorimetry; Fluorescence polarization; 31P NMR <br> <a target="_blank" href="http://www.sciencedirect.com/science/article/pii/S0887233311001408 "> Texto integral </a> <br> <br>

Abstract (EN): 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 9