Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes
| Autor: | Fumiko Nagai, Toshinari Suzuki, Yoshio Nakagawa, Hisashi Kamimura |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Mitochondria Liver Oxidative phosphorylation Mitochondrion Mitochondrial Membrane Transport Proteins Mitochondrial apoptosis-induced channel Ion Channels Membrane Potentials Cyclosporin a Fenfluramine Animals Cells Cultured Pharmacology Cell Death biology Mitochondrial Permeability Transition Pore Cytochrome c Cytochromes c Rats Inbred F344 Rats Biochemistry Mitochondrial permeability transition pore Dietary Supplements Cyclosporine Hepatocytes biology.protein Biophysics ATP–ADP translocase Mitochondrial Swelling Intracellular |
| Zdroj: | European Journal of Pharmacology. 529:33-39 |
| ISSN: | 0014-2999 |
| Popis: | The role of mitochondrial membrane permeability transition in N -nitrosofenfluramine-induced cell injury was studied in mitochondria and hepatocytes isolated from rat liver. Mitochondrial permeability transition has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, N -nitrosofenfluramine (0.25 to 1.0 mM) in the presence of Ca 2+ (50 μM) elicited a concentration-dependent induction of mitochondrial swelling dependent on mitochondrial permeability transition and the release of cytochrome c , both of which were prevented by pretreatment with a specific inhibitor of mitochondrial permeability transition, cyclosporin A (0.2 μM). The effects of N -nitrosofenfluramine on mitochondria were more potent than those of fenfluramine, which is a sympathomimetic amine with anorectic action. The pretreatment of isolated hepatocytes with cyclosporin A (2 μM) partially but not completely prevented N -nitrosofenfluramine (0.6 mM; a low toxic dose)-induced cell death, loss of cellular ATP, formation of cell blebs and decrease in mitochondrial membrane potential. These results suggest that the onset of N -nitrosofenfluramine-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of mitochondrial permeability transition accompanied by mitochondrial depolarization, the release of cytochrome c and depletion of intracellular ATP through uncoupling of oxidative phosphorylation. |
| Databáze: | OpenAIRE |
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