Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes.
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 microM) 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 microM). 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 microM) 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.
Nakagawa
Yoshio
Y
Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, Shinjuku-ku, Tokyo 169-0073, Japan. Yoshio_1_Nakagawa@member.metro.tokyo.jp
Suzuki
Toshinari
T
Kamimura
Hisashi
H
Nagai
Fumiko
F
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D019587:Dietary Supplements / Q000633:toxicity*; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C493137:nitrosofenfluramine; D005277:Fenfluramine; D016572:Cyclosporine; D045304:Cytochromes c