Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition.
Troglitazone, a thiazolidinedione class antidiabetic drug, was withdrawn from the market because of its severe idiosyncratic hepatotoxicity. It causes a mitochondrial permeability transition (MPT), which may in part contribute to its hepatotoxicity. In the present study, the mechanism of troglitazone mitochondrial toxicity was investigated in isolated rat liver mitochondria. Mitochondrial swelling induced by 10 μM troglitazone was attenuated by bromoenol lactone (BEL), an inhibitor of Ca²+-independent phospholipase A₂ (iPLA₂). In contrast, that induced by 50 μM troglitazone was exacerbated by BEL. This exacerbation was diminished by addition of 2mM glutathione, an antioxidant. Oxygen consumption by state 3 respiration in isolated mitochondria was also decreased by troglitazone, but it was not affected by BEL. Mitochondrial swelling induced by 10 μM troglitazone was completely attenuated in the absence of Ca²+ while that induced by 50 μM troglitazone was not affected. Addition of 1 μM cyclosporin A (CsA), an inhibitor of MPT pores, completely attenuated swelling induced by 10 μM troglitazone while it only partly diminished that induced by 50 μM troglitazone. Thus, the MPT induced by 10 and 50 μM troglitazone are regulated by different mechanism; the MPT induced by 10 μM troglitazone is regulated by the activation of iPLA₂ and caused by the opening of CsA-regulating MPT pores followed by accumulation of Ca²+ in mitochondria, while that induced by 50 μM troglitazone is partly regulated by reactive oxygen species and mainly caused by the opening of CsA-insensitive MPT pores.
Okuda
Takuya
T
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Norioka
Misaki
M
Shitara
Yoshihisa
Y
Horie
Toshiharu
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002839:Chromans / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000633:toxicity*; D000077288:Troglitazone
D002839:Chromans; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077288:Troglitazone