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The mitochondrial permeability transition contributes to acute ethanol‐induced apoptosis in rat hepatocytes
Author(s) -
Higuchi Hajime,
Adachi Masayuki,
Miura Soichiro,
Gores Gregory J.,
Ishii Hiromasa
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.26380
Subject(s) - cytochrome c , mitochondrial permeability transition pore , oxidative stress , apoptosis , mitochondrion , reactive oxygen species , hepatocyte , chemistry , caspase 3 , oxidative phosphorylation , caspase , microbiology and biotechnology , biochemistry , biology , programmed cell death , in vitro
Acute ethanol intoxication induces oxidative stress and apoptosis in primary cultured hepatocytes. Oxidative stress can trigger mitochondrial cytochrome c release initiating the mitochondrial pathway of apoptosis. Based on this information, we formulated the hypothesis that ethanolinduced oxidative stress causes mitochondrial dysfunction resulting in apoptosis. In the present study, we found that the mitochondrial membrane permeability transition (MPT) is essential for induction of mitochondrial cytochrome c release and caspase activation of ethanol. The short‐term incubation with ethanol (50 mmol/L) induced the MPT, cytochrome c release, caspase activation, and apoptosis of cultured rat hepatocytes. Hepatocyte apoptosis was prevented by caspase inhibitors ( i.e., Z‐VAD‐fmk, DEVD‐cho, and DMQD‐cho). An MPT inhibitor, cyclosporin A, also prevented ethanol‐induced cytochrome c release, caspase activation, and apoptosis, suggesting that acute ethanol‐induced apoptosis is MPT dependent. Ethanol‐induced MPT was also attenuated by N'N'‐dimethylthiourea (DMTU, a scavenger of hydrogen peroxide, 10 mmol/L) and N ‐acetyl‐cysteine (NAC, an antioxidant, 5 mmol/L). Preventing hepatocyte MPT by DMTU or NAC attenuated cytochrome c release as well as caspase activation, suggesting that ethanol‐induced oxidative stress mediates the MPT. Thus, acute ethanol induces MPT via oxidative stress, and the MPT mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol.