The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes

H. Higuchi, M. Adachi, S. Miura, G. J. Gores, H. Ishii

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108 Citations (Scopus)

Abstract

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 ethanol-induced 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.

Original languageEnglish
Pages (from-to)320-328
Number of pages9
JournalHepatology
Volume34
Issue number2
DOIs
Publication statusPublished - 2001

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Hepatocytes
Permeability
Ethanol
Apoptosis
Cytochromes c
Membranes
Caspases
Oxidative Stress
Caspase Inhibitors
Acetylcysteine
Mitochondrial Membranes
Hydrogen Peroxide
Cyclosporine
Antioxidants
1,3-dimethylthiourea

ASJC Scopus subject areas

  • Hepatology

Cite this

The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes. / Higuchi, H.; Adachi, M.; Miura, S.; Gores, G. J.; Ishii, H.

In: Hepatology, Vol. 34, No. 2, 2001, p. 320-328.

Research output: Contribution to journalArticle

Higuchi, H. ; Adachi, M. ; Miura, S. ; Gores, G. J. ; Ishii, H. / The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes. In: Hepatology. 2001 ; Vol. 34, No. 2. pp. 320-328.
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