Antiarrhythmic Amiodarone Mediates Apoptotic Cell Death of HepG2 Hepatoblastoma Cells through the Mitochondrial Pathway
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概要
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The antiarrhythmic amiodarone is known to cause hepatic toxicity. Recently, much attention has been devoted to the role of apoptosis in the pathogenesis of drug-induced cytotoxicity. The aim of this study is to investigate whether apoptosis contributes to hepatic toxicity caused by amiodarone and, if so, by which mechanism. HepG2 human hepatoblastoma cells were incubated for 48 hours with various concentration of amiodarone. To determine apoptotic cells, concentration of cytochrome c in the cytosol fraction, caspase-9 and -3 activities, and the percentage of the cells with hypodiploid DNA were measured quantitatively by flow cytometric assay or ELISA. The expression of Bcl-2-related proteins was examined by Western blot analysis. Amiodarone induced cytochrome c release into the cytosol fraction, activation of caspase-9 and caspase-3, and the occurrence of hypodiploid cells beginning at 10 μg/ml in the HepG2 cells. However, 2.5 μg/ml of amiodarone, a clinically attainable serum level, did not significantly. The expression of Bcl-xL but neither Bcl-2 nor Bax was decreased in the amiodarone-treated cells. Thus, amiodarone-induced cell death related with cytochrome c release and caspases in the HepG2 cells, suggesting that the drug causes hepatic toxicity in part through the induction of apoptosis. It is our conclusion that the amiodarone-induced apoptosis of HepG2 cells proceeds via the mitochondrial pathway, and is mediated by the downregulation of Bcl-xL.
- 長崎大学の論文
著者
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YAMASHITA Shunichi
Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences
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Ohtsuru Akira
Nagai Takashi Memorial International Hibakusha Medical Center Nagasaki University Hospital Nagasaki
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Yamashita Shunichi
Department Of Molecular Medicine Atomic Bomb Disease Institute Nagasaki University Graduate School O
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Kawakami Atsushi
Division Of Immunology Endocrinology And Metabology Department Of Translational Medical Sciences Cou
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Isomoto Shojiro
Division of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences
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Yamashita Shunichi
Division Of Radiation Biology Department Of Radiology And Radiation Biology Course Of Life Sciences
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Kawakami Atsushi
Division Of Biological Science Nagoya University Graduate School Of Science
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Yamashita Shunichi
Department Of Cell Physiology Atomic Disease Institute Nagasaki University School Of Medicine
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