D-Galactosamine Induced Hepatocyte Apoptosis is Inhabited in vivo and in Cell Culture by a Calcium Calmodulin Antagonist, Chlorpromazine, and a Calcium Channel Blocker, Verapamil
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概要
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Studies were conducted in C57BL/6N Crj male mice and in cultured hepatocytes to clarify the relationship between galactosamine (GalN) induced apoptosis and [Ca2+]i kinetics. Chlorpromazine (CPZ), a Ca2+-calmodulin antagonist, and verapamil (VR), a Ca2+-channel blocker each inhibited GalN-induced DNA fragmentation and the appearance of apoptotic bodies. The kinetics of calcium uptake were evaluated using a calcium analyzer with the acetoxymethyl ester of fura-PE3 (fura-PE3/AM, 2.5 M) as the calcium reporter. An increase in [Ca2+]i was detected in the cultured hepatocytes within 3 hours after treatment with 20 mM GalN; this increase was inhibited by pretreatment with either 20 M CPZ or 30 M VR. Ca2+ imaging by confocal laser scanning microscopy showed that increase in [Ca2+]i after treatment with GalN was initially localized around nuclei, while [Ca2+]i signals were later diffuse and observed throughout the cytoplasm. The activities of lactate dehydrogenase (LDH) and serum glutamate-pyruvate transaminase (sGPT), used as indicators of plasma membrane damage and leakage, however, were not reduced by pretreatment with CPZ or VR. From these findings, we infer that the DNA fragmentation in GalN-induced hepatocyte apoptosis is associated with an elevation in the perinuclear concentration of Ca2+, but GalN-induced necrotic cell death is triggered through pathway(s) that are insensitive to blockage of Ca 2+ influx and therefore appear to occur independently of elevation in [Ca2+]i. These results help to clarify the role of calcium flux in hepatocyte apoptosis and necrosis induced by exposure to hepatotoxins in vivo and in vitro.
- 社団法人 日本実験動物学会の論文
- 2003-01-01
著者
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吉川 泰弘
東京大学 大学院農学生命科学研究科実験動物学教室
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YOSHIKAWA Yasuhiro
Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University
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Doi K
Department Of Veterinary Pathology Faculty Of Agriculture The University Of Tokyo
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土井 邦雄
残留農薬研究所
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Doi Kunio
Department of Veterinary Pathology, Faculty of Agriculture, The University of Tokyo
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ITAGAKI Shin-ichi
Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University
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KAWAMURA Seiji
Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, the University
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Yoshikawa Yasuhiro
Dep. Of Biomedical Sci. Graduate School Of Agricultural And Life Sciences The Univ. Of Tokyo
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Kyuwa S
Univ. Tokyo Tokyo Jpn
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Kyuwa Shigeru
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences The University Of
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Kyuwa Shigeru
Dep. Of Biomedical Sci. Graduate School Of Agricultural And Life Sciences The Univ. Of Tokyo
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Harada Ken-ichi
Department Of Human Pathology Kanazawa University Graduate School Of Medicine
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Doi Kunio
日本生物科学研究所
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土井 邦雄
Department Of Veterinary Pathology Graduate School Of Agricultural And Life Sciences The University
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TSUTSUI Shigeki
Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University
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KARAKI Hideaki
Department of Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The Univer
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Yoshikawa Y
Dep. Of Biomedical Sci. Graduate School Of Agricultural And Life Sciences The Univ. Of Tokyo
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Yoshikawa Yasuhiro
Department Of Biomedical Science Graduate School Of Agricultural And Life Science University Of Toky
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Doi Kunio
Department Of Applied Chemistry Nagoya Institute Of Technology
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Kawamura Seiji
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences The University Of
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Doi Kunio
Faculty Of Agriculture The University Of Tokyo
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吉川 泰弘
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences The University Of
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板垣 慎一
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences The University Of
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Itagaki Shin-ichi
Department Of Biomedical Science The University Of Tokyo
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Kyuwa Shigeru
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences University Of Tok
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Kyuwa Shigeru
Center For Experimental Medicine Institute Of Medical Science The University Of Tokyo
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Yoshikawa Yasuhiro
Department Of Biomedical Science Faculty Of Agriculture The University Of Tokyo
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吉川 泰弘
Department Of Biomedical Science Faculty Of Agriculture The University Of Tokyo
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Itagaki Shin-ichi
Department Of Biomedical Science Faculty Of Agriculture The University Of Tokyo
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Karaki Hideaki
Department Of Veterinary Pharmacology Graduate School Of Agricultural And Life Sciences The Universi
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Itagaki Shin-ichi
Department Of Biomedical Science Faculty Of Agriculyure The University Of Tokyo
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Karaki Hideaki
Department Of Veterinary Medicine Faculty Of Agriculture Iwate University
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吉川 泰弘
Dep. Of Biomedical Sci. Graduate School Of Agricultural And Life Sciences The Univ. Of Tokyo
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Tsutsui Shigeki
Department Of Biomedical Science Graduate School Of Agricultural And Life Sciences The University Of
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Harada Ken-ichi
Department Of Clinical Pharmacology Jichi Medical School
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Harada Ken-ichi
Department Of Veterinary Pharmacology Graduate School Of Agricultural And Life Sciences The Universi
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Kawamura Seiji
Department Of Biomedical Science Faculty Of Agriculture And Life Sciences University Of Tokyo
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Karaki Hideaki
Department of Veterinary Medical Sciences, Faculty of Agriculture, The University of Tokyo
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KAWAMURA Seiji
Department of Agriculture, The University of Tokyo
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