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首页> 外文期刊>Experimental Animals >D-Galactosamine Induced Hepatocyte Apoptosis is Inhibited in vivo and in Cell Culture by a Calcium Calmodulin Antagonist, Chlorpromazine, and a Calcium Channel Blocker, Verapamil
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D-Galactosamine Induced Hepatocyte Apoptosis is Inhibited in vivo and in Cell Culture by a Calcium Calmodulin Antagonist, Chlorpromazine, and a Calcium Channel Blocker, Verapamil

机译：D-半乳糖胺诱导的肝细胞凋亡在体内和细胞培养中被钙调蛋白拮抗剂，氯丙嗪和钙通道阻滞剂维拉帕米抑制。

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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 [Ca~(2+)]i kinetics. Chlorpromazine (CPZ), a Ca~(2+)-calmodulin antagonist, and verapamil (VR), a Ca~(2+)-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 μM) as the calcium reporter. An increase in [Ca~(2+)]i was detected in the cultured hepatocytes within 3 hours after treatment with 20 mM GaIN; this increase was inhibited by pretreatment with either 20 μM CPZ or 30 μM VR. Ca~(2+) imaging by confocal laser scanning microscopy showed that increase in [Ca~(2+)]i after treatment with GalN was initially localized around nuclei, while [Ca~(2+)]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 Ca~(2+), 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 [Ca~(2+)]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.
机译：在C57BL / 6N Crj雄性小鼠和培养的肝细胞中进行了研究，以阐明半乳糖胺（GalN）诱导的细胞凋亡与[Ca〜（2 +）] i动力学之间的关系。 Ca〜（2 +）-钙调蛋白拮抗剂氯丙嗪（CPZ）和Ca〜（2+）通道阻滞剂维拉帕米（VR）分别抑制GalN诱导的DNA片段化和凋亡小体的出现。使用钙分析仪，以fura-PE3的乙酰氧基甲基酯（fura-PE3 / AM，2.5μM）作为钙报告分子，评估钙摄取的动力学。 20 mM GaIN处理后3小时内，在培养的肝细胞中检测到[Ca〜（2 +）] i的增加；通过使用20μMCPZ或30μMVR预处理可以抑制这种增加。通过共聚焦激光扫描显微镜对Ca〜（2+）成像显示，用GalN处理后[Ca〜（2 +）] i的增加最初位于细胞核周围，而[Ca〜（2 +）] i信号随后扩散并在整个细胞质中观察到。乳酸脱氢酶（LDH）和血清谷氨酸-丙酮酸转氨酶（sGPT）的活性，被用作质膜损伤和渗漏的指标，但是，用CPZ或VR预处理并没有降低其活性。从这些发现，我们推断GalN诱导的肝细胞凋亡中的DNA片段化与Ca〜（2+）的核周浓度升高有关，但GalN诱导的坏死性细胞死亡是通过不敏感的途径触发的阻碍Ca〜（2+）流入，因此似乎独立于[Ca〜（2 +）] i的升高而发生。这些结果有助于阐明钙通量在体内和体外暴露于肝毒素诱导的肝细胞凋亡和坏死中的作用。

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