Extensive alteration of genomic DNA and rise in nuclear Ca2+ in vivo early after hepatotoxic acetaminophen overdose in mice.
Extensive alteration of genomic DNA and rise in nuclear Ca2+ in vivo early after hepatotoxic acetaminophen overdose in mice.
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DOI：
10.1007/978-1-4684-5877-0_90
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发表时间：
1991
影响因子：
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通讯作者：
S. Ray;C. Sorge;A. Tavacoli;J. Raucy;G. Corcoran
中科院分区：
文献类型：
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作者：
S. Ray;C. Sorge;A. Tavacoli;J. Raucy;G. Corcoran
许多注意力已经落在Ca 2+和它似乎在致死细胞损伤过程中发挥的关键作用上（Schanne等人，1979;摩尔，1980;朱厄尔等人，1982年）。Ca 2+似乎作为主要的细胞内信使，将烷基化或过氧化引起的初始损伤传递到对细胞活力至关重要的离散二级位点。尽管如此，细胞死亡的Ca 2+假说的几个方面仍然难以捉摸，包括最初受损的Ca 2+调节位点的位置对细胞死亡很重要，以及在过度Ca 2+活性下恶化的重要功能或功能的实际身份。细胞死亡被认为通过两种不同的过程发生;细胞凋亡，或在生理事件如器官发育和细胞更新期间观察到的程序性细胞死亡，以及坏死，或在实质性病理损伤之后的非程序性细胞死亡（Wyllie，1980;杜瓦尔and Wyllie，1986）。导致未成熟胸腺细胞凋亡的许多步骤是明确的。这些包括Ca 2+流入细胞、细胞核中的核酸内切酶活化和DNA降解成坏死中未观察到的周期性片段（Cohen和杜克，1984; McConkey等人，1988年a）。本研究评估对乙酰氨基酚诱导的肝坏死是否可能与细胞凋亡过程共享某些关键步骤。已知毒性剂量的对乙酰氨基酚会导致Ca 2+在肝脏中积累，并且细胞溶质Ca 2+活性在2小时内升高（Corcoran等人，1987年，1988年）。我们现在检查细胞核中对乙酰氨基酚诱导的坏死中未经检查的Ca 2+活性的致死作用，并且我们专门监测基因组DNA作为这种形式的细胞死亡中的关键次要靶点。
Much attention has fallen upon Ca2+and the critical role it appears to play in the process of lethal cell injury (Schanne et al., 1979; Moore, 1980; Jewell et al., 1982). Ca2+appears to serve as the principal intracellular messenger that conveys initial damage arising from alkylation or peroxidation to discrete secondary sites that are essential to cell viability. Nonetheless, several aspects of the Ca2+hypothesis of cell death remain elusive, including the location of initially damaged Ca2+regulatory sites important to cell death, and the actual identity of the vital function or functions that deteriorate under excessive Ca2+activity. Cell death is believed to occur via two distinct processes; apoptosis, or the programmed cell death seen during physiological events such as organ development and cell renewal, and necrosis, or the unprogrammed cell death that follows substantive pathologic insult (Wyllie, 1980; Duvall and Wyllie, 1986). A number of the steps leading to apoptosis in immature thymocytes are well defined. These include Ca2+influx into the cell, endonuclease activation in the nucleus, and DNA degradation into periodic fragments not seen in necrosis (Cohen and Duke, 1984; McConkey et al., 1988a). The present study assesses whether acetaminophen-induced liver necrosis may share certain key steps in common with the process of apoptosis. Toxic doses of acetaminophen are known to cause Ca2+to accumulate in liver and cytosolic Ca2+activity to rise within 2 hr (Corcoran et al., 1987, 1988). We now examine the nucleus for lethal actions of unchecked Ca2+activity in acetaminophen-induced necrosis, and we specifically monitor genomic DNA as a critical secondary target in this form of cell death.