Reactive oxygen species in the normal and acutely injured liver.
Reactive oxygen species in the normal and acutely injured liver.
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DOI：
10.1016/j.jhep.2011.01.006
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发表时间：
2011-07
影响因子：
25.7
通讯作者：
Ramachandran A
中科院分区：
文献类型：
--
作者：
Jaeschke H;Ramachandran A
肝脏在线粒体和过氧化氢中产生低水平的活性氧（ROS），特别是超氧化物，作为各种氧化酶的正常功能[1]。大量的线粒体及其从电子传递链的复合物I和III中泄漏电子的能力使其在数量上成为ROS最重要的细胞内来源[1]。由于细胞膜中存在多不饱和脂肪酸、大量未受保护的蛋白质巯基和DNA碱基，ROS的形成对细胞是危险的。因此，细胞必须发展复杂的防御系统。每个肝细胞表达超氧化物歧化酶（胞质溶胶中的SOD 1;线粒体中的SOD 2）、谷胱甘肽过氧化物酶（胞质溶胶和线粒体）、过氧化氢酶（过氧化物酶体）、硫氧还蛋白（胞质溶胶中的Trx 1;线粒体中的Trx 2）和过氧化物酶（胞质溶胶中的Prx-I、-II、-VI;线粒体中的Prx-III、-V）[1]（图1A）。此外，肝细胞在所有细胞隔室中含有mM浓度的谷胱甘肽，在细胞膜中具有自由基断链抗氧化剂（维生素E），并保持氧化还原活性铁与储存或转运蛋白紧密结合[1]。由于这种针对ROS的多层防御系统，肝细胞，特别是肝细胞，具有代谢和有效解毒ROS和修复氧化损伤的实质性能力。因此，在现实的体内条件下，灾难性的自由基事件（如脂质过氧化）很少是细胞死亡的原因[2]。相反，活性氧通常会导致细胞内稳态的紊乱，如果不能有效地抵消，这可能会导致细胞死亡。活性氧形成增加和防御系统受损导致细胞死亡的一个例子是对乙酰氨基酚（APAP）过量，这是西方国家急性肝衰竭的主要原因[3]。APAP的反应性代谢产物消耗胞质溶胶和线粒体中的谷胱甘肽（GSH），并与细胞蛋白结合，导致线粒体内形成ROS和过氧亚硝酸盐[3]（图1A）。在缺乏线粒体GSH的情况下，线粒体氧化应激触发线粒体渗透性转换（MPT）孔的打开，这导致膜电位的崩溃和ATP合成的停止。此外，线粒体膜间蛋白核酸内切酶G和凋亡诱导因子易位到细胞核并引起DNA片段化[3]。受损的线粒体抗氧化防御系统的关键作用清楚地证明了深刻的肝保护，如果ROS
Livers generate low levels of reactive oxygen species (ROS), especially superoxide, in mitochondria and hydrogen peroxide as normal function of various oxidases [1]. The large number of mitochondria and their capacity to leak electrons from complex I and III of the electron transport chain make them quantitatively the most important intracellular source of ROS [1]. ROS formation is dangerous for cells due to the presence of polyunsaturated fatty acids in cellular membranes, the substantial number of unprotected protein sulfhydryl groups and DNA bases. Therefore, cells had to develop sophisticated defense systems. Each liver cell expresses superoxide dismutases (SOD1 in the cytosol; SOD2 in mitochondria), glutathione peroxidases (cytosol and mitochondria), catalase (peroxisomes), thioredoxins (Trx1 in cytosol; Trx2 in mitochondria) and peroxiredoxins (Prx-I,-II,-VI in the cytosol; Prx-III,-V in mitochondria)[1](Figure 1A). In addition, liver cells contain mM concentrations of glutathione in all cellular compartments, have radical chain-breaking antioxidants (vitamin E) in cell membranes and keep redox-active iron tightly bound to storage or transport proteins [1]. Because of this multi-layer defense system against ROS, liver cells and especially hepatocytes, have a substantial capacity to metabolize and effectively detoxify ROS and repair oxidant damage. Therefore, under realistic in vivo conditions, catastrophic free radical events such as lipid peroxidation are rarely the cause of cell death [2]. Instead, ROS generally cause disturbances of the cellular homeostasis and, if not effectively counteracted, this can lead to cell death.An example where the combination of increased ROS formation and impaired defense systems causes cell death is acetaminophen (APAP) overdose, which is the leading cause of acute liver failure in Western countries [3]. The reactive metabolite of APAP depletes glutathione (GSH) in the cytosol and in mitochondria and binds to cellular proteins, which causes formation of ROS and peroxynitrite inside mitochondria [3](Figure 1A). In the absence of mitochondrial GSH, the mitochondrial oxidant stress triggers the opening of the mitochondrial permeability transition (MPT) pore, which causes the collapse of the membrane potential and cessation of ATP synthesis. In addition, mitochondrial intermembrane proteins endonuclease G and apoptosis-inducing factor translocate to the nucleus and cause DNA fragmentation [3]. The critical role of the impaired mitochondrial antioxidant defense system is clearly demonstrated by the profound hepatoprotection if ROS
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