The role of oxidative stress in chemical carcinogenesis
The role of oxidative stress in chemical carcinogenesis
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DOI：
10.2307/3433929
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发表时间：
1998-02-01
影响因子：
10.4
通讯作者：
Walborg, EF
中科院分区：
文献类型：
--
作者：
Klaunig, JE;Xu, Y;Walborg, EF
当活性氧（ROS）的产生超过靶细胞的抗氧化能力之间的平衡时，就会产生氧化应激;可能会发生活性氧与关键细胞大分子相互作用造成的氧化损伤。ROS可以与细胞蛋白质、脂质和DNA相互作用并修饰细胞蛋白质、脂质和DNA，这导致靶细胞功能改变。氧化损伤的积累与急性和慢性细胞损伤有关，包括可能参与癌症的形成。急性氧化损伤可产生选择性细胞死亡和细胞增殖的代偿性增加。这种刺激可能导致新启动的癌前细胞的形成和/或增强潜伏启动的癌前细胞的选择性克隆扩增。同样，亚致死性急性氧化损伤可能会产生无法修复的DNA损伤，并导致新突变的形成，并可能导致新启动的细胞。相反，持续的慢性氧化损伤可能导致正常细胞生长控制机制的非致死性改变。细胞氧化应激可以改变细胞间通讯、蛋白激酶活性、膜结构和功能以及基因表达，并导致细胞生长的调节。我们研究了氧化应激的作用，作为一种可能的机制，非遗传毒性致癌物可能发挥作用。在使用选择性小鼠肝脏致癌物狄氏剂的研究中，观察到肝脏抗氧化剂浓度的物种特异性和剂量依赖性降低，同时ROS形成和氧化损伤增加。这种氧化应激的增加与肝细胞DNA合成的增加相关。补充抗氧化剂可防止狄氏醇引起的细胞变化。我们的研究结果表明，非遗传毒性致癌物（ii他们通过氧化机制发挥作用）的影响可能会在啮齿类动物中放大，但不会在灵长类动物中，因为啮齿类动物对ROS更敏感。其他人报告的这些结果和发现支持氧化诱导的损伤在癌症过程中的潜在作用，特别是在促进阶段。
Oxidative stress results when the balance between the production of reactive oxygen species (ROS) overrides the antioxidant capability of the target cell; oxidative damage from the interaction of reactive oxygen with critical cellular macromolecules may occur. ROS may interact with and modify cellular protein, lipid, and DNA, which results in altered target cell function. The accumulation of oxidative damage has been implicated in both acute and chronic cell injury including possible participation in the formation of cancer. Acute oxidative injury may produce selective cell death and a compensatory increase in cell proliferation. This stimulus may result in the formation of newly initiated preneoplastic cells and/or enhance the selective clonal expansion of latent initiated preneoplastic cells. Similarly, sublethal acute oxidative injury may produce unrepaired DNA damage and result in the formation of new mutations and, potentially, new initiated cells. In contrast, sustained chronic oxidative injury may lead to a nonlethal modification of normal cellular growth control mechanisms. Cellular oxidative stress can modify intercellular communication, protein kinase activity, membrane structure and function, and gene expression, and result in modulation of cell growth. We examined the role of oxidative stress as a possible mechanism by which nongenotoxic carcinogens may function. in studies with the selective mouse liver carcinogen dieldrin, a species-specific and dose-dependent decrease in liver antioxidant concentrations with a concomitant increase in ROS formation and oxidative damage was seen. This increase in oxidative stress correlated with an increase in hepatocyte DNA synthesis. Antioxidant supplementation prevented the dieldrin-induced cellular changes. Our findings suggest that the effect of nongenotoxic carcinogens (ii they function through oxidative mechanisms) may be amplified in rodents but not in primates because of rodents' greater sensitivity to ROS. These results and findings reported by others support a potential role for oxidative-induced injury in the cancer process specifically during the promotion stage.