Woolley P V, Kumar S, Fitzgerald P, Simpson R T
Department of Medicine, Georgetown University Medical Center, Washington, DC 20007.
Carcinogenesis. 1987 Nov;8(11):1657-62. doi: 10.1093/carcin/8.11.1657.
Ascorbic acid (vitamin C) is an important intracellular reducing agent. It also has been suggested to be (i) a protective agent against development of cancer, (ii) a therapeutic agent for malignancies and (iii) a mutagen. We have found that high concentrations of ascorbate leads to DNA damage in several in vivo and in vitro situations. Guinea-pigs receiving oral 1-methyl-1-nitrosourea (MNU) were used as a whole animal model. Administration of sodium ascorbate prior to MNU increased strand breakage in pancreatic DNA. Concentrations of ascorbate greater than 0.5 mM increased the frequency of DNA strand breaks caused by MNU in both L1210 murine leukemia cells and guinea-pig pancreatic cells in tissue culture; ascorbate alone led to DNA strand breaks in the latter cells. Investigations of the mechanism of DNA damage were carried out with purified DNA. Ascorbate produced single- and double-strand breaks in plasmid DNA. Cleavage was catalyzed by copper(II), inhibited by catalase and blocked by the presence of thiols. We conclude that superoxide and hydrogen peroxide produced during the oxidation of ascorbate leads to generation of hydroxyl free radicals that can mediate DNA strand scissions and potentiate the effects of alkylating carcinogens.
抗坏血酸（维生素C）是一种重要的细胞内还原剂。也有人认为它是：（i）预防癌症发生的保护剂；（ii）治疗恶性肿瘤的药剂；（iii）诱变剂。我们发现在几种体内和体外情况下，高浓度的抗坏血酸盐会导致DNA损伤。将接受口服1-甲基-1-亚硝基脲（MNU）的豚鼠用作整体动物模型。在给予MNU之前给予抗坏血酸钠会增加胰腺DNA中的链断裂。在组织培养中，浓度大于0.5 mM的抗坏血酸盐会增加MNU在L1210小鼠白血病细胞和豚鼠胰腺细胞中引起的DNA链断裂频率；单独的抗坏血酸盐会导致后一种细胞中的DNA链断裂。使用纯化的DNA对DNA损伤机制进行了研究。抗坏血酸盐在质粒DNA中产生单链和双链断裂。切割由铜（II）催化，受过氧化氢酶抑制，并被硫醇的存在所阻断。我们得出结论，抗坏血酸氧化过程中产生的超氧化物和过氧化氢会导致羟基自由基的产生，这些自由基可介导DNA链断裂并增强烷基化致癌物的作用。
