Cochrane C G
Department of Immunology, Scripps Research Institute, La Jolla, California 92037.
Am J Med. 1991 Sep 30;91(3C):23S-30S. doi: 10.1016/0002-9343(91)90280-b.
Oxidants, generated by stimulated leukocytes, induce a variety of distinct biochemical changes in target cells. Hypochlorous acid (HOCl), produced by the action of peroxidase on hydrogen peroxide (H2O2) in the presence of chloride ions, acts at low molar concentrations (10-20 microM) to damage proteins on cell membranes and destroy their function. H2O2 rapidly permeates cells and causes inhibition of adenosine triphosphate (ATP) synthesis via both glycolytic and oxidative phosphorylation (mitochondrial) pathways. In the glycolytic pathway, damage is limited to the step involving glyceraldehyde-3-PO4 dehydrogenase (GAPDH). This results from both an attack of H2O2 on GAPDH and, indirectly, by a reduction in concentration of the GAPDH cofactor, nicotinamide adenine dinucleotide (NAD). This latter effect was found to result from activation of the enzyme, poly(adenosine diphosphate) (ADP)-ribose polymerase, an enzyme involved in deoxyribonucleic acid (DNA) repair. DNA damage in target cells was found at low concentrations of H2O2 (20-80 microM) in many cell types. Strand breaks and base hydroxylation were observed, resulting in the generation of hydroxyl radicals (.OH) from H2O2, in the presence of a transition metal. DNA damage resulted in either cell injury and death or mutations of the base sequence and amino acid residues. These latter effects led to malignant transformations in cultured cells in both tissue cultures of the cells, and in vivo in athymic mice. Exposure of a proto-oncogene, K-ras 4B, also led to the development of a malignant transformation by virtue of mutations in codon positions 12 and 61. Thus, oxidant effects on target cells can damage multiple functional pathways inside the cells, as well as give rise to malignant transformation via DNA damage.
受刺激的白细胞产生的氧化剂会在靶细胞中引发多种不同的生化变化。在氯离子存在的情况下，过氧化物酶作用于过氧化氢（H2O2）产生的次氯酸（HOCl），在低摩尔浓度（10 - 20微摩尔）时就会作用于细胞膜上的蛋白质并破坏其功能。H2O2能迅速渗透进入细胞，并通过糖酵解和氧化磷酸化（线粒体）途径抑制三磷酸腺苷（ATP）的合成。在糖酵解途径中，损伤仅限于涉及甘油醛-3-磷酸脱氢酶（GAPDH）的步骤。这是由于H2O2对GAPDH的攻击，以及间接导致的GAPDH辅因子烟酰胺腺嘌呤二核苷酸（NAD）浓度降低所致。后一种效应被发现是由聚（二磷酸腺苷）（ADP）-核糖聚合酶的激活引起的，该酶参与脱氧核糖核酸（DNA）修复。在许多细胞类型中，低浓度的H2O2（20 - 80微摩尔）就能导致靶细胞中的DNA损伤。观察到链断裂和碱基羟基化，在过渡金属存在的情况下，会导致从H2O2产生羟基自由基（·OH）。DNA损伤导致细胞损伤和死亡，或者碱基序列和氨基酸残基发生突变。后一种效应在细胞的组织培养以及无胸腺小鼠体内均导致培养细胞发生恶性转化。原癌基因K-ras 4B的暴露，也由于密码子位置12和61的突变而导致恶性转化的发生。因此，氧化剂对靶细胞的作用既能损害细胞内的多种功能途径，也能通过DNA损伤引发恶性转化。
