Nair Urmila, Bartsch Helmut, Nair Jagadeesan
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Free Radic Biol Med. 2007 Oct 15;43(8):1109-20. doi: 10.1016/j.freeradbiomed.2007.07.012. Epub 2007 Jul 20.
Persistent oxidative stress and excess lipid peroxidation (LPO), induced by inflammatory processes, impaired metal storage, and/or dietary imbalance, cause accumulations and massive DNA damage. This massive DNA damage, along with deregulation of cell homeostasis, leads to malignant diseases. Reactive aldehydes produced by LPO, such as 4-hydroxy-2-nonenal, malondialdehyde, acrolein, and crotonaldehyde, react directly with DNA bases or generate bifunctional intermediates which form exocyclic DNA adducts. Modification of DNA bases by these electrophiles, yielding promutagenic exocyclic adducts, is thought to contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. Ultrasensitive detection methods have facilitated studies of the concentrations of promutagenic DNA adducts in human tissues, white blood cells, and urine, where they are excreted as modified nucleosides and bases. Thus, immunoaffinity-(32)P-postlabeling, high-performance liquid chromatography-electrochemical detection, gas chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, immunoslotblot assay, and immunohistochemistry have made it possible to detect background concentrations of adducts arising from endogenous LPO products in vivo and studies of their role in carcinogenesis. These background adduct levels in asymptomatic human tissues occur in the order of 1 adduct/10(8) and in organs affected by cancer-prone inflammatory diseases these can be 1 or 2 orders of magnitude higher. In this review, we critically discuss the accuracy of the available methods and their validation and summarize studies in which measurement of exocyclic adducts suggested new mechanisms of cancer causation, providing potential biomarkers for cancer risk assessment in humans with cancer-prone diseases.
由炎症过程、金属储存受损和/或饮食失衡诱导的持续性氧化应激和过量脂质过氧化（LPO）会导致积累和大量DNA损伤。这种大量DNA损伤，连同细胞稳态失调，会引发恶性疾病。LPO产生的反应性醛，如4-羟基-2-壬烯醛、丙二醛、丙烯醛和巴豆醛，直接与DNA碱基反应或生成形成环外DNA加合物的双功能中间体。这些亲电试剂对DNA碱基的修饰产生促突变性环外加合物，被认为与氧化应激诱导的LPO相关的诱变和致癌作用有关。超灵敏检测方法促进了对人体组织、白细胞和尿液中促突变性DNA加合物浓度的研究，这些加合物以修饰的核苷和碱基形式排泄。因此，免疫亲和 - （32）P后标记、高效液相色谱 - 电化学检测、气相色谱 - 质谱、液相色谱 - 串联质谱、免疫斑点印迹分析和免疫组织化学使得检测体内内源性LPO产物产生的加合物背景浓度以及研究它们在致癌作用中的作用成为可能。无症状人体组织中的这些背景加合物水平约为1个加合物/10（8），而在易患癌症的炎症性疾病影响的器官中，这些水平可能高出1或2个数量级。在本综述中，我们批判性地讨论了现有方法的准确性及其验证，并总结了其中环外加合物测量提示癌症病因新机制的研究，为易患癌症疾病的人类癌症风险评估提供潜在生物标志物。
