Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis
Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis
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DOI：
10.1016/j.cdp.2004.07.004
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发表时间：
2004-01-01
影响因子：
--
通讯作者：
Nair, J
中科院分区：
文献类型：
--
作者：
Bartsch, H;Nair, J
在慢性炎症过程中，过量的自由基和脂质过氧化（LPO）产生的dna反应性醛（DNA-reactive aldehyde），会破坏细胞稳态，并驱使正常细胞向恶性肿瘤发展。乙烯（epsilon）修饰的DNA碱基是由DNA与LPO的主要产物反式-4-羟基-2-壬烯醛反应产生的。我们研究了易患癌症疾病患者的器官、血液或尿液中epsilon-DNA加合物的稳态水平，特别是与持续炎症过程有关的疾病。我们已经开发了灵敏和特异性的方法来检测加合物在体内。肝乙烯加合物水平在威尔森氏病和原发性血色素沉着症患者中显著升高。过量的铜/铁储存引起氧化应激和lpo来源的dna损伤，与疾病的发病机制有关，这一点在威尔逊病模型lec大鼠的研究中得到证实。当酒精相关性肝炎、脂肪肝、纤维化和肝硬化患者与无症状肝脏患者进行比较时，除肝炎患者外，所有患者均出现肝脏dna损伤。在诊断为慢性肝炎、肝硬化和肝细胞癌的hbv感染患者中测量尿中乙烯-脱氧腺苷的排泄量：与对照组相比，患者尿中乙烯-脱氧腺苷水平增加了20-90倍。总之：epsilon-DNA加合物可能作为评估炎性癌症易发疾病进展的潜在标记物。此外，人类化学预防干预的有效性可以通过使用我们的无创尿液检测来验证。影响易发癌组织中epsilon-DNA加合物稳态水平的机制和宿主因素正在研究中。(C) 2004国际预防肿瘤学会。Elsevier Ltd.出版。版权所有。
During chronic inflammatory processes an excess of free radicals and DNA-reactive aldehydes from lipid peroxidation (LPO) are produced, which deregulate cellular homeostasis and can drive normal cells to malignancy. Etheno (epsilon)-modified DNA bases are generated by reactions of DNA with a major LPO product, trans-4-hydroxy-2-nonenal. We investigated steady state levels of epsilon-DNA adducts in organs, blood or urine from patients with cancer prone diseases, especially when related to persistent inflammatory processes. We have developed sensitive and specific methods for adduct detection in vivo. Hepatic etheno-adduct levels were significantly elevated in patients with Wilson's disease and primary hemochromatosis. Excess storage of copper/ironcausing oxidative stress and LPO-derived DNA-damage, are implicated in disease pathogenesis as confirmed by studies in LEC-rats, a model for Wilson's disease. When patients with alcohol related hepatitis, fatty liver, fibrosis and cirrhosis were compared with asymptomatic livers, excess hepatic DNA-damage was seen in all patients, except those with hepatitis. Etheno-deoxyadenosine excreted in urine was measured in HBV-infected patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma: as compared to controls, patients had 20-90-fold increased urinary levels. In conclusion: epsilon-DNA adducts may serve as potential markers for assessing progression of inflammatory cancer-prone diseases. Also the efficacy of human chemopreventive interventions could be verified by using our non-invasive urine assay. Mechanisms and host-factors that influence the steady-state levels of epsilon-DNA adducts in cancer prone tissues are under investigation. (C) 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.