Bartsch Helmut, Nair Jagadeesan
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Langenbecks Arch Surg. 2006 Sep;391(5):499-510. doi: 10.1007/s00423-006-0073-1. Epub 2006 Aug 15.
Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases.
Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn's disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed.
Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.
由生物、化学和物理因素诱导的慢性炎症与人体多个部位患癌风险增加有关。慢性炎症过程会诱导氧化/亚硝化应激和脂质过氧化（LPO），从而产生过量的活性氧（ROS）、活性氮（RNS）和DNA反应性醛类。DNA与这些主要的LPO产物反应会产生错编码的乙烯基和丙酰基修饰的DNA碱基。研究了受持续性炎症过程影响的器官中LPO衍生的（乙烯基）DNA加合物的稳态水平，将其作为评估炎症性易患癌疾病进展的潜在先导标志物。
使用超灵敏且特异的检测方法分析人体组织、细胞和尿液，发现慢性胰腺炎、溃疡性结肠炎和克罗恩病患者受影响器官中的乙烯基DNA加合物水平显著升高。酒精性肝病患者的肝脏DNA损伤过量，从肝炎、脂肪肝到肝硬化呈逐渐增加趋势。乙型肝炎病毒相关慢性肝炎和肝硬化患者尿液中DNA修复后排出的乙烯基脱氧腺苷增加了90倍。本文综述了可能控制炎症组织中DNA损伤的潜在机制，包括受损或失衡的DNA修复途径。
炎症过程以自我延续的方式诱导持续性氧化/亚硝化应激和过量的LPO，并导致靶器官中DNA损伤的逐渐积累。与细胞稳态失调一起，由此产生的基因变化成为慢性炎症相关人类疾病发病机制的驱动力。因此，由ROS、RNS和LPO终产物引起的DNA损伤稳态水平为风险预测提供了有前景的分子特征，也为预防措施提供了潜在靶点和生物标志物。
