Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mutat Res. 2010 Jan 5;683(1-2):23-8. doi: 10.1016/j.mrfmmm.2009.10.002.
Chronic inflammatory processes induce oxidative and nitrative stress that trigger lipid peroxidation (LPO), whereby DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE) are generated. Miscoding etheno-modified DNA adducts including 1,N(6)-etheno-2'-deoxyadenosine (epsilondA) are formed by reaction of HNE with DNA-bases which are excreted in urine, following elimination from tissue DNA. An ultrasensitive and specific immunoprecipitation/HPLC-fluorescence detection method was developed for quantifying epsilondA excreted in urine. Levels in urine of Thai and European liver disease-free subjects were in the range of 3-6 fmol epsilondA/micromol creatinine. Subjects with inflammatory cancer-prone liver diseases caused by viral infection or alcohol abuse excreted massively increased and highly variable epsilondA-levels. Groups of Thai subjects (N=21) with chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC) due to HBV infection had 20, 73 and 39 times higher urinary epsilondA levels, respectively when compared to asymptomatic HBsAg carriers. In over two thirds of European patients (N=38) with HBV-, HCV- and alcohol-related liver disease, urinary epsilondA levels were increased 7-10-fold compared to healthy controls. Based on this pilot study we conclude: (i) high urinary epsilondA-levels, reflecting massive LPO-derived DNA damage in vivo may contribute to the development of HCC; (ii) epsilondA-measurements in urine and target tissues should thus be further explored as a putative risk marker to follow malignant progression of inflammatory liver diseases in affected patients; (iii) etheno adducts may serve as biomarkers to assess the efficacy of (chemo-)preventive and therapeutic interventions.
慢性炎症过程会引发氧化和硝化应激，从而触发脂质过氧化 (LPO)，由此产生的 DNA 反应性醛，如反式-4-羟基-2-壬烯醛 (HNE)。HNE 与 DNA 碱基反应形成的错配乙醯基修饰的 DNA 加合物，包括 1,N(6)-乙醯基-2'-脱氧腺苷 (epsilondA)，随后从组织 DNA 中排出并排泄到尿液中。我们开发了一种超灵敏和特异的免疫沉淀/HPLC-荧光检测法来定量尿液中排出的 epsilondA。泰国和欧洲无肝病受试者的尿液中 epsilondA 水平范围为 3-6 fmol epsilondA/微摩尔肌酐。患有病毒性感染或酒精滥用引起的炎症性易患癌症的肝脏疾病的受试者，其排出的 epsilondA 水平显著增加且高度可变。由于乙型肝炎病毒感染导致慢性肝炎、肝硬化或肝细胞癌 (HCC) 的泰国受试者组 (N=21)，其尿液中的 epsilondA 水平分别比无症状 HBsAg 携带者高 20、73 和 39 倍。在超过三分之二的乙型肝炎病毒 (HBV)、丙型肝炎病毒 (HCV) 和酒精相关的欧洲肝病患者 (N=38) 中，与健康对照组相比，尿液中的 epsilondA 水平增加了 7-10 倍。基于这项初步研究，我们得出结论：(i) 高尿液 epsilondA 水平反映了体内大量 LPO 衍生的 DNA 损伤，可能有助于 HCC 的发展；(ii) 因此，应进一步探索尿液和靶组织中的 epsilondA 测量值，作为受影响患者炎症性肝病恶性进展的潜在风险标志物；(iii) 乙醯基加合物可作为生物标志物，评估（化学）预防和治疗干预的疗效。
