High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases

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,N6-etheno-2′-deoxyadenosine (ɛdA) 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 ɛdA excreted in urine. Levels in urine of Thai and European liver disease-free subjects were in the range of 3–6 fmol ɛdA/μmol creatinine. Subjects with inflammatory cancer-prone liver diseases caused by viral infection or alcohol abuse excreted massively increased and highly variable ɛdA-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 ɛdA 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 ɛdA levels were increased 7–10-fold compared to healthy controls. Based on this pilot study we conclude: (i) high urinary ɛdA-levels, reflecting massive LPO-derived DNA damage in vivo may contribute to the development of HCC; (ii) ɛdA-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.