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,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.
Nair
Jagadeesan
J
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Srivatanakul
Petcharin
P
Haas
Claudia
C
Jedpiyawongse
Adisorn
A
Khuhaprema
Thiravud
T
Seitz
Helmut K
HK
Bartsch
Helmut
H
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking; D000447:Aldehydes / Q000652:urine; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000652:urine; D016022:Case-Control Studies; D018736:DNA Adducts / Q000652:urine; D004249:DNA Damage; D003839:Deoxyadenosines / Q000652:urine*; D005060:Europe; D006509:Hepatitis B / Q000235:genetics / Q000652:urine*; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000652:urine*; D008113:Liver Neoplasms / Q000235:genetics / Q000652:urine*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
C115182:1,N(6)-etheno-2'-deoxyadenosine; D000447:Aldehydes; D018736:DNA Adducts; D003839:Deoxyadenosines; D006514:Hepatitis B Surface Antigens; C027576:4-hydroxy-2-nonenal