Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis.
Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.
Nair
Jagadeesan
J
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Gansauge
Frank
F
Beger
Hans
H
Dolara
Piero
P
Winde
Günther
G
Bartsch
Helmut
H
D015415:Biomarkers / Q000032:analysis; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003424:Crohn Disease / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D010084:Oxidation-Reduction; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000378:metabolism*
D015415:Biomarkers; D018736:DNA Adducts