Accumulation of lipid peroxidation-derived DNA lesions: potential lead markers for chemoprevention of inflammation-driven malignancies.
Chronic inflammatory processes produce an excess of ROS and DNA-reactive aldehydes from lipid peroxidation (LPO), such as trans-4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), which can modify cellular macromolecules and drive to malignancy. Etheno-modified DNA bases are generated inter alia by reaction of DNA with the major LPO product, HNE. We are investigating steady-state levels of etheno-DNA adducts in organs with diseases related to persistent inflammatory processes that can lead to malignancies. We have developed ultrasensitive and specific methods for the detection of etheno-DNA base adducts in human tissues and in 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. When patients with alcohol abuse-related hepatitis, fatty liver, fibrosis and cirrhosis were compared with asymptomatic livers, excess hepatic DNA damage was seen in the three latter patient groups. Etheno-deoxyadenosine excreted in urine was measured in HBV-infected patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma. As compared to controls, these patients had up to 90-fold increased urinary levels. Impaired or imbalanced DNA-repair pathways may influence the steady-state levels of etheno-DNA adducts in inflamed tissues. In conclusion, etheno-DNA adducts may serve as potential lead markers for assessing progression of inflammatory cancer-prone diseases. If so, the efficacy of human chemopreventive interventions for malignant disease prevention could be verified.
Bartsch
Helmut
H
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. h.bartsch@dkfz.de
Nair
Jagadeesan
J
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts; D004249:DNA Damage; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008315:Malondialdehyde / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D018384:Oxidative Stress; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors
D000447:Aldehydes; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D000431:Ethanol; D008315:Malondialdehyde; C027576:4-hydroxy-2-nonenal