Carcinogenesis, Vol. 23, No. 12, 2081-2086,
December 2002
© 2002 Oxford University Press
CARCINOGENESIS |
Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking*
1 German Cancer Research Center (DKFZ), Division of Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany,
2 University of Maastricht, Department of Health Risk Analysis and Toxicology, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands and
3 Thoraxklinik Heidelberg-Rohrbach, Amalienstraße 5, 69126 Heidelberg, Germany
Cigarette smokers inhale a broad range of carcinogens derived from tobacco and its pyrolysis products, including free radicals, which induce oxidative stress and subsequent lipid peroxidation (LPO). Miscoding carcinogen–DNA adducts are formed by cigarette smoke constituents and are thought to initiate lung carcinogenesis. The presence of various types of DNA damage was therefore analyzed in tumor adjacent uninvolved lung tissues of 13 smoking and 11 non-smoking operated lung cancer patients. O4-ethylthymidine (O4etT), 1,N6-ethenodeoxyadenosine (
dA) and 3,N4-ethenodeoxycytidine (dC) were determined by immuno-enriched 32P-postlabeling. Polycyclic aromatic hydrocarbon (PAH)–DNA adducts were measured as diagonal radioactive zones after nuclease P1 enriched 32P-postlabeling. Mean O4etT and PAH–DNA adduct levels were higher in lung DNA of smokers than of non-smokers (O4etT/108 thymidine: 3.8 versus 1.6, P < 0.01; PAH–DNA adducts/108 nucleotides: 11.2 versus 2.2, P < 0.01). Pulmonary etheno–DNA adduct levels did not differ between smokers and non-smokers, but large inter-individual variations were observed (80- and 250-fold differences for dA and dC, respectively). As all smokers (except one) refrained from smoking at least for 1 week before surgery, our results demonstrate the persistence of O4etT and PAH–DNA adducts in human lung. A positive correlation obtained between O4etT and PAH–DNA adducts (R = 0.65, P < 0.01) suggests that both adducts are formed from cigarette smoke as the main exposure source. We conclude that in addition to the DNA adducts derived from PAH and tobacco-specific nitrosamines, miscoding O4etT lesions are formed by cigarette smoke that contribute to the increased genomic instability and increased lung cancer risk in smokers.
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