DISTRIBUTION OF 7-ALKYL-2'-DEOXYGUANOSINE ADDUCT LEVELS IN HUMAN LUNG

Human lung tissue is frequently studied as a target organ for DNA dama ge from carcinogen-DNA adducts, In order to assess the distribution of carcinogen-DNA adducts in human lung, we measured 7-methyl-2'-deoxygu anosine-3'-monophosphate (7-methyl-dGp), 7-ethyl-2'-deoxyguanosine-3'- monophosphate (7-ethyl-dGp) and 4-hydroxy-(3-pyridyl)-1-butanone (HPB) -releasing DNA adducts in different lobes, The first two result from e xposure to N-nitrosamines, including tobacco-specific nitrosamines, an d the latter only from tobacco-specific nitrosamines. Using a chemical ly-specific P-32-postlabeling assay for 7-alkyl-2'-deoxyguanosines, ad ducts were measured in eight separate lung segments of ten autopsy don ors, 7-Methyl-dGp levels were detected in all eighty samples (range fr om 0.3 to 11.5 adducts/10(7) dGp; mean 2.5 +/- 2.3 adducts/10(7) dGp), 7-Ethyl-dGp were detected in all but five of the samples (range from <0.1 to 7.1 adducts/10(7) dGp; mean 1.6 +/- 1.7 adducts/10(7) dGp). 7- Methyl-dGp levels were approximately 1.5-fold higher than 7-ethyl-dGp levels, and they were positively correlated with each other in most in dividuals. There was no consistent pattern of adduct distribution in t he different lobar segments, Most individuals, especially those with t he lowest levels, had similar levels among the lobes, while those with the highest levels had a widely variable pattern ranging as much as t en-fold, Moreover, 7-methyl-dGp and 7-ethyl-dGp levels in all people s howed a highly significant inter-individual variation (P = 0.0001), Th e levels of 7-alkyl-2'-deoxyguanosine among individuals could not be e xplained by differences in tobacco exposure (measured by serum cotinin e), onset of death, gender, age, race, blood ethanol, or ventilation a nd perfusion variability, In an effort to corroborate 7-alkyl-2'-deoxy guanosine adducts variability among lobes or individuals, we sought to determine a correlation with HPB-releasing DNA adducts as an independ ent marker of tobacco exposure. However, this tobacco-specific carcino gen-DNA adduct could not be detected in four individuals tested (detec tion limit: 0.3 adducts per 10(7) dGp), Based upon the lack of 7-alkyl -2'-deoxyguanosine discernible adduct patterns, no conclusions could b e drawn regarding a potential relationship to lobar cancer incidence. The results indicate that in studies of carcinogen-DNA adducts, such a s 7-alkyl-dGp in human lungs, for most individuals a random lung sampl e would be representative of other parts of the lungs, Some individual s however might be misclassified due to highly variable 7-alkyl-dGp le vels.