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The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a lung carcinogen in rats and may be a cause of lung cancer in smokers. NNK is metabolized by cytochromes P450 to intermediates that react with DNA forming methyl, pyridyloxobutyl (POB), and pyridylhydroxybutyl (PHB) adducts, which are critical in carcinogenesis. The methyl adduct O(6)-methylguanine (O(6)-methyl-G) has miscoding properties, but there are no reports on levels of this adduct in rats treated chronically with NNK in the drinking water, nor has its levels been compared with those of POB- and PHB-DNA adducts. We used liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring to quantify O(6)-methyl-G in lung and liver DNA of rats treated with a carcinogenic dose of 10 ppm of NNK in the drinking water and sacrificed after 1, 2, 5, 10, 16, and 20 weeks. The maximal level of O(6)-methyl-G in lung DNA, 2550 +/- 263 fmol/mg DNA, was reached at 5 weeks and was significantly greater (P &lt; 0.05) at that point than all other adducts (measured previously) except O(2)-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine. Overall levels of O(6)-methyl-G in lung were intermediate between those of total POB- and PHB-DNA adducts. In liver, the wave of O(6)-methyl-G peaked at 2 weeks while that of total POB-DNA adducts peaked at 10 weeks, and levels of total PHB-DNA adducts were low throughout. The results of this study demonstrate that substantial amounts of O(6)-methyl-G are formed at various time points in lung and liver DNA of rats treated chronically with NNK, supporting its role in carcinogenesis.

drug metabolism and disposition/dmd online

Comparative Levels of <i>O</i><sup>6</sup>-Methylguanine, Pyridyloxobutyl-, and Pyridylhydroxybutyl-DNA Adducts in Lung and Liver of Rats Treated Chronically with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

Comparative Levels of O6-Methylguanine, Pyridyloxobutyl-, and Pyridylhydroxybutyl-DNA Adducts in Lung and Liver of Rats Treated Chronically with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

Comparative Levels of O⁶-Methylguanine, Pyridyloxobutyl-, and Pyridylhydroxybutyl-DNA Adducts in Lung and Liver of Rats Treated Chronically with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone