Mass Spectrometric Quantitation of Apurinic/Apyrimidinic Sites in Tissue DNA of Rats Exposed to Tobacco-Specific Nitrosamines and in Lung and Leukocyte DNA of Cigarette Smokers and Nonsmokers
Year: 2020
Type: article
Abstract: Metabolic activation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N ′-nitrosonornicotine (NNN) results in formation of reactive electrophiles that modify DNA to produce a variety of products including methyl, 4-(3-pyridyl)-4-oxobutyl (POB)-, and 4-(3-pyridyl)-4-hydroxybutyl adducts. Among these are adducts such as 7-POB-deoxyguanosine (N 7 POBdG) which can lead to apurinic/apyrimidinic (AP) sites by facile hydrolysis of the base-deoxyribonucleoside bond. In this study, we used a recently developed highly sensitive mass spectrometric method to quantitate AP sites by derivatization with O -(pyridin-3-yl-methyl)hydroxylamine (PMOA) (detection limit, 2 AP sites per 10 8 nucleotides). AP sites were quantified in DNA isolated from tissues of rats treated with NNN and NNK and from human lung tissue and leukocytes of cigarette smokers and nonsmokers. Rats treated with 5 or 21 mg/kg bw NNK for 4 days by s.c. injection had 2–6 and 2–17 times more AP sites than controls in liver and lung DNA ( p < 0.05). Increases in AP sites were also found in liver DNA of rats exposed for 10 and 30 weeks ( p < 0.05) but not for 50 and 70 weeks to 5 ppm of NNK in their drinking water. Levels of N 7 POBG were significantly correlated with AP sites in rats treated with NNK. In rats treated with 14 ppm ( S )-NNN in their drinking water for 10 weeks, increased AP site formation compared to controls was observed in oral and nasal respiratory mucosa DNA ( p < 0.05). No significant increase in AP sites was found in human lung and leukocyte DNA of cigarette smokers compared to nonsmokers, although AP sites in leukocyte DNA were significantly correlated with urinary levels of the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). This is the first study to use mass spectrometry based methods to examine AP site formation by carcinogenic tobacco-specific nitrosamines in laboratory animals and to evaluate AP sites in DNA of smokers and nonsmokers.
Source: Chemical Research in Toxicology
Institutions: University of Minnesota, Masonic Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Awards: LABORATORY ASSESSMENT OF TOBACCO USE BEHAVIOR AND EXPOSURE TO TOXINS AMONG USERS, G2814592496, Metabolism of Carcinogenic Tobacco-Specific Nitrosamines, Metabolism of Carcinogenic Tobacco-Specific Nitrosamines, Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation, G795411066, Cancer Center Support Grant
OpenAlex ID: W3081044412