Dataset Information

Contribution of Tobacco Use and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone to Three Methyl DNA Adducts in Urine.

ABSTRACT: Human urinary DNA adducts may be useful surrogate biomarkers to estimate carcinogen exposure and activation, particularly if such adducts are of high selectivity from a specific carcinogen source. In this report, we provided evidence supporting tobacco use and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the dominant source for 3-methyladenine (3-mA), while nontobacco factors contribute significantly to 7-methylguanine and 1-methyladenine in the urine. Upon confirmation in human urine samples from larger populations in the future, urinary 3-mA may be used to estimate NNK bioactivation in smokers and to facilitate the development of a chemopreventive agent against NNK-induced carcinogenesis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6547140 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Contribution of Tobacco Use and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone to Three Methyl DNA Adducts in Urine.

Wang Yi Y Narayanapillai Sreekanth S Hu Qi Q Fujioka Naomi N Xing Chengguo C

Chemical research in toxicology 20180824 9

Human urinary DNA adducts may be useful surrogate biomarkers to estimate carcinogen exposure and activation, particularly if such adducts are of high selectivity from a specific carcinogen source. In this report, we provided evidence supporting tobacco use and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being the dominant source for 3-methyladenine (3-mA), while nontobacco factors contribute significantly to 7-methylguanine and 1-methyladenine in the urine. Upon confirmation in human ur ...[more]

PMID: 30136842

Similar Datasets

Project description:The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are potent pulmonary carcinogens in rats. NNK and NNAL require metabolic activation to express their carcinogenicity. Cytochrome P450-catalyzed alpha-hydroxylation at the methyl position of NNK or NNAL generates reactive intermediates, which alkylate DNA to form pyridyloxobutyl (POB)-DNA adducts or pyridylhydroxybutyl (PHB)-DNA adducts. NNK is metabolized to NNAL in a reversible and stereoselective manner, and the tissue-specific retention of (S)-NNAL is believed to be important to the carcinogenicity of NNK. In the present study, we investigated the formation of POB- and PHB-DNA adducts in extrahepatic tissues of F344 rats treated chronically with NNK and (R)- and (S)-NNAL (10 ppm in the drinking water, 1-20 weeks). POB- and PHB-DNA adducts were quantified in nasal olfactory mucosa, nasal respiratory mucosa, oral mucosa, and pancreas of treated rats. Adduct formation in the nasal respiratory mucosa exceeded that in the other tissues. O(2)-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dThd) or O(2)-[4-(3-pyridyl)-4-hydroxybut-1-yl]thymidine (O(2)-PHB-dThd) was the major adduct, followed by 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua) or 7-[4-(3-pyridyl)-4-hydroxybut-1-yl]guanine (7-PHB-Gua). There was a remarkable similarity in adduct formation between the NNK and the (S)-NNAL groups, both of which were distinctively different from that in the (R)-NNAL group. For example, in the nasal olfactory mucosa, POB-DNA adduct levels in the NNK and (S)-NNAL groups were not significantly different from each other, while (R)-NNAL treatment generated 6-33 times lower amounts of POB-DNA adducts than did NNK treatment. In contrast, (R)-NNAL treatment produced significantly higher levels of PHB-DNA adducts than did NNK or (S)-NNAL treatment. Similar trends were observed in the nasal respiratory mucosa, oral mucosa, and pancreas. These results suggest extensive retention of (S)-NNAL in various tissues of NNK-treated rats and support a mechanism in which the preferential metabolism of NNK to (S)-NNAL, followed by sequestration of (S)-NNAL in the target tissues and reoxidation to NNK, is important to NNK tumorigenesis.

Project description:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are carcinogenic in animal models and are believed to play an important role in human lung carcinogenesis for cigarette smokers. Cytochrome P450-mediated metabolism of these tobacco-specific nitrosamines produces reactive species that alkylate DNA in the form of pyridyloxobutyl (POB)- or pyridylhydroxybutyl (PHB)-DNA adducts. Understanding the formation mechanism and overall levels of these adducts can potentially enhance cancer prevention methods through the identification of particularly susceptible smokers. Previous studies have identified and measured a panel of POB- and PHB-DNA base adducts of dGuo, dCyd, and Thd; however, dAdo adducts have yet to be determined. In this study, we complete this DNA adduct panel by identifying and quantifying levels of NNK- and NNAL-derived dAdo adducts in vitro and in vivo. To accomplish this, we synthesized standards for expected dAdo-derived DNA adducts and used isotope-dilution LC-ESI+-MS/MS to identify POB adducts formed in vitro from the reaction of 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) with calf thymus DNA. Adduct levels were then quantified in lung and liver DNA of rats chronically treated with NNK or NNAL for 50 weeks using similar LC-MS detection methods. The in vitro studies identified N6-POB-dAdo and N1-POB-dIno as products of the reaction of NNKOAc with DNA, which supports our proposed mechanism of formation. Though both N6-dAdo and N1-dIno adducts were found in vitro, only N6-dAdo adducts were found in vivo, implying possible intervention by DNA repair mechanisms. Analogous to previous studies, levels of N6-POB-dAdo and N6-PHB-dAdo varied both with tissue and treatment type. Despite the adduct levels being relatively modest compared to most other POB- and PHB-DNA adducts, they may play a biological role and could be used in future studies as NNK- and NNAL-specific DNA damage biomarkers.

Dataset Information

Contribution of Tobacco Use and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone to Three Methyl DNA Adducts in Urine.

Publications

Contribution of Tobacco Use and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone to Three Methyl DNA Adducts in Urine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets