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

Upadhyaya, Pramod; Lindgren, Bruce R.; Hecht, Stephen S.

doi:10.1124/dmd.109.027078

Cited by 36 publications

(47 citation statements)

References 16 publications

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“…For DNA adduct analyses, DNA samples were extracted from lung tissues, hydrolyzed and purified as described previously (Upadhyaha et al, 2009). A stable-isotope liquid chromatography–nanoelectrospray high-resolution tandem mass spectrometry–parallel reaction monitoring (LC–NSI-HRMS/MS–PRM) method was used to analyze the DNA samples as described elsewhere (Lao et al, 2006; Balbo et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability

Song¹,

Kirtane²,

Upadhyaya³

et al. 2014

International Journal of Pharmaceutics

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Indole-3-carbinol (I3C), a constituent of commonly consumed Brassica vegetables, has been shown to have anticancer effects in a variety of preclinical models of lung cancer. However, it has shown only limited efficacy in clinical trials, likely due to its poor oral bioavailability. Intranasal administration of I3C has the potential to enhance the pulmonary accumulation of the drug, thereby improving its availability at the target site of action. In this study, we developed a liposomal formulation of I3C and evaluated its lung delivery and chemopreventive potential in tobacco smoke carcinogen [4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK)]-treated mice. Intranasal administration of I3C liposomes led to a ~100-fold higher lung exposure of I3C than the oral route of administration. Further, intranasal delivery of liposomal I3C led to a significant reduction (37%; p<0.05) in the levels of the DNA adduct formation induced by NNK treatment. Liposomal I3C also significantly increased (by 10-fold) the expression of CYP1A1, a cytochrome P450 enzyme known to increase the detoxification of chemical carcinogens by enhancing their metabolism. Overall, our findings demonstrate that intranasal administration of liposomal I3C has the potential to significantly improve the efficacy of I3C for lung cancer chemoprevention.

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Section: Methodsmentioning

confidence: 99%

Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability

Song¹,

Kirtane²,

Upadhyaya³

et al. 2014

International Journal of Pharmaceutics

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“…17,18,36,37 LC-ESI + -MS/MS conditions were the same as described above for our in vitro experiment except SRM transitions were added for N 6 -PHB-dAdo ( m/z 401.1 → m/z 132.1), N 1 -PHB-dIno ( m/z 402.1 → m/z 286.1), and [ 15 N 5 ] N 6 -PHB-dAdo ( m/z 406.1 → m/z 132.1) at collision energies of 26, 10, 26 eV, respectively. Corresponding fragmentation patterns are shown in Figure S2.…”

Section: Methodsmentioning

confidence: 99%

Analysis and Identification of 2′-Deoxyadenosine-Derived Adducts in Lung and Liver DNA of F-344 Rats Treated with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol

Carlson

Upadhyaya

Villalta

et al. 2018

Chem. Res. Toxicol.

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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 in 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.

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“…28, 29, 61, 89, 120 The levels of hydroxybutyl DNA adducts are lower than the levels of the pyridyloxobutyl DNA adducts. 28, 121 As with O 2 -pobdThd, O 2 -phbdT accumulates in lung DNA with chronic treatment. 121 …”

Section: Contribution Of Specific Dna Adducts To the Genotoxic Andmentioning

confidence: 99%

Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK

Peterson

2016

Chem. Res. Toxicol.

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The tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals. It is classified as a Group 1 human carcinogen by the International Agency for Cancer Research. NNK is bioactivated upon cytochrome P450 catalyzed hydroxylation of the carbon atoms adjacent to the nitrosamino group to both methylating and pyridyloxobutylating agents. Both pathways generate a spectrum of DNA damage that contributes to the overall mutagenic and toxic properties of this compound. NNK is also reduced to form 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which is also carcinogenic. Like NNK, NNAL requires metabolic activation to DNA alkylating agents. Methyl hydroxylation of NNAL generates pyridylhydroxybutyl DNA adducts and methylene hydroxylation leads to DNA methyl adducts. The consequence of this complex metabolism is that NNK generates a vast spectrum of DNA damage, any of which can contribute to the overall carcinogenic properties of this potent pulmonary carcinogen. This article reviews the chemistry and the genotoxic properties of the collection of DNA adducts formed from NNK. In addition, it provides evidence that multiple adducts contribute to the overall carcinogenic properties of this chemical. Which adduct contributes to the genotoxic effects of NNK depends on the context, such as the relative amounts of each DNA alkylating pathway occurring in the model system, the levels and genetic variants of key repair enzymes and the gene targeted for mutation.

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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

Cited by 36 publications

References 16 publications

Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability

Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability

Analysis and Identification of 2′-Deoxyadenosine-Derived Adducts in Lung and Liver DNA of F-344 Rats Treated with the Tobacco-Specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol

Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK

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