Mutations induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lacZ and cII genes of Muta™ Mouse

Hashimoto, Kiyohiro; Ohsawa, Koh-ichi; Kimura, Masaaki

doi:10.1016/j.mrgentox.2004.02.010

Cited by 23 publications

(14 citation statements)

References 24 publications

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“…Secondly, the formation of DNA adducts and their role in the development of pulmonary tumors in rodents following exposure to NNK is highly cell-specific (Belinsky et al, 1991). Thirdly, in vivo metabolic activation of NNK in the lung could result in pyridyloxobutylating species which bind to DNA at multiple hotspots of which only some are essential for mutagenesis (Ziegel et al, 2004;Hashimoto et al, 2004;Herzog et al, 2006). Therefore, a high background of total HPB-releasing DNA adducts in samples of peripheral lung from sources other than NNK could mask the presence of biologically relevant adducts at specific sites of DNA in susceptible cell populations.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

Schlöbe¹,

Hölzle²,

Hatz

et al. 2008

Toxicology

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Section: Discussionmentioning

confidence: 99%

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

Schlöbe¹,

Hölzle²,

Hatz

et al. 2008

Toxicology

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“…Studies in Muta ™ transgenic mice demonstrated that NNK was a potent inducer of lacZ and cII mutations in both lungs and liver. 113 Unlike the mutation spectrum in K- ras when the mutations were almost exclusively GC to AT mutations, the dominant mutation in the cII gene was AT to TA mutations, followed by AT to CG mutations. There was a more modest increase in GC to AT mutations at this gene loci.…”

Section: Contribution Of Specific Dna Adducts To the Genotoxic Andmentioning

confidence: 98%

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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“…Since these mutations were GC to AT transitions and GC to TA transversions, it is likely that O 6 -pobdG is responsible, in part, for these mutations. Both NNK and NNN have been shown to be mutagenic in target tissues in lac Z and lac I transgenic mice [88, 99–101]. The resulting transgene mutation spectra have only been reported for NNK [88, 101].…”

Section: Mutagenic Activity Of Pyridyloxobutyl Dna Adductsmentioning

confidence: 99%

“…Both NNK and NNN have been shown to be mutagenic in target tissues in lac Z and lac I transgenic mice [88, 99–101]. The resulting transgene mutation spectra have only been reported for NNK [88, 101]. NNK induced an increased rate of GC to AT transitional mutations at non-CpG sites as well as AT to TA transitional mutations and a mixture of transversion mutations (AT to GC, AT to CG, GC to CG, and GC to TA).…”

Section: Mutagenic Activity Of Pyridyloxobutyl Dna Adductsmentioning

confidence: 99%

Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco‐Specific Nitrosamines

Peterson¹

2010

Journal of Nucleic Acids

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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN) are tobacco-specific nitrosamines present in tobacco products and smoke. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers. These Group 1 human carcinogens are metabolized to reactive intermediates that alkylate DNA. This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds. This DNA route generates 7-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxycytosine, O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxythymidine, and O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine as well as unstable adducts which dealkylate to release 4-hydroxy-1-{3-pyridyl)-1-butanone or depyriminidate/depurinate to generate abasic sites. There are multiple repair pathways responsible for protecting against the genotoxic effects of these adducts, including adduct reversal as well as base and nucleotide excision repair pathways. Data indicate that several DNA adducts contribute to the overall mutagenic properties of pyridyloxobutylating agents. Which adducts contribute to the carcinogenic properties of this pathway are likely to depend on the biochemistry of the target tissue.

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Mutations induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lacZ and cII genes of Muta™ Mouse

Cited by 23 publications

References 24 publications

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims

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

Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco‐Specific Nitrosamines

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