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

Abstract

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.

A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer

“…Even if we cannot rule out the involvement of other defects in DNA repair genes, mutations imputed to COSMIC-5-like signatures may be a direct consequence of exposure to the carcinogen. Since tobacco-specific nitrosamines similar to BBN can generate bulky DNA adducts that are substrates for NER [ 43 ], the extended BBN exposure might saturate the DNA repair capabilities of bladder cells, resulting in mutagenesis patterns equivalent to those linked to ERCC2 defects.…”

Roles of translesion synthesis DNA polymerases in the potent mutagenicity of tobacco-specific nitrosamine-derived O2-alkylthymidines in human cells

“…It is well established that NNK, a tobacco specific nitrosamine, is a potent carcinogen in experimental animals and humans [4, 33, 34]. During metabolic activation of NNK, multiple reactive intermediates are generated that react with DNA, forming adducts, which are presumed to play a role in chemical carcinogenesis [8].…”

Tobacco-Specific Nitrosamine-Derived O2-Alkylthymidines Are Potent Mutagenic Lesions in SOS-Induced Escherichia coli

“…1,2 NNK is a potent lung carcinogen, but it also induces tumors in the liver, nasal cavity, and pancreas. 3,4 NNN induces tumors in the esophagus, nasal cavity, and respiratory tract.…”