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.
Highlights
Tobacco use has been linked to a variety of human cancers, including lung, oral cavity, esophagus, pharynx, larynx, urinary bladder, pancreas, and liver cancers [1]
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
This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds
Summary
Tobacco use has been linked to a variety of human cancers, including lung, oral cavity, esophagus, pharynx, larynx, urinary bladder, pancreas, and liver cancers [1]. 4(Methylnitrosamino)-1-(3pyridyl)1-butanone (NNK) and N -nitrosonornicotine (NNN) are two of the most potent tobacco-specific nitrosamines present in tobacco products and smoke [8]. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers [8]. Adenocarcinoma is the most common type of lung cancer observed in humans, having surpassed squamous cell carcinoma [12,13,14,15,16] This shift in histology has been attributed not to improvements in diagnoses but rather to changing cigarette design, which has changed smoking behavior resulting in increased uptake of tobacco-specific nitrosamines by smokers [14]. For the purpose of this paper, we will focus on the pyridyloxobutylation pathway
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have