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Recent Studies on Mechanisms of Bioactivation and Detoxification of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK), A Tobacco-Specific Lung Carcinogen
Published in Roger O. McClellan, Critical Reviews in Toxicology, 2017
Collectively, the presently available results favor an important role for O6-mG in tumor induction by NNK in the A/J mouse; studies in rats uniformly indicate that other factors, including DNA pyridyloxobutylation, are critical. Oxidative damage to DNA and single-strand breaks also may be involved in tumor induction by NNK. Although this discussion has focused on DNA damage and its role in carcinogenesis, other factors are clearly involved. Lung tumor induction by NNK in the C3H mouse resulted in ras activation, as in the A/J mouse, yet the tumors were smaller and less numerous than in the A/J mouse.74 In the C57BL/6 mouse, another “resistant” strain, O6-mG formation by NNK was similar to that observed in the A/J mouse, but K-ras activation and tumor formation were less prevalent.75
Introduction
Published in R. A. Jenkins, M. R. Guerin, B. A. Tomkins, The Chemistry of Environmental Tobacco Smoke, 2000
R. A. Jenkins, M. R. Guerin, B. A. Tomkins
N-Nitrosamines are potentially important constituents of ETS because many are carcinogenic and because tobacco smoking is thus far their only identified source in nonoccupational indoor air. N-nitrosamines of concern (e.g., Hoffmann et al. 1987) fall into two classes, the Volatile Nitrosamines (VNAs) and the Tobacco-Specific Nitrosamines (TSNAs). VNAs of concern include nitrosodimethylamine (NDMA), nitrosodiethylamine (NDEA), and nitrosopyrrolidine (NPYR). TSNAs of concern in ETS exposure are Nn i t r o s o n o r n i c o t i n e (NNN) and 4 - ( m e t h y 1 -nitrosamino)-l -(3-pyridyl)-l-butanone (NNK). NNN and NNK are especially potent carcinogens in hamsters, rats, and mice when applied topically, and NNK has been identified as a possible human lung carcinogen.
Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis
Published in Journal of Environmental Science and Health, Part C, 2019
Dongying Li, William H. Tolleson, Dianke Yu, Si Chen, Lei Guo, Wenming Xiao, Weida Tong, Baitang Ning
Exposures to environmental agents may affect miRNA levels which then affect CYP expression and CYP-dependent chemical bioactivation and carcinogenesis. Lung cancer is a leading cause of cancer death in the world and 80-90% of all lung cancers can be attributed to tobacco smoking.77,78 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen that contributes to lung cancer development.79 Kalscheuer et al.66 used male F344 rats treated with NNK for 20 weeks, an early stage of lung carcinogenesis in this model, to identify changes in expression profiles for pulmonary miRNAs. They found that NNK treatment decreased the expression of cancer-associated miRNAs, including miR-34, miR-101, miR-126*, and miR-199; however, the NNK treatment upregulated rat CYP2A3 (an ortholog of human CYP2A13), which is the primary catalyst of NNK bioactivation in the lungs. They demonstrated that miR-126* interacts with an MRE present in the 3′-UTR of CYP2A3 mRNA, suggesting that NNK enhances its oncogenic effects through downregulation of miR-126* to release its block on the expression of CYP2A3 to potentiate further NNK metabolism.
Effects of tobacco compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the expression of epigenetically regulated genes in lung carcinogenesis
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Sun Woo Jin, Jong Seung Im, Jae Hyeon Park, Hyung Gyun Kim, Gi Ho Lee, Se Jong Kim, Seung Jun Kwack, Kyu-Bong Kim, Kyu Hyuck Chung, Byung Mu Lee, Sam Kacew, Hye Gwang Jeong, Hyung Sik Kim
Therefore, identifying the epigenetic regulation of target genes induced by NNK may provide additional clues regarding novel biomarkers which occur in cigarette smoking-initiated pulmonary carcinogenesis. The aim of this study was to identify epigenetically regulated target genes in mouse lung tissues following intratracheal administration of NNK. It was postulated that NNK exposure alters DNA methylation patterns in promoter regions, leading to increased susceptibility to lung carcinogenesis occurrence.