Recent studies on mechanisms of bioactivation and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen.
This article reviews recent advances in the biochemistry and molecular biology of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific pulmonary carcinogen believed to be involved in the induction of lung cancer in smokers. Several aspects of NNK bioactivation are addressed, including identification of its metabolites in laboratory animals and humans, cytochrome P450 enzyme involvement in its metabolic activation, DNA and protein adduct formation, biological significance of the major DNA adducts formed, and mutations in oncogenes from tumors induced by NNK. Collectively, the presently available data provide a reasonably clear picture of NNK bioactivation in rodents, although there are still important gaps in our mechanistic understanding of NNK-induced tumorigenesis. The studies in rodents and primates have facilitated development of methods to assess NNK bioactivation in humans, which will be applicable to studies of lung cancer susceptibility and prevention.
Hecht
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American Health Foundation, Valhalla, NY 10595, USA.
D000818:Animals; D000830:Animals, Laboratory; D002273:Carcinogens / Q000009:adverse effects / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D051379:Mice; D009154:Mutation; D009602:Nitrosamines / Q000009:adverse effects / Q000378:metabolism*; D009857:Oncogenes / Q000187:drug effects; D010947:Plants, Toxic; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D051381:Rats; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D014026:Nicotiana / Q000737:chemistry
D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)