Recent studies on mechanisms of bioactivation and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific lung carcinogen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)163-181
Number of pages19
JournalCritical Reviews in Toxicology
Volume26
Issue number2
DOIs
StatePublished - Jan 1 1996

Keywords

  • 0-methylguanine
  • 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone
  • Cytochromes
  • DNA adducts
  • DNA methylation
  • DNA pyridyloxobutylation
  • Glucuronidation
  • Hemoglobin adducts
  • K-ras oncogenes
  • Lung carcinogenesis
  • Metabolic activation
  • P450

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