Synthesis of tobacco-specific N-nitrosamines and their metabolites and results of related bioassays

Shantu Amin, Dhimant Desai, Stephen S. Hecht, Dietrich Hoffmann

Research output: Contribution to journalReview articlepeer-review

34 Scopus citations


Tobacco-specific N-nitrosamines (TSNA) are the most abundant, strong carcinogens in tobacco smoke. Seven TSNA have been identified in tobacco products: N'-nitrosonornicotine (NNN), N'-nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), and 4-(methylnitrosamino)-4-3-pyridyl)butyric acid (iso-NNAC). The syntheses of these compounds are reviewed. The syntheses of 14C- and 3H-labeled NNK as well as metabolites of NNK and NNN are also discussed. Comparative assays for lung tumorigenesis in female A/J mice were carried out for six of the TSNA and for two related compounds, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR). They yielded the following ranking of potency: NDMA>NNK>NNAL> NPYR>NNN>NAB. Iso-NNAL and iso-NNAC were inactive. These results are also compared with previous assays of TSNA carcinogenicity in rats and hamsters.

Original languageEnglish (US)
Pages (from-to)139-147
Number of pages9
JournalCritical Reviews in Toxicology
Issue number2
StatePublished - 1996

Bibliographical note

Funding Information:
Our studies are supported by grants CA-29580, CA-44377, andNO1-CP-21 I15 from the U.S. National Cancer Institute.


  • Carcinogenicity
  • Esophagus
  • Lung
  • Metabolic activation
  • Oral cavity
  • Pancreas
  • Synthesis
  • Tobacco-specific N-nitrosamines
  • α-hydroxylation.


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