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Review
. 2022 May 4;23(9):5109.
doi: 10.3390/ijms23095109.

Metabolism and DNA Adduct Formation of Tobacco-Specific N-Nitrosamines

Yupeng Li  1   2 , Stephen S Hecht  1
Affiliations
Review

Metabolism and DNA Adduct Formation of Tobacco-Specific N-Nitrosamines

Yupeng Li et al. Int J Mol Sci. .

Abstract

The tobacco-specific N-nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as "carcinogenic to humans" by the International Agency for Research on Cancer. In 1998, we published a review of the biochemistry, biology and carcinogenicity of tobacco-specific nitrosamines. Over the past 20 years, considerable progress has been made in our understanding of the mechanisms of metabolism and DNA adduct formation by these two important carcinogens, along with progress on their carcinogenicity and mutagenicity. In this review, we aim to provide an update on the carcinogenicity and mechanisms of the metabolism and DNA interactions of NNK and NNN.

Keywords: DNA adducts; NNK; NNN; metabolism; tobacco-specific N-nitrosamines.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Mechanisms of formation of tobacco-specific N-nitrosamines.
Scheme 2
Scheme 2
Mechanisms of NNK and NNAL metabolism.
Scheme 3
Scheme 3
Stereochemistry of the formation of NNAL and its glucuronides.
Scheme 4
Scheme 4
DNA-reactive intermediates formed by NNK and NNAL metabolism.
Figure 1
Figure 1
Structures of POB DNA base and phosphate adducts.
Figure 2
Figure 2
Structures of PHB DNA base and phosphate adducts.
Figure 3
Figure 3
Levels of PHB DNA adducts in lung and pancreatic DNA of rats treated with 5 ppm NNK or NNAL enantiomers in the drinking water for 10, 30, 50, or 70 weeks. NNK: filled circle; (S)-NNAL: square; (R)-NNAL: cross. Adapted from ref. [24], with the permission of Oxford University Press.
Figure 4
Figure 4
Structures of methyl DNA adducts and DNA adducts derived from formaldehyde.
Figure 5
Figure 5
Structures of isotope-labeled NNKs and AMMN.
Scheme 5
Scheme 5
Pathways of NNN metabolism.
Figure 6
Figure 6
Levels of N7-POB-Gua (open bars) and O2-POB-Thd (striped bars) in the tissues of rats treated with (S)- or (R)-NNN in the drinking water for up to 70 weeks. Adapted with permission from ref. [179]. Copyright 2013 American Chemical Society.
Figure 7
Figure 7
DNA adducts formed by NNN 5′-hydroxylation.
Figure 8
Figure 8
Structure of N6,N6-DHB-dAdo.
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