Context matters: Contribution of specific DNA adducts to the genotoxic properties of the tobacco-specific nitrosamine NNK

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The tobacco-specific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals. It is classified as a Group 1 human carcinogen by the International Agency for Cancer Research. NNK is bioactivated upon cytochrome P450 catalyzed hydroxylation of the carbon atoms adjacent to the nitrosamino group to both methylating and pyridyloxobutylating agents. Both pathways generate a spectrum of DNA damage that contributes to the overall mutagenic and toxic properties of this compound. NNK is also reduced to form 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is also carcinogenic. Like NNK, NNAL requires metabolic activation to DNA alkylating agents. Methyl hydroxylation of NNAL generates pyridylhydroxybutyl DNA adducts, and methylene hydroxylation leads to DNA methyl adducts. The consequence of this complex metabolism is that NNK generates a vast spectrum of DNA damage, any form of which can contribute to the overall carcinogenic properties of this potent pulmonary carcinogen. This Perspective reviews the chemistry and genotoxic properties of the collection of DNA adducts formed from NNK. In addition, it provides evidence that multiple adducts contribute to the overall carcinogenic properties of this chemical. The adduct that contributes to the genotoxic effects of NNK depends on the context, such as the relative amounts of each DNA alkylating pathway occurring in the model system, the levels and genetic variants of key repair enzymes, and the gene targeted for mutation.

Original languageEnglish (US)
Pages (from-to)420-433
Number of pages14
JournalChemical research in toxicology
Issue number1
StatePublished - Jan 17 2017

Bibliographical note

Funding Information:
Lisa A. Peterson: 0000-0001-8715-4480 Funding The research on NNK conducted in Lisa Peterson’s lab is or has been funded by the following research grants from the National Institutes of Health: CA59887, CA115309, CA138338, and CA184987. The Analytical Biochemistry Shared Resource at the University of Minnesota is supported in part by Cancer Center Support Grant CA-77598. Notes The author declares no competing financial interest. Biography Lisa Peterson is a professor in the Division of Environmental Health Sciences and co-leader of the Carcinogenesis and Chemoprevention program in the Masonic Cancer Center, University of Minnesota. Her Ph.D. is in Pharmaceutical Chemistry from the University of California, San Francisco, where she studied with Neal Castagnoli, Jr. After postdoctoral studies with Fred Guengerich at Vanderbilt University, she joined Stephen Hecht’s group at the American Health Foundation in Valhalla, NY. In 1997, Lisa moved to the University of Minnesota. Her research focuses on mechanisms by which chemicals initiate carcinogenesis. She is an Associate Editor for Chemical Research in Toxicology.

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