Role of aldehydes in the toxic and mutagenic effects of nitrosamines

Lisa A. Peterson, Anna M. Urban, Choua C. Vu, Meredith E. Cummings, Lee C. Brown, Janel K. Warmka, Li Li, Elizabeth V. Wattenberg, Yesha Patel, Daniel O. Stram, Anthony E. Pegg

Research output: Contribution to journalArticle

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Abstract

α-Hydroxynitrosamine metabolites of nitrosamines decompose to a reactive diazohydroxide and an aldehyde. To test the hypothesis that the aldehydes contribute to the harmful effects of nitrosamines, the toxic and mutagenic activities of three model methylating agents were compared in Chinese hamster ovary cells expressing or not expressing human O6- alkylguanine DNA alkyltransferase (AGT). N-Nitrosomethylurethane (NMUr), acetoxymethylmethylnitrosamine (AMMN), and 4-(methylnitrosamino)-4-acetoxy-1-(3- pyridyl)-1-butanone (NNK-4-OAc) are all activated by ester hydrolysis to methanediazohydroxide. NMUr does not form an aldehyde, whereas AMMN generates formaldehyde, and NNK-4-OAc produces 4-oxo-1-(3-pyridyl)-1-butanone (OPB). Since these compounds were likely to alkylate DNA to different extents, the toxic and mutagenic activities of these compounds were normalized to the levels of the most cytotoxic and mutagenic DNA adduct, O6-mG, to assess if the aldehydes contributed to the toxicological properties of these methylating agents. Levels of 7-mG indicated that the differences in cytotoxic and mutagenic effects of these compounds resulted from differences in their ability to methylate DNA. When normalized against the levels of O6-mG, there was no difference between these three compounds in cells that lacked AGT. However, AMMN and NNK-4-OAc were more toxic than NMUr in cells expressing AGT when normalized against O6-mG levels. In addition, AMMN was more mutagenic than NNK-4-OAc and MNUr in these cells. These findings demonstrate that the aldehyde decomposition products of nitrosamines can contribute to the cytotoxic and/or mutagenic activity of methylating nitrosamines.

Original languageEnglish (US)
Pages (from-to)1464-1473
Number of pages10
JournalChemical research in toxicology
Volume26
Issue number10
DOIs
StatePublished - Nov 4 2013

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Nitrosamines
Nitrosomethylurethane
Poisons
Aldehydes
Butanones
pyrazine-2-diazohydroxide
Cells
DNA Adducts
DNA
Metabolites
Cricetulus
Toxicology
Formaldehyde
Ovary
Hydrolysis
Esters
Decomposition

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Peterson, L. A., Urban, A. M., Vu, C. C., Cummings, M. E., Brown, L. C., Warmka, J. K., ... Pegg, A. E. (2013). Role of aldehydes in the toxic and mutagenic effects of nitrosamines. Chemical research in toxicology, 26(10), 1464-1473. https://doi.org/10.1021/tx400196j
Peterson, Lisa A. ; Urban, Anna M. ; Vu, Choua C. ; Cummings, Meredith E. ; Brown, Lee C. ; Warmka, Janel K. ; Li, Li ; Wattenberg, Elizabeth V. ; Patel, Yesha ; Stram, Daniel O. ; Pegg, Anthony E. / Role of aldehydes in the toxic and mutagenic effects of nitrosamines. In: Chemical research in toxicology. 2013 ; Vol. 26, No. 10. pp. 1464-1473.
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abstract = "α-Hydroxynitrosamine metabolites of nitrosamines decompose to a reactive diazohydroxide and an aldehyde. To test the hypothesis that the aldehydes contribute to the harmful effects of nitrosamines, the toxic and mutagenic activities of three model methylating agents were compared in Chinese hamster ovary cells expressing or not expressing human O6- alkylguanine DNA alkyltransferase (AGT). N-Nitrosomethylurethane (NMUr), acetoxymethylmethylnitrosamine (AMMN), and 4-(methylnitrosamino)-4-acetoxy-1-(3- pyridyl)-1-butanone (NNK-4-OAc) are all activated by ester hydrolysis to methanediazohydroxide. NMUr does not form an aldehyde, whereas AMMN generates formaldehyde, and NNK-4-OAc produces 4-oxo-1-(3-pyridyl)-1-butanone (OPB). Since these compounds were likely to alkylate DNA to different extents, the toxic and mutagenic activities of these compounds were normalized to the levels of the most cytotoxic and mutagenic DNA adduct, O6-mG, to assess if the aldehydes contributed to the toxicological properties of these methylating agents. Levels of 7-mG indicated that the differences in cytotoxic and mutagenic effects of these compounds resulted from differences in their ability to methylate DNA. When normalized against the levels of O6-mG, there was no difference between these three compounds in cells that lacked AGT. However, AMMN and NNK-4-OAc were more toxic than NMUr in cells expressing AGT when normalized against O6-mG levels. In addition, AMMN was more mutagenic than NNK-4-OAc and MNUr in these cells. These findings demonstrate that the aldehyde decomposition products of nitrosamines can contribute to the cytotoxic and/or mutagenic activity of methylating nitrosamines.",
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Peterson, LA, Urban, AM, Vu, CC, Cummings, ME, Brown, LC, Warmka, JK, Li, L, Wattenberg, EV, Patel, Y, Stram, DO & Pegg, AE 2013, 'Role of aldehydes in the toxic and mutagenic effects of nitrosamines', Chemical research in toxicology, vol. 26, no. 10, pp. 1464-1473. https://doi.org/10.1021/tx400196j

Role of aldehydes in the toxic and mutagenic effects of nitrosamines. / Peterson, Lisa A.; Urban, Anna M.; Vu, Choua C.; Cummings, Meredith E.; Brown, Lee C.; Warmka, Janel K.; Li, Li; Wattenberg, Elizabeth V.; Patel, Yesha; Stram, Daniel O.; Pegg, Anthony E.

In: Chemical research in toxicology, Vol. 26, No. 10, 04.11.2013, p. 1464-1473.

Research output: Contribution to journalArticle

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AU - Peterson, Lisa A.

AU - Urban, Anna M.

AU - Vu, Choua C.

AU - Cummings, Meredith E.

AU - Brown, Lee C.

AU - Warmka, Janel K.

AU - Li, Li

AU - Wattenberg, Elizabeth V.

AU - Patel, Yesha

AU - Stram, Daniel O.

AU - Pegg, Anthony E.

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Peterson LA, Urban AM, Vu CC, Cummings ME, Brown LC, Warmka JK et al. Role of aldehydes in the toxic and mutagenic effects of nitrosamines. Chemical research in toxicology. 2013 Nov 4;26(10):1464-1473. https://doi.org/10.1021/tx400196j