Abstract
N-Nitrosodialkylamines are metabolically activated by hydroxylation at the carbon atom alpha to the N-nitroso group. Spontaneous cleavage of the C-N bond in the α-hydroxynitrosamine leads to production of an alkydiazohydroxide that decomposes to an alkydiazonium ion. In principle, the diazonium ion can lose nitrogen to form a carbonium ion, although we have presented evidence that carbonium ions are not involved in DNA alkylation (Park et al., 1980). It is not known which of the activated species first interacts with the DNA. The α-hydroxynitrosamine has a half life of the order of seconds at physiological pH (Mochizuki et al., 1980), and may be the transport form of the activated carcinogen (Gold and Linda, 1979) which diffuses from its site of synthesis into the nucleus. The α-hydroxynitrosamine may also be the species which first interacts with the DNA.
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References
Archer, M.C. and Labuc, G.E. (1985). Nitrosamines. In Bioactivation of Foreign Compounds (M.W. Anders, Ed.) pp. 403–429, Academic Press, New York.
Briscoe, W.T. and Cotter, L.E. (1984). The effects of neighboring bases on N-methylN-nitrosourea alkylation of DNA. Chem.-Biol. Interact 52, 103–110.
Briscoe W.T. and Cotter L.E. (1985). DNA sequence has an effect on the extent and kinds of alkylation of DNA by a potent carcinogen. Chem.-Biol. Interact. 56, 321–331.
Gold, B. and Linder, W. B. (1979). a-Hydroxynitrosamines: transportable metabolites of dialkylnitrosamines. J. Am. Chem. Soc. 101, 6772–6773.
Milligan, J.R. and Archer, M.C. (1988). Alkylation of individual genes in rat liver by the carcinogen N-nitrosodimethylamine. Biochem. Biophys. Res. Comm. 155, 14–17.
Mochizuki M., Anjo, T. and Okada, M. (1980). Isolation and characterization of N-alkyl-N-(hydroxymethyl)nitrosamines from N-alkyl-N-(hydroperoxymethyl)nitrosamines by deoxygenation. Tetrahedron Lett. 21, 3693–3696.
Park, K.K., Archer, M.C. and Wishnok, J.S. (1980). Alkylation of nucleic acids by Nnitroso-di-N-propylamine: evidence that carbonium ions are not significantly involved. Chem.-Biol. Interact. 29, 139–144.
Peck, L.J. Nordheim, A., Rich, A. and Wang, J.C. (1982). Flipping of cloned d(pCpG)n.d(pCpG)n DNA sequences from right to left-handed helical structure by salt, Co (III), or negative supercoiling. Proc. Nati. Acd. Sci. USA 79, 4560–4564.
Saenger, W., Hunter, W.N. and Kennard, O. (1986). DNA conformation is determined by economics in the hydration of phosphate groups. Nature 324, 385–388.
Van de Sande, J.H. and Jovin, T.M. (1987). Z DNA, the left-handed helical form of poly[d(G-C)] in MgC12-ethanol, is biologically active. EMBO J. 1 115–120.
Wells, R.D. (1988). Unusal DNA structures. J. Biol. Chem. 263, 1095–1098.
Zarbl, H., Sukumar, S., Arthur, A.V., Martin-Zanca, D. and Barbacid, M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature 315, 382–385.
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© 1991 Plenum Press, New York
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Archer, M.C., Milligan, J.R., Skotnicki, S., Lu, SJ. (1991). Reactive Metabolites from N-Nitrosamines. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_68
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DOI: https://doi.org/10.1007/978-1-4684-5877-0_68
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