Summary
Carcinogenic and mutagenic N-nitrosodialkylamines are metabolically activated through α-hydroxylation. The synthesis, chemical properties, and microbial mutagenicity of α-hydroxy N-nitrosamines have been reported previously. Potent mutagenicity of four N-nitroso-N-(hydroxymethyl)-alkylamines (alkyl-methyl, ethyl, propyl, and butyl) was demonstrated in the present study in V79 Chinese hamster cells, ouabain resistance being used as an indicator. All the compounds were strong mutagens in the absence of metabolic activation systems. The mutagenic and cytotoxic potencies correlated well with each other, and depended on the alkyl group, decreasing in potency in the following order: methyl>ethyl >propyl=butyl. Their alkylating reactivity was measured by alkylation of thiophenol, and a good linear relationship was observed between the mutagenic and cytotoxic potencies and their alkylating reactivity. The mutagenic and cytotoxic potencies of the α-hydroxy N-nitrosamines in V79 cells were well correlated with those of α-acetoxy and α-hydroperoxy N-nitrosamines with respect to the effect of alkyl group. The results obtained here supported further that α-hydroxy N-nitrosamine is the active species in the metabolic activation of N-nitrosodialkylamine.
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Abbreviations
- MEM:
-
Eagle's minimal éssential medium
- PE:
-
plating efficiency
- MY:
-
mutation yield
- MF:
-
mutation frequency
References
Arlett CF, Turnbull D, Harcourt SA, Lehmann AR, Colella CM (1975) A comparison of the 8-azaguanine and ouabain resistance systems for the selection of induced mutant Chinese hamster cells. Mutat Res 33:261–278
Bradley MO, Bhuyan B, Francis MC, Langenbach R, Peterson A, Huberman E (1981) Mutagenesis by chemical agents in V79 Chinese hamster cells: A review and analysis of the literature. A report of the Gene-Tox Program. Mutat Res 87:81–142
Cairns J, Robins P, Sedgwick B, Talmud P (1981) The inducible repair of alkylated DNA. Prog Nucleic Acid Res Mol Biol 26:237–244
Druckrey H (1975) Chemical carcinogenesis on N-nitroso derivatives. Gann Monogr Cancer Res 17:107–132
Haynes RH, Eckardt F (1980) Mathematical analysis of mutation-induction kinetics. In: de Seres FJ, Hollaender A (eds) Chemical mutagens: Principles and methods for their detection, vol 6. Plenum Press, New York, pp 271–307
Huang GF, Mochizuki M, Anjo T, Okada M (1981) Mutagenicity of N-alkyl-N(α-acetoxyalkyl)nitrosamines in V79 Chinese hamster cells in relation to alkylating activity. Gann 72:531–538
Jones CA, Huberman E (1980) A sensitive hepatocyte-mediated assay for the metabolism of nitrosamines to mutagens for mammalian cells. Cancer Res 40:406–411
Kohda KH, Mochizuki M, Anjo T, Okada M (1982) Mutagenicity of N-alkyl-N-(α-hydroperoxyalkyl)nitrosamines in V79 Chinese hamster cells in relation to alkylating activity. Gann 73:522–530
Mochizuki M, Anjo T, Okada M (1978) Syntheses of N-alkyl-N-(α-acetoxyalkyl)nitrosamines, model compounds for metabolically activated N,N-dialkylnitrosamines. Chem Pharm Bull 26:3905–3908
Mochizuki M, Suzuki E, Anjo T, Wakabayashi Y, Okada M (1979) Mutagenic and DNA-damaging effects of N-alkyl-N-(α-acetoxyalkyl)nitrosamines, models for metabolically activated N, N-dialkylnitrosamines. Gann 70:663–670
Mochizuki M, Anjo T, Okada M (1980a) Isolation and characterization of N-alkyl-N-(hydroxymethyl)nitrosamines from N-alkyl-N-(hydroperoxymethyl)nitrosamines by deoxygenation. Tetrahedron Lett 21:3693–3696
Mochizuki M, Anjo T, Wakabayashi Y Sone T, Okada M (1980b) Formation of N-alkyl-N-(1-hydroperoxyalkyl)nitrosamines from N-alkyl-N-(l-acetoxyalkyl)nitrosamines. Tetrahedron Lett 21:1761–1764
Mochizuki M, Sone T, Anjo T, Okada M (1980c) Synthesis of N-alkyl-N-(l-hydroperoxyalkyl)nitrosamines by oxygenation of lithiated dialkylnitrosamines. Tetrahedron Lett 21:1765–1766
Mochizuki M, Anjo T, Takeda K, Suzuki E, Sekiguchi N, Huang GF, Okada M (1982) Chemistry and mutagenicity of α-hydroxy nitrosamines. IARC, Lyons (Seientific Publications no 41, pp 553–559)
Okada M, Suzuki E, Anjo T, Mochizuki M (1975) Mutagenicity of α-acetoxydialkylnitrosamines: Model compounds for an ultimate carcinogen. Gann 66:457–458
Okada M, Mochizuki M, Anjo T, Sone T, Wakabayashi Y, Suzuki E (1980) Formation, deoxygenation and mutagenicity of α-hydroperoxydialkylnitrosamines. IARC, Lyons (Scientific Publications no. 31, pp 71–79)
Roller PP, Shimp DR, Keefer LK (1975) Synthesis and solvolysis of methyl(acetoxymethyl)nitrosamine. Solution chemistry of the presumed carcinogenic metabolite of dimethylnitrosamine. Tetrahedron Lett: 2065–2068
Scribner JD, Ford GP (1982) n-Propyldiazonium ion alkylates O6 of guanine with rearrangement, but alkylates N-7 without rearrangement. Cancer Lett 16:51–56
Wiessler M (1974) Synthese α-funktioneller Nitrosamine. Angew Chem 86:817–818
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Dedicated to Professor Hermann Druckrey on the occasion of his 80th birthday
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Mochizuki, M., Osabe, M., Anjo, T. et al. Mutagenicity of α-hydroxy N-nitrosamines in V79 Chinese hamster cells. J Cancer Res Clin Oncol 108, 290–295 (1984). https://doi.org/10.1007/BF00390460
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DOI: https://doi.org/10.1007/BF00390460