Carcinogenic nitrosamines as formaldehyde precursors
Keywords:
Nitrosamines, Dimethylnitrosamine (DMNA), Formaldehyde precursors, Metabolic activation, Cytochrome P450 (CYP 2E1), Carcinogenesis, DNA methylation, Aminoacetonitrile (AAN), Excited formaldehyde, Reactive oxygen species (ROS)Abstract
The study investigates the metabolic activation of nitrosamines, particularly dimethylnitrosamine (DMNA), and their role as precursors to formaldehyde. Research demonstrates that DMNA is metabolically activated by the cytochrome P450 (CYP 2E1) enzyme system, primarily through alpha-hydroxylation. This process generates formaldehyde as a major product, which, especially in an excited state, may play a crucial role in DNA methylation and the initiation of malignant transformations.
Experimental results show that aminoacetonitrile (AAN) inhibits DMNA-induced carcinogenesis. This protective action occurs through two main mechanisms: first, AAN rapidly reacts with the generated formaldehyde to form a trimeric MAAN compound; second, AAN eliminates reactive oxygen species (ROS) produced by the induced CYP 2E1 enzyme. These findings suggest that the role of activated formaldehyde in the methylation process cannot be neglected, challenging the traditional view that only the methyl carbonium ion is responsible for carcinogenicity.
References
Magee, P. N., Montesano, R., and Preussman, R., N-Nitroso compound and related carcinogens. In Charles Searle (Ed), Chemical Carcinogens, Am. Chem. Soc. Monogr., Washington DC, 173, 491-625 (1976).
Mirvish, S. S., Kinetics of dimethylamine nitrosation in relation to nitrosamine carcinogenesis, J. Nat. Cancer Inst. 44(3), 633-639 (1970).
Sander, J. and Seif, F., Bacterial reduction of nitrate in the human stomach as a cause of a nitrosamine formation, Arzneimittelforschung, 19(7), 1091-1093 (1969).
Challis, B. C. and Bartlett, C. D., Possible cocarcinogenic effect of coffee constituents, Nature, 254, 532-533 (1973).
Sander, J., Schweinsberg, F. and Menz, H. P., Studies on the origin of carcinogenic nitrosamines in the stomach, Hoppe Seylers Z. Physiol. Chem. 349(12), 1691-1697 (1968).
Sawicki, E., Sawicki, C., in Aldehydes Photometric Analysis, edited by R. Bechler and D.M. W. Anderson (Academic Press, New York, 1978) pp. 63-79.
Schlag, P., Böchler, R. and M. Peter, Nitrite and nitrosamines in gastric juice: risk factors for gastric cancer, Scand. J. Gastroenterol, 17, 145-150 (1982).
Hoffmann, D., Adams, J. D., Brunnemann, K. D., Rivenson, A. and Hecht, S. S., Tobacco specific N-nitrosamines: occurrence and bioassays. In H. Bartsch, J.K. O'Neill, M. Castegnaro and M. Okada (eds), N-Nitroso Compounds: occurrence and Biological Effects, IARC Scientific Publication No. 41. Lyon, France, pp. 309-418.
Finc, D. H., Rounbehler, D. P., Blecher, N.M. and Epstein, S. S., N-nitroso compounds in air and water, Int. Conf. On Environmental Sensing and Assessment Las Vegas, October (1975).
Tate, R. L. and Alexander, M., Stability of nitrosamines in samples of lake water, soil and sewage, J. Natl. Cancer Inst., 54, 327-330 (1975).
Dressel, J., Landwirt. Forsch. Sonderheft, 28, 273 (1973).
Magee, P. N., Toxic liver injury, the metabolism of dimethylnitrosamine, Biochem. J. 64(4), 672-682 (1956).
Magee, P. N. and Farber, E., Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo, Biochem. J. 83, 114-124 (1962).
Mochizuki, M., Anjo, T., Takeda, K., et al., Proc. Seventh Int. Meeting on N-Nitroso Compounds: Occurrence and Biological Effects, IARCH, Tokyo, 1981, p.553.
Weisburger, E. K., Russfield, A. B., et al., Testing of twenty-one environmental aromatic amines or derivatives for long-term toxicity or carcinogenicity, J. Environ. Pathol. Toxicol 2(2) 325-356 (1978).
Lijynsky, W., Lov, J. and Ross, E. A., Mechanism of alkylation of nucleic acids by nitrosodimethylamine, Nature, 218, 1174 (1968).
Bebert, D. W., Nelson, D. R., et al., The P450 superfamily: update listing of all genes and recommended nomenclature for the chromosomal loci, DNA Cell. Biol., 8(1), 1-13 (1989).
Nelson, D. R., Kamataki, T., et al., The p450 superfamily: update on new sequences, gene mapping, accession numbers, early-trivial names of enzymes, and nomenclature, DNA Cell. Biol. 12(1), 1-51 (1993).
Porter, T. D. and Coon, M. J., Multiplicity of isoforms, substrates, and catalytic and regulatory mechanism, J. Biol. Chem., 266(21), 13469-13472 (1991).
Okey, A. B., Enzyme induction in the cytochrome P-450 system, Pharmacol. Ther. 45(2) 241-298 (1990).
Conney, A. H., Induction of microsomal cytochrome P-450 enzymes, Life Sci. 39(26), 2493-2518 (1986).
Bock, K. W., Lipp, H. P., Bock-Hennig, B. S., Xenobiotica 20(11), 1101-1111 (1990).
Soucek, P., Gut, I., Cytochromes P-450 in rats: structures, functions, properties: relevant human forms, Xenibiotica 22(1), 83-103 (1992).
Nedelcheva, V., Gut, I., P-450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer, Xenobiotica 24(12), 1151-1175 (1994).
Gonzalez, F. J., Gelboin, H. V., Role of human cytochromes P450 in the metabolic activation chemical carcinogens and toxins, Drug. Metab. Rev. 26(1,2), 163-183 (1994).
Ingelman-Sundberg, M., Johansson, I., et al., Ethanol-inducible cytochrome P4502E1: genetic polymorphism regulation, and possible role in the etiology of alcohol-induced liver disease, Alcohol 10(6), 447-452 (1993).
Grilli, S., Prodi, G., Identification of dimethylnitrosamine metabolites in vitro, Gann, 66(5), 473-480 (1975).
Czygan, P., Greim, H., et al., Microsomal metabolism of dimethylnitrosamine and the cytochrome P-450 dependence of its activation to a mutagen, Cancer Res., 33, 2983-2986 (1973).
Lake, B. G., Heading, C. E., et al., Some studies on the metabolism in vitro of dimethylnitrosamine by rat liver, Biochem. Soc. Trans., 2, 610-612 (1974).
Chau, L. Y., Dagani, D., and Archer, M. C., Kinetic studies on the hepatic microsomal metabolism of dimethylnitrosamine, diethylnitrosamine, and methylethylnitrosamine in the rat, J. Natl. Cancer Inst., 61, 517-521 (1978).
Jensen, D. E., Lotlikar, P. D. and Magee, P. N., The in vitro methylation of DNA by microsomally-activated dimethylnitrosamine and its correlation with formaldehyde production, Carcinogenesis, 2(4), 349-354 (1981).
Farrelly, G. and Stewart, M. L., The metabolism of a series of methylnitrosamines, Carcinogenesis, 3(11), 1299-1302 (1982).
Magee, P. N., Pegg, A. E., Swann, P. F., Molecular mechanism of chemical carcinogenesis, in: Grundmann E.(ed), Handbuch der Allgemeinen Pathologie, Springer, 320-420 (1975).
Loveless, A., A possible relevance of O6 alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides, Nature, 223, 206-207 (1969).
Pegg, A. F., Formation and metabolism of alkylated purines: Possible role in carcinogenesis by N-nitroso compounds and alkylating agents, Adv. Cancer Res. 25, 195-269 (1977).
Fiume, L., Inhibitory action of aminoacetonitrile of hydropic degeneration and necrosis induced by chloroform in the rat liver and kidney, Sperimentale, 112, 365-375 (1962).
Fiume, L. and Roffia, S., Inhibition by aminoacetonitrile of dimethylnitrosamine metabolism in the rat's liver, Nature, 206(989), 1157-1158 (1965).
Hadjiolov, A., The inhibition of dimethylnitrosamine carcinogenesis in rat liver by aminoacetonitrile, Z. f. Krebsforsch., 76, 91-92 (1971).
Wawzonek, K. S., Ponseti, L. V., et al., Science, N.Y., 121, 63 (1955).
Magee, P. N., Toxic liver injury: inhibition of protein synthesis in rat liver by dimethylnitrosamine in vivo, Biochem. J. 70(4), 606-611 (1958).
Fiume, L., Aminoacetonitrile action on the inhibition of the protein synthesis produced in the rat liver by dimethylnitrosamine, Nature, 201, 615 (1964).
Albert, E., Sellakumas, A. R., et al., Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat, J. Natl. Cancer Inst. 68(4), 597 (1982).
Grafstrom, R., Fornace, A. J., et al., Formaldehyde damage to DNA and inhibition of DNA repair in human bronchial cell, Science, 220, 218 (1983).
Adreozzi, P., Hopfinger, A. J., Klopman, G., Theoretical study of N-nitrosamines and their presumed proximate carcinogens, Cancer Biochem. Biophys. 4, 209-220 (1980).
Lijinsky, W., Lov, J., Ross, A. E., Mechanism of alkylation of nucleic acids by nitrosodimethylamine, Nature, 218, 1174-1175 (1968).
Szarvas, T., Szatlóczky, E., Volford, J., Trézi, L., Tyihák, E., Rusznák, I., Determination of endogenous formaldehyde level in human blood and urine by dimedon-14C radiometric method, J. Radioanal. Nucl. Chem. Letters, 106(6), 357-367 (1986).
Klager, J., J. prakt. Chem., (2), 65, 192 (1902).
Johnson, J. and Rinehardt, H. R., J. Am. Chem. Soc., 46(768), 1659 (1924).
Magee, P. N. and Barnes, J. M., Carcinogenic nitroso compounds, Adv. Cancer Res. 10, 168-246 (1967).
Magee, P. N. and Swann, P. F., Nitroso compounds, Br. Med. Bull. 25, 240-244 (1969).
Mager, J., Halbreich, A., et al., Antidotal effect of aminoacetonitrile against the biochemical injury... induced in vivo by carbon tetrachloride or dimethylnitrosamine, Biochem. Biophys. Res. Commun. 18, 576-581 (1965).
Magee, P. N., Farber, E., Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo, Biochem. J. 83, 114-124 (1962).
Frei, J. V., Swenson, D. H., et al., Alkylation of deoxyribonucleic acids in vivo in various organs of C57BL mice... Biochem. J. 174(3), 1031-1044 (1978).
Ross, A. E., Keefer, L., Lijinsky, W., Alkylation of nucleic acids of rat liver and lung by deuterated N-nitrosodiethylamine in vivo, J. Natl Cancer Inst. 47(4), 789-795 (1971).
Loew, G. H., Poulsen, M. T., et al., Mechanistic structure-activity studies of carcinogenic dialkylnitrosamine, Int. J. Quantum Chem. Quantum Biol. Symp. 10, 201 (1983); Mol. Toxicol. 1(1), 35-47 (1987).
Thomson, C., Reynolds, C. A., A theoretical study of N-nitrosamine metabolites... Int. J. Quantum Chem. 30, 751 (1986).
Tyihák, E., Trézl, L., and Rusznák, L., Spontaneous Ne-methylation of L-lysine by formaldehyde, Pharmazie, 35(1), 19-20 (1980).
Trézl, L., Rusznák, I., Tyihák, E., et al., Spontaneous Ne-methylation and Ne-formylation reactions between L-lysine and formaldehyde inhibited by L-ascorbic acid, Biochem. J. 214, 289-292 (1983).
Turberville, C., Craddock, V. M., Methylation of nuclear proteins by dimethylnitrosamine and by methionine in the rat in vivo, Biochem. J. 124(4), 725-730 (1971).
Johannson, E. B. and Tjälve, H., The distribution of (14C)-dimethylnitrosamine in mice... Toxicol. Appl. Pharmacol. 45(2), 565-572 (1978).
Sawicki, E. and Sawicki, C. R., Aldehydes, Photometric Analysis: Formaldehyde Precursors, Academic Press, 2-17 (1978).
Lewis, D. F. V., in: Cytochromes P450, Structure, Function and Mechanism, Taylor & Francis, London, 149-150 (1996).
Ruckpaul, K., Rein, H., Effect of enzyme inducers on biotransformation, Z. Gesamte Hyg. 30(9), 482-484 (1984).
Uvarov, V. Yu., et al., Heme maintains catalytically active structure of cytochrome P450, Febs Lett, 260(2), 309-312 (1990).
Lewis, D. F. V., in: Cytochromes P450, Structure, Function and Mechanism, Taylor & Francis, London, 84-86 (1996).
Mengaretdinov, D. E., et al., Inactivation of cytochrome P450 by hydrogen peroxide... Biochimia, 54(7), 1102-1107 (1989).
Ortiz de Montellano, P. R., Costa, A. K., Dissociation of cytochrome P450, inactivation and induction, Archiv Biochem. Biophys. 251(2), 514-524 (1986).
Trézl, L., Rusznák, I., et al., Int. Conf. On the Role of Formaldehyde in Biological System, Balatonfüred, Hungary, p. 51 (1985).
Trézl, L., Rusznák, L., et al., 2nd Int. Conf. On the Role of Formaldehyde in Biological Systems, Keszthely, Hungary, p. 147 (1987).
Lichszteld, K. and Kruk, I., Singlet molecular oxygen in formaldehyde oxidation, Z. f. Physikalische Chemie Neue Folge, 108, 167-172 (1977).
Trézl, L. and Pipek, J., Formation of excited formaldehyde in model-reactions simulating real biological systems, J. Molecular Structure (Theochem), 170, 213-223 (1988).
Duran, N., Faljoni, A., Singlet oxygen formation during peroxidase catalyzed degradation of carcinogenic N-nitrosamine, Biochem. Biophys. Res. Commun. 83(1), 287-294 (1978).
Pegg, A. E., Inhibition of the alkylation of nucleic acids and the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile, Chem. Biol. Interact. 23(2), 273-279 (1978).
Szarvas, T., Trézl, L. (not published).
Loew, G. H., Chadha, M. S., and Chang, S., A molecular orbital and chemical study of aminoacetonitrile... J. Theor. Biol. 35(2), 359-373 (1972).
Downloads
Published
Issue
Section
License
Copyright (c) 2016 opyright © [year] The Author(s). Published by AJ-RED under the Creative Commons Attribution 4.0 International License (CC BY 4.0).
This work is licensed under a Creative Commons Attribution 4.0 International License.
Articles published in AJ-RED are made freely available under the Creative Commons Attribution 4.0 International License (CC BY 4.0). Under this license, anyone may share, copy, redistribute, adapt, and build upon the published work for any purpose, including commercial use, provided that appropriate credit is given to the original authors, the title of the work and the journal are cited, and a link to the license is provided. Authors retain full copyright of their work. No permission is required from the authors or the publisher for uses permitted by the license. For the full terms of the CC BY 4.0 license, see: https://creativecommons.org/licenses/by/4.0/
