Abstract
From investigations of the metabolism of many carcinogenic compounds emerged the concept of the metabolic activation to reactive metabolites. This led to the conclusion that ultimate reactive forms are trapped to a major extent by unspecific reactions with noncritical cell constituents. To evaluate the consequences with regard to the question of the existence of threshold doses for carcinogens, it appears necessary to define the detrimental effects on the molecular level and to measure interactions with critical cellular targets. A rationale for demonstrating a threshold dose could be derived if the ratio of noncritical to critical interactions increased with lower doses and/or if a tolerable minimum number of events could be determined, particularly with irreversible changes.
Zusammenfassung
Untersuchungen über das Schicksal vieler carcinogener Stoffe bei Versuchstieren haben zu dem Konzept von der Entstehung reaktionsfähiger Metaboliten im Stoffwechsel geführt. Daraus wurde gefolgert, daß der größte Teil der reaktionsfähigen Moleküle unspezifisch und mit nichtkritischen Zellbestandteilen reagiert und dadurch abgefangen wird. Welche Rolle dies bei der Frage nach der Existenz von Schwellenwerten bei Carcinogenen spielt, hängt davon ab, inwieweit es gelingt den Schaden auf molekularer Ebene zu definieren und damit die Wechselwirkung mit kritischen Zellbestandteilen messen zu können. Voraussetzung für die rationale Eingrenzung eines wirkungsfreien Dosisbereichs scheint zu sein, daß sich das Verhältnis von nichtkritischen zu kritischen Reaktionen mit abnehmender Dosis erhöht und/oder daß — vor allem bei irreversiblen Veränderungen — eine tolerierbare Mindestzahl von Ereignissen erkennbar wird.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bahl, O. P., Gutmann, H. R.: On the binding of the carcinogen N-2-fluorenylacetamide to rat serum albumin in vivo. Biochim. biophys. Acta (Amst.) 90, 391–393 (1964).
Bannasch, P., Papenburg, I., Ross, W.: Cytomorphologische und morphometrische Studien der Hepatocarcinogenese. I. Reversible und irreversible Veränderungen am Cytoplasma der Leberparenchymzellen bei Nitrosomorpholin-vergifteten Ratten. Z. Krebsforsch. 77, 108–133 (1972).
Barry, E. J., Gutmann, H. R.: Interaction of aromatic amines with rat liver protein in vivo I. Preferential labeling of a cytoplasmic protein or proteins by N-2 fluorenylacetamide-9-14C. J. biol. Chem. 241, 4600–4609 (1966)
Bartsch, H., Traut, M., Hecker, E.: On the metabolic activation of N-hydroxy-N-2 acetylaminofluorene. III. Oxidation with horseradish peroxidase to yield 2 nitrosofluorene and N-acetoxy-N-2-acetylaminofluorene. Biochim. biophys. Acta (Amst.) 237, 567–578 (1971)
Bartsch, H., Miller, J. A., Miller, E. C.: One electron non-enzymatic and enzymatic oxidation products of various carcinogenic aromatic acethydroxamic acids. Biochim. biophys. Acta (Amst.) 278, 40–51 (1972)
Chen, T. T., Heidelberger, C.: Quantitative studies on the malignant transformation of mouse prostate cells by carcinogenic hydrocarbons in vitro. Int. J. Cancer 4, 166–178 (1969)
De Baun, J. R., Miller, E. C., Miller, J. A.: N-hydroxy-2-acetylaminofluorene sulfotransferase: Its probable role in carcinogenesis and in protein-(methionin-S-yl) binding in rat liver. Cancer Res. 30, 577–595 (1970)
Dinman, B. D.: “Non concept” of “no-threshold”: Chemicals in the environment. Science 175, 495–497 (1972)
Druckrey, H., Preussmann, R., Matzkies, F., Ivankovic, S.: Selektive Erzeugung von Darmkrebs bei Ratten durch 1,2-Dimethylhydrazin. Naturwissenschaften 54, 285–286 (1967)
Druckrey, H., Schmähl, D.: Quantitative Analyse der experimentellen Krebs erzeugung. Naturwissenschaften 49, 217–228 (1962)
Epstein, S., Ito, N., Merkow, L., Farber, E.: Cellular analysis of liver carcinogenesis: the induction of large hyperplastic nodules in the liver with 2-fluorenylacetamide or ethionine and some aspects of their morphology and glycogen metabolism. Cancer Res. 27, 1702–1711 (1967)
Farber, E.: Biochemistry of carcinogenesis. Cancer Res. 28, 1859–1869 (1968)
Flaks, B., Lukas, J.: Persistent ultrastructural changes in pancreatic acinar cells induced by 4-acetylaminofluorene. Chem.-Biol. Interaction 6, 91–98 (1973)
Goodman, J. I., Potter, van R.: Evidence for DNA repair synthesis and turnover in rat liver following ingestion of 3′-methyl-4-dimethylaminoazobenzene. Cancer Res. 32, 766–775 (1972)
Grantham, P. H., Weisburger, E. K., Weisburger, J. H.: Dehydroxylation and deacetylation of N-hydroxy-N-2-fluorenylacetamide by rat liver and brain homogenates. Biochim. biophys. Acta (Amst.) 107, 414–424 (1965)
Grover, P. L., Sims, P.: Interaction of the K-region epoxides of phenanthrene and dibenz(a,h)anthracene with nucleic acids and histone. Biochem. Pharmacol. 19, 2251–2259 (1970)
Hawks, A., Swann, P. F., Magee, P. N.: Probable methylation of nucleic acids of mouse colon by 1,2-dimethylhydrazine in vivo. Biochem. Pharmacol. 21, 432–433 (1972)
Huberman, E., Sachs, L.: Cell susceptibility to transformation and cytotoxicity by the carcinogenic hydrocarbon benz(a)pyrene. Proc. nat. Acad. Sci. (Wash.) 56, 1123–1129 (1966)
Irving, C. C., Veazey, R. A.: Persistent binding of 2-acetylaminofluorene to rat liver DNA in vivo and consideration of the mechanism of binding of N-hydroxy-2 acetylamonofluorene to rat liver nucleic acids. Cancer Res 29, 1799–1804 (1969)
Irving, C. C., Veazey, R. A., Russel, L. T.: Possible role of the glucuronide con jugate in the biochemical mechanism of binding of the carcinogen N-hydroxy 2-acetylaminofluorene to rat liver deoxyribonucleic acid in vivo. Chem.-Biol. Interactions 1, 19–26 (1969/1970)
Irving, C. C., Wiseman, R.: Studies on the carcinogenicity of the glucuronides of N-hydroxy-2-acetylaminofluorene and N-2-fluorenylhydroxylamine in the rat. Cancer Res. 31, 1645–1648 (1971)
Jungmann, R. A., Schweppe, J. S.: Binding of chemical carcinogens to nuclear proteins of rat liver. Cancer Res. 32, 952–959 (1972)
Ketterer, B., Ross-Mansell, P., Whitehead, J. K: The isolation of carcinogen binding protein from livers of rats given 4-dimethylaminoazobenzene. Biochem. J. 103, 316–324 (1967)
Kriek, E.: On the mechanism of action of carcinogenic aromatic amines I. Binding of 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene to rat liver nucleic acids. Chem.-Biol. Interactions 1, 3–17 (1969)
Kriek, E.: Persistent binding of a new reaction product of the carcinogen N-hydroxy-N-2-acetylaminofluorene with guanine in rat liver DNA in vivo. Cancer Res. 32, 2042–2048 (1972)
Krüger, F. W., Osswald, H., Walker, G., Schelten, E.: Untersuchungen zur Organ otrophie der alkylierenden Wirkung von Dimethylnitrosamin und Nitrosomethylharnstoff in vivo. Z. Krebsforsch. 74, 434–447 (1970)
Kuroki, T., Heidelberger, C.: Determination of the h-protein in transformable and transformed cells in culture. Biochemistry 11, 2116–2124 (1972)
Kuroki, T., Huberman, E., Marquardt, H., Selkirk, I. K., Heidelberger, C., Grover, P. L., Sims, P.: Binding of K-region epoxides and other derivatives of benz(a)anthracene and dibenz(a,h)anthracene to DNA, RNA and protein of transformable cells. Chem.-Biol. Interactions 4, 389–397 (1971/1972)
Litwak, G., Ketterer, B., Arias, I. M.: Ligandin — A protein which binds steroids, bilirubin, carcinogens and several exogenous organic anions. Nature (Lond.) 234, 466–467 (1971)
Lotlikar, P. D., Luha, L.: Acylation of carcinogenic hydroxamic acids by carbamoyl phosphate to form reactive esters. Biochem. J. 124, 69–74 (1971)
Louis, C. J., Blunck, I. M.: Alteration in the distribution of basic soluble rat liver proteins during azo dye carcinogenesis. Cancer Res. 31, 2110–2115 (1971)
Magee, P. N.: Interaction of carcinogens with nucleic acids in vivo. The possible significance of methylation reactions. The Jerusalem Symposia on Quantum Chemistry and Biochemistry. Israel Acad. Sci. a. Humanity I, 298–304 (1969)
Miller, J. A.: Carcinogenesis by chemicals: An overview. G.H.A. Clowes Memorial Lecture. Cancer Res. 30, 559–576 (1970)
Miller, J. A., Miller, E. C.: Metabolic activation of carcinogenic aromatic amines and amides via N-hydroxylation and N-hydroxy esterification and its relationship to ultimate carcinogens as electrophilic reactants. The Jerusalem Symposia on Quantum Chemistry and Biochemistry. Israel Acad. Sci. a. Humanity I, 237–261 (1969)
Miller, J. A., Miller, E. C.: Chemical carcinogenesis: Mechanisms and approaches to its control. J. nat. Cancer Inst. 47, V-XIV (1971)
Szafarz, D., Weisburger, J. H.: Stability of binding of label from N-hydroxy-N-2-fluorenylacetamide to intracellular targets, particularly deoxyribonucleicacid in rat liver. Cancer Res. 29, 962–968 (1969)
Schenk, J., Neumann, H.-G.: Binding of aromatic amine metabolites to fatty acids in vivo. (Unpublished)
Scribner, J. D., Miller, J. A., Miller, B. C.: Nucleophilic substitution on carcinogenic N-acetoxy-N-arylacetamides. Cancer Res. 30, 1570–1579 (1970)
Sorof, S.: Carcinogen-protein conjugates in liver carcinogenesis. The Jerusalem Symposia on Quantum Chemistry and Biochemistry. Israel Acad. Sci. a. Humanity I, 208–217 (1969)
Stier, A., Reitz, I., Sackmann, E.: Radical accumulation in liver microsomal membranes during biotransformation of aromatic amines and nitro compounds. Naunyn Schmiedebergs Arch. Pharmacol. 274, 189–191 (1972)
Sugimoto, T., Terayama, H.: Pattern of 2-methyl-4-dimethylaminoazobenzene-binding proteins in the livers of partially hepatectomized rats and of continuously dye-fed rats in comparison with 3′-methyl-4-dimethylaminoazo-benzene. Cancer Res. 32, 1878–1883 (1972)
Turberville, C., Craddock, V. M.: Methylation of nuclear proteins by dimethylni trosamine and by methionine in the rat in vivo. Biochem. J. 124, 725–739 (1971)
Weil, C. S.: Guidelines for experiments to predict the degree of safety of a material for man. Toxicol. appl. Pharmacol. 21, 194–199 (1972)
Weisburger, J. H., Yamamoto, R. S., Williams, G. M., Grantham, P. H., Matsushima, T., Weisburger, E. K.: On the sulfate ester of N-hydroxy-N-2-fluorenylacetamide as a key ultimate hepatocarcinogen in the rat. Cancer Res. 32, 491–500 (1972)
Wunderlich, V., Schütt, M., Böttger, M., Graffi, A.: Preferential alkylation of mitochondrial dioxyribonucleic acid by N-methyl-N-nitroso urea. Biochem. J. 118, 99–109 (1970)
Author information
Authors and Affiliations
Additional information
Herrn Professor Dr. Adolf Butenandt zum 70. Geburtstag gewidmet.
Rights and permissions
About this article
Cite this article
Neumann, H.G. Ultimate electrophilic carcinogens and cellular nucleophilic reactants. Arch. Toxicol. 32, 27–38 (1974). https://doi.org/10.1007/BF00334609
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00334609