Abstract
Most chemical carcinogens are chemically unreactive per se and need metabolic activation to the ultimate carcinogenic species. The enzyme pattern responsible for the generation and disposition of reactive metabolites constitutes one important early contribution to the control of chemical carcinogenesis. Especially well studied is the group of enzymes responsible for the control of reactive epoxides. Many natural as well as manmade foreign compounds, including pharmaceuticals, possess olefinic or aromatic double bonds. Such compounds can be transformed to epoxides by microsomal monooxygenases present in many mammalian organs. By virtue of their electrophilic reactivity such epoxides may spontaneously react with nucleophilic centers in the cell and thus covalently bind to DNA, RNA and protein. Such alterations of critical cellular macromolecules may disturb the normal biochemistry of the cell and lead to cytotoxic, mutagenic and/or carcinogenic effects. Enzymes controlling the concentration of such epoxides are an important contributing factor in the control of chemical carcinogenesis. Several microsomal monooxygenases exist differing in activity and substrate specificity. With respect to large substrates, some monooxygenases preferentially attack on one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Enzymes metabolizing such epoxides represent a further determining factor. These enzymes include epoxide hydrolases, glutathione transferases and dihydrodiol dehydrogenases. These enzymes do not play a pure inactivating role but can in some cases also act as co-activating enzymes. Enzymes involved in biosynthesis and further metabolism of epoxides differ in quantity and also in substrate specificity between organs, developmental stages, sexes and animal species. Differences in susceptibilities between species and individuals are often causally linked to these metabolic differences.
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References
Boyland, E. (1986) Xenobiotica, 16, 899–913
Grover, P. L. (1986) Xenobiotica, 16, 915–931
Parke, D. V. (1987) Arch. Toxicol., 60, 5–15
Wixtrom, R. N. and Hammock, B. D. (91850 in Biochemical Pharmacology and Toxocology, Vol. I, Methodological Aspects of Drug Metabolizing Enzymes (Zakim, D. and Vessey, D. A. eds.) pp. 1-93. John Wiley and Sons, New York
Mannervik, B. (1985) Advances in Enzymology and Related Areas of Molecular Biology 57, 357–417
Lein, J. (1987) Ph.D. Thesis, University of Mainz, FRG.
Oesch, F. and Glatt, H. R. (1976) in Tests in Chemical Carcinogenesis. IARC Scientific Publications NO 12 (Montesano, R. ed.) p. 255. International Agency for Research on Cancer, Lyon
Levin, W., Wood, A. W., Wislocki, P. G., Chang, R. L., Kapitulnik, J., Mah, H. D., Yagi, H., Jerina, D. M. and Conney, A. H. (1978) in Polycyclic Hydrocarbons and Cancer, Vol. 1. (Gelboin, H. V. and Ts’o, P. O. P. eds.) p. 189. Academic Press,New York
Oesch, F. (1979) Arch. Toxicol., 5upp. 2, 215–227
Bentley, P., Oesch, F. and Glatt, H. R. (1977) Arch. Toxicol. 39, 65–75
Lehr, R. E. and Jerina, D. M. (1977) Arch. Toxicol. 39, 1–6
Siege, T. J., Viaje, A., Bracken, W. M., Berry, D. L., Fischer, S. M., Miller, D. R. and Leclerc, S. M. (1977) Cancer Lett. 3, 23–30
Kapitulnik, J., Wislocki, P. G., Levin, W., Yagi H., Jerina, D. M. and Conney, A. H. (1978) Cancer Res. 38, 354–358
Kapitulnik, j., Wislocki, P. G., Levin, W., Yagi, H., Thakker, D. R., Akagi, H., Kereeda, M., Jerina, D. M. and Conney, A. H. (1978) Cancer Res. 38, 2661–2665
Thakker, D. R., Yagi, H., Levin, W., Wood, A. W., Conney, A.H. and Jerina D. M. (1985) in Bioactivation of Foreign Compounds (Anders, M. W. ed.) pp. 177–242. Academic Press, Washington
Sims, P. (1970) Biochem. Pharmacol. 19, 795–818
Tierney, B., Hewer, A. D., Mac Nicoll, A. D., Gervasi, P. G., Rattle, F., Walsh, C., Grover, P. L. and Sims (1978) Chem. Biol. Interact, 23, 243–257
Thakker, D. R., Levin, W., Yagi, H., Ryan, D., Thomas, P. E., Karle, J. M., Lehr, R. E., Jerina, D. M., and Conney, A.H. (1979) Mol. Pharmacol. 15, 138–153
Wood, A. W., Levin, W., Chang, R. L., Lehr, R. E., Schaefer-Bidder, M,. Karle, J. M., Jerina, D. M. and Conney, A. H. (1977) Proc. Natl. Acad. Sci. USA 74, 3176–3179
Wislocki, P. G., Kapitulnik, J., Levin, W., Lehr, R., Schaefer-Bidder, M., Karle, J, M., Jerina, D. M. and Conney, A. H. (1978) Cancer Res. 38, 693–696
Desch, F. (1973) Xenobiotica 3, 305–340
Bentley, P. and Desch, F. (1975) FEES Lett. 59, 291–295
Oesch, F. (1974) Biochem. J. 139, 77–88
Wood, A. W., Levin, W., Lu, A. Y. H., Yagi, H., Hernandez, O., Jerina D. M. and Conney, A. H. (1976) J. Biol. Chem. 251, 4882–4890
Glatt, H. R., Friedberg, T., Grover, P. L., Sims, P. and Desch, F. (1983) Cancer Res. 43, 5713–5717
Sims, P., Grover, P. L., Swaisland, A., Pal, K. and Hewer, A. (1974) Nature 25, 226–228
Humbermann, E., Sachs, L., Yang, S. K. and Gelboin, H. V. (1976) Proc. Natl. Acad. Sol. USA 73, 607–611
Newbold, R. F. and Brookes, P. (1976) Nature 261, 52–54
Slaga, T. J., Viaje, A, Berry, D. L., Bracken, W. M., Buty, S. G. and Scribner, J. D. (1976) Cancer Lett. 2, 115–122
Wislocki, P. G., Wood, A. W., Chang, R. L., Levin, W., Yagi. H., Hernandez, 0., Jerina, D. M. and Conney, A. H. (1976) Biochem. Biophys. Res. Commun. 68, 1006–1012
Hecht, S. S., La Voie, E., Mazzorese, R., Amin, S., Bedenko, V. and Hoffmann, D. (1978) Cancer Res. 38, 2191–2198
Vigny, P., Kindts, M., Duquesne, M., Cooper, O. S., Grover, P. L. and Sims, P. (1980) Carcinogenesis 1, 33 41
MacNicoll, A. D., Cooper, C. S., Ribeiro, 0., Pal, K., Hewer, A., Grover P. L. and Sims, P. (1981) Cancer Lett. 11, 243–249
Glatt, H. R. and Desch, F. (1977) Arch. Toxicol. 39, 87–96
Glatt, H. R., Billings, R., Platt, K. L. and Oesch, F. (1981) Cancer Res. 41, 270 — 277
Guenthner, T. M., Jernstrom, B. and Orrenius, S. (1980) Carcinogenesis 1, 407–418
Glatt, H. R., Vogel, K., Bentley, P. and Desch, F. (1979) Nature 277, 319–320
Glatt, H. R., Cooper, C. S., Grover, P. L., Sims, P., Bentley, P., Mertes, M., Waechter, F., Vogel, K., Guenthner, T. M. and Desch, F. (1982) Science 215, 1507 1509
Malaveille, C., Kuroki, T., Sims, P., Grover, P. L. and Bartsch, H. (1977) Mutat. Res. 44, 313–326
Wood, A. W., Chang, R. L., Levin, W., Lehr, R. E., Schaefer-Ridder, M., Karle, J. M., Jerina, D. M. and Conney, A. H. (1977) Proc. Natl. Acad. Sci. USA 74, 2746–2750
Cooper, C. S., MacNicoll, A. D., Riveiro, 0., Gervasi, G. P., Hewer, A., Walsh, C., Pal, K. and Grover, P. L (1980) Cancer Lett 9, 53–59
Schladt, L., Thomas, H., Hartmann, R. and Oesch, F. (1988) Eur. J. Biochem, in press
Milbert, U., Worner, W. and Desch. F. (1986) in Primary Changes and Control Factors in Carcinogenesis (Friedberg, T. and Oesch, F. eds.) pp. 14–21. Deutscher Fachschriften-Verlag, Wiesbaden
Bentley, P., Shcmassmann, H. U., Sims, P. and Oesch, F. (1976) Eur. J. Biochem. 69, 97–103
Jerina, D. M., Dansette, P. M., Lu, A. Y. H. and Levin, W. (1977) Mol. Pharmacol. 13, 342–351
Parkinson, A.., Safe, S.H., Robertson, L. W., Thomas, P. E., Ryan,z1). E., Reik, L. M. and Levin, W. 91983) J. Biol. Chem. 258, 5967–5976
Smith, M. T. and Orrenius, S. (1984) in Drug Metabolism and Drug Toxicity (Mitchell, J. R. and Horning, M. G. eds.) pp. 71–98. Raven Press, New York
Vogel, K., Bentley, P., Platt, K. L. and Oesch, F. (1980) J. Biol. Chem. 255, 9621–9625
Jacobsen, K. B. and Kaplan, N. 0. (1957) J. Biol. Chem. 226, 603–603
Kalhorn, T. F., Thummel, K. E., Nelson, S. D. and Slattery, J. T. (1985) Anal. Biochem. 151, 343–347
Nemoto, N. and Gelboin, H. V. (1976) Biochem. Pharmacol. 25, 1221–1226
Nemoto, N., Takayama, S. and Gelboin, H. V. (1978) Chem. Biol. Interact. 23, 19–30
Bock, K. W., Lilienblum, W., Fischer, G., Schirmer, G. and Bock-Henning, B. S. (1987) Arch. Toxicol. 60, 22–29
Habig, W. H. Pabst, M. J. and Jakoby, W. B. (1974) J. Biol. Chem. 249, 7130–7139
Friedberg, T., Milbert, U., Bentley, P., Guenthner, T. M. and Oesch, F. (1983) Biochem, J. 215, 617–625
Jakoby, W. B., Ketley, J. N. and Habig, W. H. (1976) in Glutathione: Metabolism and Function, Vol. 6 (Arias, I. and Jakoby, W. eds.) p. 213. Raven Press, New York
Stasiecki, P., Oesch, F., Bruder, G., Jarasch, E. D. and Franke, W. W. (1980) Eur. J. Cell Biol. 21, 79–92
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Oesch, F., Thomas, H. (1989). Metabolism of Chemical Carcinogens. In: Garner, R.C., Hradec, J. (eds) Biochemistry of Chemical Carcinogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0539-2_2
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DOI: https://doi.org/10.1007/978-1-4613-0539-2_2
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