Abstract
Halogenated ethylenes are metabolized to reactive intermediates which covalently bind to different cellular targets.
Vinyl chloride and vinyl bromide metabolites bind to DNA, preferably to N-7 of deoxyguanosine. With RNA, 1,N6-ethenoadenosine and 3,N4-ethenocytidine moieties are formed.
All the haloethylenes in which this effect has been studied form metabolites capable of alkylating proteins, preferably at free sulfhydryl groups.
Also, there is alkylation by haloethylene metabolites of cellular coenzymes. An observed increased exhalation of acetone by rats exposed to different haloethylenes can possibly be explained by alkylation of cytosolic coenzyme A. Such metabolic effects may serve as an indicator for reactive metabolite formation in vivo and should be more investigated.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Allemand, H., Pessayre, D., Descatoire, V., Degott, C., Feldmann, G., Benhamou, J.P.: Metabolic activation of trichloroethylene into a chemically reactive metabolite toxic to the liver. J. Pharmacol. Exp. Ther. 204, 714–723 (1978)
Andersen, M.E., Jones, R.A., Jenkins, L.J.: The acute toxicity of single, oral doses of 1,1-dichloroethylene in the fasted male rat. Toxicol. App. Pharmacol. 46, 227–234 (1978)
Banerjee, S., Van Duuren, B.L.: Covalent binding of the carcinogen trichloroethylene in hepatic microsomal proteins and to exogenous DNA in vitro. Cancer Res. 38, 776–780 (1978)
Barbin, A., Bresil, H.; Croisy, A., Jacquinon, P., Mallaveille, C., Montesano, R., Bartsch, H.: Liver microsomes mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem. Biophys. Res. Commun. 67, 596–603 (1975)
Bartsch, H., Malaveille, C., Barbin, A., Planche, G.: Mutagenic and alkylating metabolites of haloethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissue. Arch. Toxicol. 41, 249–277 (1979)
Bolt, H.M.: Metabolic activation of halogenated ethylenes. In:“Primary Liver Tumors; Remmer, H., Bolt, H.H., Bannasch, P., Popper, H., eds., p. 285–294. MTP Press, Lancaster, U.K. (1978)
Bolt, H.M.: Die toxikologische Beurteilung halogenierter Athylene. Arbeitsmedizin-Sozialmedizin-Präventivmedizin 15, 49–53 (1980)
Bolt, H.M., Buchter, A., Wolowski, L., Gil, D.L., Bolt, W.: Incubation of 14C-trichloroethylene vapor with rat liver microsomes: uptake of radioactivity and covalent protein binding of metabolites. Int. Arch. Env. Occup. Hlth. 39, 103–111 (1977)
Bolt, H.M., Filser, J.G., Hinderer, R.K.: Rat liver microsomal uptake and irreversible protein binding of 1,2-14C-vinyl bromide. Toxicol. Appl. Pharmacol. 44, 481–489 (1978)
Bolt, H.M., Laib, R.J.: Covalent binding of drug metabolites to DNA - a tool of predictive value? Arch. Toxicol. in press (1980)
Bolt, H.M., Filser, J.G., Laib, R.J., Ottenwälder, H.: Binding kinetics of vinyl chloride and vinyl bromide at very low doses. Arch. Toxicol. Suppl. 3, 129–142 (1980)
Bolt, H.M., Kappus, H., Buchter, A., Bolt, W.: Untersuchungen zum Stoffwechsel von Vinylchlorid unter dem Blickpunkt der chemischen Kanzerogenese. Verh. Dtsch. Ges. Arbeitsmedizin (Gentner, Stuttgart) 16, 181–186 (1976b)
Bolt, H.M., Kappus, H., Kaufmann, R., Appel, K.E., Buchter, A., Bolt, W.: Metabolism of 14C-vinyl chloride in vitro and in vivo. INSERM Symposia Series (Paris) 52, 151–163 (1976a)
Bolt, H.M., Laib, R.J., Stöckle, G.: Formation of preneoplastic haptocellular foci by vinyl bromide in newborn rats. Arch. Toxicol. 43, 83–84 (1979)
Bolt, H.M., Link, B.: Zur Toxikologie von Perchlor- äthylen. Verh. Dtsch. Ges. Arbeitsmedizin(Gentner, Stuttgart) 20, (1980) in press.
Bonse, G., Henschler, D.: Chemical reactivity, biotransformation, and toxicity of polychlorinated aliphatic compounds. CRC Crit. Rev. Toxicol. 5, 395–409 (1976)
Bonse, G., Urban, Th., Reichert, D., Henschler, D.: Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylenes in the isolated perfused liver preparation. Biochem. Pharmacol. 24, 1829–1834 (1975)
Burton, K.: Biochemist’s Handbook, p. 90. London (1961)
Conolly, R.B., Jaeger, R.J., Szabo, S.: Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl chloride, and vinyl bromide after Arochlor 1254 pretreatment. Exp. Mol. Pathol. 28, 25–33 (1978)
Drew, R.T., Patel, J.M., Van Stee, E.W.: The effects of vinyl bromide in rats pretreated with phenobarbital or diethylmaleate. Toxicol. Appl. Pharmacol. 37, 176–177 (1976)
Filser, J.G., Bolt, H.M.: Pharmacokinetics of halogenated ethylenes in rats. Arch. Toxicol. 42, 123–136 (1979)
Filser, J.G., Bolt, H.M.: Characteristics of haloethylene-induced acetonemia in rats. Arch. Toxicol. 45, 109–116 (1980)
Filser, J.G., Bolt, H.M., Kimmich, K., Bencsâth, F.A.: Exhalation of acetone by rats on exposure to trans1,2-dichloroethylene and related compounds. Toxicol. Lett. 2, 247–252 (1978)
Green, T., Hathway, D.E.: Interactions of vinyl chloride with rat liver DNA in vivo. Chem. -biol. Interact. 22, 211–224 (1978)
Guengerich, G.F., Crawford, W.M., Watanabe, P.G.: Activation of vinyl chloride to covalently bound metabolites: roles of 2-chloroethylene oxide and 2chloroacetaldehyde. Biochemistry 18, 5177–5182 (1979)
Hathway, D.E.: Comparative mammalian metabolism of vinyl chloride and vinylidene chloride in relation to oncogenic potential. Environ. Hlth. Perspect. 21, 55–59 (1977)
Henschler, D., Romen, W., Elsässer, H.M., Reichert, D., Eder, E., Radwan, Z.: Carcinogenicity study of trichloroethylene by longterm inhalation in three animal species. Arch. Toxicol. 43, 237–248 (1980)
Jaeger, R.J., Shoner, L.G., Coffman, L.: 1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of 14C radio-activity following inhalation exposure in rats. Environ. Hlth. Perspect. 21, 113–119 (1977)
Jocelyn, P.C.: Biochemistry of the SH-group, p. 63–64, Academic Press, London/New York (1972)
Jones, B.K., Hathway, D.E.: The biological fate of vinylidene chloride in rats. Chem.-biol. Interact. 20, 27–41 (1978)
Kappus, H., Bolt, H.M., Buchter, A., Bolt, W.: Rat liver microsomes catalyse covalent binding of 14C-vinyl chloride to macromolecules. Nature 257, 134–135 (1975)
Kappus, H., Bolt, H.M., Buchter, A., Bolt, W.: Liver microsomal uptake and transformation to protein alkylating metabolites in vitro. Toxicol. Appl. Pharmacol. 37, 461–471 (1976)
Köster, U., Albrecht, D., Kappus, H.: Lipid peroxidation induced by different halogenated aliphatic hydrocarbons as measured by malondialdehyde formation in vitro and by ethane evolution in vivo. In: Industrial and Environmental Xenobiotics, Excerpta Medica Internat. Congr. Series 440 (1978)
Kuss, E.: Water-soluble metabolites of estrogens. Hoppe-Seyler’s Z. physiol. Chem. 352, 817–836 (1971)
Laib, R.J., Bolt, H.M.: Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: formation of 1,N6-ethenoadenosine. Toxicology 8, 185195 (1977)
Laib, R.J., Bolt, H.M.: Formation of 3,N4-ethenocytidine moieties in RNA by vinyl chloride metabolites in vitro and in vivo. Arch. Toxicol. 39, 235–240 (1978)
Laib, R.J., Ottenwälder, H., Bolt, H.M.: Alkylation of RNA by vinyl chloride and vinyl bromide metabolites in vivo: effect on protein biosynthesis. Naunyn-Schmiedeberg’s Arch. Pharmacol. Suppl. 313, R 63 (1980)
Laib, R.J., Stöckle, G., Bolt, H.M., Kunz, W.: Vinyl chloride and trichloroethylene: comparison of alkylating effects of metabolites and induction of preneoplastic enzyme deficiencies in rat liver. J. Cancer Res. Crin. Oncol. 94, 139–147 (1979)
Lee, C.C., Bhandari, J.C., Winston, J.M., House, W.B., Peters, P.J., Dixon, R.L., Woods, J.S.: Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Hlth. Perspect. 21, 25–32 (1977)
Lutz, W.K.: In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis. Mut. Res. 65, 289–356 (1979)
Lynen, F., Reichert, E., Rueff, L.: Zum biologischen Ab- bau der Essigsäure. VI. Aktivierte Essigsäure, ihre Isolierung aus Hefe und ihre chemische Natur. Liebig’s Ann. Chem. 574 1–32 (1951)
Maltoni, C.: Recent findings on carcinogenicity of chlorinated olefins. Environ. Hlth. Perspect. 21, 1–5 (1977)
Müller, G., Norpoth, K., Eckard, R.: Identification of two urine metabolites of vinyl chloride by GC-MS investigations. Int. Arch. Occup. Environ. Hlth. 38, 69–75 (1976)
Ostermann-Golkar, S., Hultmark, D., Segerbäck, D., Calleman, C.J., Göthe, R., Ehrenberg, L., Wachtmeister, C.A.: Alkylation of DNA and proteins in mice exposed to vinyl chloride. Biochem. Biophys. Res. Commun. 76, 259–266 (1977)
Ottenwälder, H., Laib, R.J., Bolt, H.M.: Alkylation of RNA by vinyl bromide metabolites in vitro and in vivo. Arch. Toxicol. 41, 279–286 (1979)
Ottenwälder, H., Laib, R.J., Filser, J.G., Bolt, H.M.: Disposition and metabolic activation of vinyl bromide in rats. 7th Internat. Congr. Pharmacol., Paris, Abstract 719 (1978)
Pegg, D.G., Zempel, J.A., Braun, H.W., Watanabe, P.G.: Disposition of tetrachloro-14C-ethylene following oral and inhalation exposure in rats. Toxicol. Appl. Pharmacol. 51, 465–474 (1979)
Reichert, D., Werner, H.W., Metzler, M., Henschler, D.: Molecular mechanism of 1,1-dichloroethylene toxicity: excreted metabolites reveal different pathways of reactive intermediates. Arch. Toxicol. 42, 159–169 (1979)
Reitz, R.H., Watanabe, P.G., McKenna, M.J., Quast, J.F.: Gehring, P.J.: Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: a comparative study with dimethylnitrosamine. Toxicol. App. Pharmacol. 52, 357–370 (1980)
Robinson, A.M., Williamson, D.H.: Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol. Rev. 60, 143–187 (1980)
Schoental, R.: Alkylation of coenzymes and the acute effects of alkylating hepatotoxins. FEBS Lett. 61, 111–114 (1976)
Schumann, A.M., Quast, J.F., Watanabe, P.G.: The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity. Toxicol. App. Pharmacol. in press.
Uehleke, H., Poplawski-Tabarelli, S.: Irreversible binding of 14C-labelled trichloroethylene to mice liver constituents in vivo and in vitro. Arch. Toxicol. 37, 289–294 (1977)
Van Duuren, B.L., Banerjee, S.: Covalent interaction of metabolites of the carcinogen trichloroethylene in rat hepatic microsomes. Cancer Res. 36, 24192422 (1976)
Watanabe, P.G., Hefner, R.E., Gehring, P.J.: Vinyl chloride induced depression of hepatic non-protein sulfhydryl content and effects on bromosulphalein clearance in rats. Toxicology 6, 1–8 (1976a)
Watanabe, P.G., McGowan, G.R., Madrid, E.O., Gehring, P.G.: Fate of 14C-vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37, 49–59 (1976b)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1982 Springer Science+Business Media New York
About this chapter
Cite this chapter
Bolt, H.M., Filser, J.G., Laib, R.J. (1982). Covalent Binding of Haloethylenes. In: Snyder, R., et al. Biological Reactive Intermediates—II. Advances in Experimental Medicine and Biology, vol 136. Springer, New York, NY. https://doi.org/10.1007/978-1-4757-0674-1_49
Download citation
DOI: https://doi.org/10.1007/978-1-4757-0674-1_49
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4757-0676-5
Online ISBN: 978-1-4757-0674-1
eBook Packages: Springer Book Archive