The Role of Glutathione in the Toxicity of Xenobiotic Compounds: Metabolic Activation of 1,2-Dibromoethane by Glutathione

  • I. Glenn Sipes
  • David A. Wiersma
  • David J. Armstrong
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


Glutathione (GSH) is a ubiquitous tripeptide involved in cellular defense mechanisms and the metabolism of xenobiotic compounds. Detoxification of free radicals and activated oxygen species by direct reaction, as well as that mediated by the enzymic activity of glutathione peroxidase, is a well known and described biochemical function.Equally well known and described is the role of GSH in conjugation. Conjugation with GSH occurs nonenzymatically and through the action of GSH S-transferases. Leukotrienes, active autacoids thought to be involved in inflammatory processes, are formed by the conjugation of GSH with fatty acids derived from arachidonic acid. One important function of GSH S-transferases is the conjugation of GSH with certain xenobiotic compounds, thus enhancing excretion of the xenobiotic. Furthermore, activated metabolites produced from xenobiotic compounds by the action of mixed function oxygenase may also be conjugated with GSH. This occurs both directly and enzymatically. The net result of conjugation with active metabolites is detoxification of these reactive chemical species. In certain cases, the GSH conjugate may ultimately result in toxic reactions. Stepwise, enzymatic degradation of certain GSH conjugates may result in reactive intermediates that result in tissue injury. Some glutathione conjugates, for example, may be enzymatically toxified by the sequential actions of gamma-glutamyl transferase and cysteine conjugate beta-lyase (Dohn and Anders, 1982). Other GSH conjugates may undergo intramolecular rearrangement to unstable intermediates that also result in toxic reactions. For example, the conjugation of vicinaldihaloalkanes may result in an intramolecular rearrangement to a reactive, transitory episulfonium ion (van Bladeren et al., 1980; Schasteen and Reed, 1981; Livesay and Anders, 1982).


Methyl Parathion Reactive Metabolite Xenobiotic Compound Mercapturic Acid Glandular Stomach 
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  1. Armstrong, D.J., Kutob, R. and Sipes, I.G. Deuterium isotope effect on the expiration and tissue distribution of 1,2-dibromoethane. The Toxicologist 5: 174, 1985.Google Scholar
  2. Brodie, B.B., Reid, W., Cho, A.K., Sipes, G., Krisha, G. and Gillette, J.R. Possible mechanism of liver nicrosis caused by aromatic organic compounds. Proc. Nat’l. Acad. Sci. U.S.A. 68: 160–164, 1971.CrossRefGoogle Scholar
  3. Clark, H.G., Cropp, P.L., Smith, J.N., Speir, T.W. and Tan, B.J.Photometric determination of methyl parathion GSH Smethyltransferase. Pestic. Biochem. Physiol. 6: 126–131, 1976.CrossRefGoogle Scholar
  4. Dohn, D.R. and Anders, M.W. The enzymatic reaction of chlorotrifluoroethylene with glutathione. Biochem. Biophys. Res. Comm. 109:1339–1345, 1982.PubMedCrossRefGoogle Scholar
  5. Edwards, K., Jackson, H., and Jones, A.R. Studies with alkylating esters-II. A chemical interpretation through metabolic studies of the antifertility effects of ethylene dimethanesulphonate and ethylene dibromide. Biochem. Pharmacol. 19: 1783–1789, 1970.PubMedCrossRefGoogle Scholar
  6. Gandolfi, A.J., Nagle, R.B., Soltis, J.J. and Plescia, F.H. Nephrotoxicity of halogenated vinyl cysteine compounds. Res. Comm. Chem. Path. Pharmacol. 33:249–261, 1981.Google Scholar
  7. Hill, D.L., Shih, T.-W., Johnston, T.P. and Struck, R.F. Macromolecular binding and metabolism of the carcinogen 1,2-dibromoethane. Cancer Res. 38:2438–2442, 1978.PubMedGoogle Scholar
  8. Jollow, D.J., Mitchell, J.R., Zampaglione, N. and Gillette, J.R. Bromobenzene induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169, 1974.PubMedCrossRefGoogle Scholar
  9. Kluwe, W.M., McNish, R., Smithson, K. and Hook, J.B. Depletion by 1,2-dibromoethane, 1,2-dibromo-3-chloropropane, tris (2,3-dibromopropyl) phosphate and hexachloro-1,3-butadiene of reduced nonprotein sulfhydryl groups in target and non-target organs. Biochem. Pharmacol. 30:2265–71, 1981.PubMedCrossRefGoogle Scholar
  10. Kohn, K.W., Erickson, L.C., Ewig, R.A. and Friedman, C.A. Fractionation of DNA from mammalian cells by alkaline elution. Biochem. 15:4629–4637, 1976.CrossRefGoogle Scholar
  11. Kowalski, B., Brittebo, E.B. and Brandt, I. Epithelial binding of 1,2-dibromoethane (EDB) in the respiratory and upper alimentary tracts of mice and rats. Cancer Res. 45:2616–2625, 1985.PubMedGoogle Scholar
  12. Letz, G.A., Pond, S.M., Osterloh, J.D., Wade, R.L. and Becker, C.E. Two fatalities after acute occupational exposure to ethylene dibromide. J. Amer. Med. Assoc. 252:2428–2431, 1984.CrossRefGoogle Scholar
  13. MacFarland, R.T., Gandolfi, A.J. and Sipes, I.G. Extra-hepatic GSHdependent metabolism of 1,2-dibromoethane (DBE) and 1,2-dibromo-3-chloropropane (DBCP) in the rat and mouse. Drug Chem. Toxicol. 7:213–227, 1984.PubMedCrossRefGoogle Scholar
  14. Nachtomi, E. The metabolism of ethylene dibromide in the rat. The enzymic reaction with glutathione in vitro and in vivo. Biochem. Pharmacol. 19:2853–2860, 1970.PubMedCrossRefGoogle Scholar
  15. NIOSH, National Institute for Occupational Safety and Health, Criteria for a recommended standard: occupational exposure to ethylene dibromide. DHEW (NIOSH) Publication No. 77–221. National Institute for Occupational Safety and Health, 1977.Google Scholar
  16. Olson, W., Habermann, R., Weisburger, E., Ward, J., and Weisburger, J. Brief communication: induction of stomach cancer in rats and mice by halogenated aliphatic fumigants. J. Natl. Cancer Inst. 51 (6): 1933, 1973.Google Scholar
  17. Ozawa, N. and Guengerich, F.P. Evidence for formation of an S-(2-(N7-guanyl)ethyl) glutathione adduct in glutathione-mediated binding of the carcinogen 1,2-dibromoethane to DNA. Proc. Nat’l. Acad. Sci. U.S.A. 80: 5266–5270, 1983.PubMedCrossRefGoogle Scholar
  18. Rowe, V., Spencer, H., McCollister, D., Hollingsworth, R., and Adams, E. Toxicity of ethylene dibromide determined on experimental animals. A.J.A. Arch. Ind. Hyg. Occupational Med. 6: 158–73, 1952.Google Scholar
  19. Schasteen, C.S. nd Reed, D.J. The mechanism of degradation by hydrolysis of S-(2-haloethyl)-cysteine analogs. The Pharmacologist 23: 176, 1981.Google Scholar
  20. Shih, T.-W. and Hill, D.L. Metabolic activation of 1,2-dibromoethane by glutathione transferase and by microsomal mixed function oxidase: further evidence for formation of two reactive metabolites. Res. Comm. Chem. Pathol. Pharmacol. 33: 449–461, 1981.Google Scholar
  21. Short, R.D., Winston, J.M., Hong, C.-B., Minor, J.L., Lee, C.-C. and Seifter, J. Effects of ethylene dibromide on reproduction in male and female rats. Toxicol. Appl. Pharmacol. 49: 97–105, 1979.PubMedCrossRefGoogle Scholar
  22. Sundheimer, D.W., White, R.D., Brendel, K. and Sipes, I.G. The bioactivation of 1,2-dibromoethane in rat hepatocytes: Covalent binding to nucleic acid. Carcinogenesis 3: 1129–1133, 1982.PubMedCrossRefGoogle Scholar
  23. van Bladeren, P.J., Breimer, D.D., Rotteveel-Smijs, G.M.T. and Mohn, G.R. Mutagenic activation of dibromoethane and diiodomethane by mammalian microsomes and glutathione S-transferases. Mut. Res. 24: 341–346, 1980a.Google Scholar
  24. van Bladeren, P.J., Breimer, D.D., Rotteveel-Smijs, G.M.T., de Jong, R.A.W., Buijs, W., van der Gen, A. and Mohr, G.R. The role of glutathione conjugation in the mutagenicity of 1,2-dibromoethane. Biochem. Pharmacol. 29: 2975–2982, 1980b.PubMedCrossRefGoogle Scholar
  25. van Bladeren, P.J., van der Gen, A., Breimer, D.D. and Mohn, G.R. Stereoselective activation of vicinal dihalogen compounds to mutagens by glutathione conjugation. Biochem. Pharmacol. 28: 2521–2524, 1979.PubMedCrossRefGoogle Scholar
  26. van Bladeren, P.J., Breimer, D.D., Rotteveel-Smijs, G.M.T., de Knijff, P., Mohn, G.R., Buis, W., van Meeteren-Wachli, B. and van der Gen, A. The relation between the structure of vicinal dihalogen compounds and their mutagenic activation via conjugation to glutathione. Carcinogenesis 2: 499–503, 1981.PubMedCrossRefGoogle Scholar
  27. Van Duuren, B., Goldschmidt, B., Loewengart, G., Smith, A., Melchionne, S., Seidman, I., and Roth, D. Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63 (6): 1433–1438, 1979.PubMedGoogle Scholar
  28. White, R.D., Petry, T.W. and Sipes, I.G.The bioactivation of 1,2-dibromoethane in rat hepatocytes: deuterium isotope effect. Ghem.-Biol. Interact 49: 225–233, 1984.CrossRefGoogle Scholar
  29. White, R.D., Gandolfi, A.J., Bowden, G.T. and Sipes, I.G. Deuterium isotope effect on the metabolism and toxicity of 1,2-dibromoethane. Toxicol. Appl. Pharmacol. 69: 170–178, 1983.PubMedCrossRefGoogle Scholar
  30. White, R.D., Sipes, I.G., Gandolfi, A.J. and Bowden, G.T. Characterization of the hepatic DNA damage caused by 1,2-dibromoethane using the alkaline elution technique. Carcinogenesis 2: 839–844, 1981.PubMedCrossRefGoogle Scholar
  31. Wiersma, D.A. and Sipes, I.G. Effect of dibromoethane and dichloroethane on the nonprotein sulfhydryl content of rat organs. The Toxicologist 3: 97, 1983a.Google Scholar
  32. Wiersma, D.A. and Sipes, I.G. Metabolism of 1,2-dibromoethane by cytosol of rat liver, forestomach and glandular stomach. Tox. Lett. 18 (Suppl 1): 155, 1983b.CrossRefGoogle Scholar
  33. Wiersma, D.A., Schnellmann, R.G. and Sipes, I.G. Human liver microsomal and cytosolic metabolic activation of 1,2-dibromoethane. The Pharmacologist 25: 104, 1983.Google Scholar
  34. Wong, L.C.K., Winston, J.M., Hong, C.B. and Plotnick, H. Carcinogenicity and toxicity of 1,2-dibromoethane in the rat. Toxicol. Appl. Pharmacol. 63: 155–165, 1982.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • I. Glenn Sipes
    • 1
  • David A. Wiersma
    • 1
  • David J. Armstrong
    • 1
  1. 1.Dept. of Pharmacology and Toxicology College of PharmacyUniv. of ArizonaTucsonUSA

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