Binding of Haloalkanes to Liver Microsomes

  • Hartmut Uehleke


During the past two decades, many investigations have shown that numerous toxic compounds are inert per se but are converted in the body to chemically reactive metabolites (1–3). The reactive metabolites or metabolic intermediates can combine with cellular constituents and may initiate methemoglobin formation (4–8), sensitization (9, 10), tumors (1), mutation (11, 12), lipid peroxidation (13, 14), or cellular necrosis (3, 15).


Carbon Tetrachloride Liver Microsome Covalent Binding Microsomal Protein Reactive Metabolite 
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  1. 1.
    J. A. Miller, Carcinogenesis by chemicals: An overview, Cancer Res. 30, 559–576 (1970).PubMedGoogle Scholar
  2. 2.
    H. Uehleke, Stoffwechsel von Arzneimitteln als Ursache von Wirkungen, Nebenwirkungen und Toxizität, Progr. Drug Res. (Basel) 15, 147–203 (1971).Google Scholar
  3. 3.
    J. R. Gillette, J. R. Mitchell, and B. B. Brodie, Biochemical mechanisms of drug toxicity, Annu. Rev. Pharmacol. 14, 271–289 (1974).CrossRefGoogle Scholar
  4. 4.
    W. Heubner, Methâmoglobinbildende Gifte, Ergeb. Physiol. 43, 8–56 (1940).Google Scholar
  5. 5.
    H. Uehleke, Biologische Oxydation und Reduktion am Stickstoff aromatischer Amino- und Nitroderivate und ihre Folgen für den Organismus, Progr. Drug. Res. (Basel) 8, 195–260 (1964).Google Scholar
  6. 6.
    A. Burger, J. Wagner, H. Uehleke, and E. Götz, Beeinflussung von Pentosephosphatzyklus und Glykolyse in Erythrocyten während Methämoglobinbildung durch Phenylhydroxylamin, Arch. Exp. Path. Pharmak. 256, 333–347 (1967).Google Scholar
  7. 7.
    H. Uehleke, Mechanisms of methemoglobin formation by therapeutic and environmental agents, in: Toxicological Problems (T. A. Loomis, ed.), Vol. 2, pp. 124–136, Proceedings Fifth International Congress of Pharmacology, Karger, Basel (1973).Google Scholar
  8. 8.
    M. Kiese, Methemoglobinemia: A Comprehensive Treatise, CRC Press, Cleveland (1974).Google Scholar
  9. 9.
    H. Uehleke, Biochemische Reaktionen als Ursache erworbener. Überempfindlichkeit gegen Fremdstoffe, Z. Immunitätsforsch. 123, 447–457 (1962).Google Scholar
  10. 10.
    H. Uehleke, Metabolite von Arznei-und Fremdstoffen als Allergene, Z. Immunitätsforsch. Suppl. 1, 22–36 (1974).Google Scholar
  11. 11.
    A. Hollaender, Chemical Mutagens: Principles and Methods for Their Detection, Plenum Press, New York (1971).Google Scholar
  12. 12.
    P. Czygan, H. Greim, A. J. Carro, F. Hutterer, F. Schaffner, H. Popper, O. Rosenthal, and D. Y. Cooper, Microsomal metabolism of dimethylnitrosamine and the cytochrome P-450 dependency of its activation to a mutagen, Cancer Res. 33, 2983–2986 (1973).PubMedGoogle Scholar
  13. 13.
    T. F. Slater, Free Radical Mechanisms in Tissue Injury, Pion, London (1962).Google Scholar
  14. 14.
    R. O. Recknagel, Carbon tetrachloride hepatotoxicity, Pharmacol. Rev. 19, 145–208 (1967).PubMedGoogle Scholar
  15. 15.
    B. B. Brodie, W. D. Reid, A. K. Cho, G. Sipes, G. Krishna, and J. R. Gillette, Possible mechanism of liver necrosis caused by aromatic organic compounds, Proc. Natl. Acad. Sci. USA 68, 160–164 (1971).PubMedCrossRefGoogle Scholar
  16. 16.
    A. Zeller, Über die Schicksale des Jodoforms und Chloroforms im Organismus, HoppeSeyler’s Z. Physiol. Chem. 8, 70–78 (1883).Google Scholar
  17. 17.
    A. Kast, Über die Schicksale einiger organischer Chlorverbindungen im Organismus, Hoppe-Seyler’s Z. Physiol. Chem. 11, 278–285 (1887).Google Scholar
  18. 18.
    C. Binz, Beiträge zur pharmakologischen Kenntnis der Halogene, Naunyn-Schmiedeberg’s Arch. Exp. Path. Pharmak. 34, 185–207 (1894).CrossRefGoogle Scholar
  19. 19.
    D. D. McCollister, W. H. Beamer, G. J. Atchison, and M. C. Spencer, The absorption, distribution and elimination of radioactive carbon tetrachloride by monkeys upon exposure to low vapour concentrations, J. Pharmacol. Exp. Ther. 102, 112–124 (1951).PubMedGoogle Scholar
  20. 20.
    T. C. Butler, Reduction of carbon tetrachloride in vivo and reduction of carbon tetrachloride and chloroform in vitro by tissues and tissue constituents, J. Pharmacol. Exp. Ther. 134, 311–319 (1961).PubMedGoogle Scholar
  21. 21.
    Z. T. Wirtschafter and M. W. Cronyn, Free radical mechanism for solvent toxicity, Arch. Environ. Health 9, 186–191 (1964).PubMedGoogle Scholar
  22. 22.
    D. Rubinstein and L. Kanics, The conversion of carbon tetrachloride and chloroform to carbon dioxide by rat liver homogenates, Can. J. Biochem. 42, 1577–1585 (1964).PubMedGoogle Scholar
  23. 23.
    A. A. Seawright and A. E. M. McLean, The effect of diet on carbon tetrachloride metabolism, Biochem. J. 105, 1055–1060 (1967).PubMedGoogle Scholar
  24. 24.
    R. C. Garner and A. E. M. McLean, Increased susceptibility to carbon tetrachloride poisoning in the rat after pretreatment with oral phenobarbitone, Biochern. Pharmacol. 18, 645–650 (1969).CrossRefGoogle Scholar
  25. 25.
    E. Cignoli and J. A. Castro, Effect of inhibitors of drug metabolizing enzymes on carbon tetrachloride hepatotoxicity, Toxicol. Appl. Pharmacol. 18, 625–637 (1971).PubMedCrossRefGoogle Scholar
  26. 26.
    R. J. Stenger and E. A. Johnson, Effects of phenobarbital pretreatment on the response of rat liver to halothane administration, Proc. Soc. Exp. Biol. Med. 140, 1319–1324 (1972).PubMedGoogle Scholar
  27. 27.
    J. G. Lavigne and C. Marchand, The role of metabolism in chloroform hepatotoxicity, Toxicol. Appl. Pharmacol. 29, 312–326 (1974).PubMedCrossRefGoogle Scholar
  28. 28.
    C. Cessi, C. Colombini, and L. Mameli, The reaction of liver proteins with a metabolite of carbon tetrachloride, Biochem. J. 101, 46–47 (1966).Google Scholar
  29. 29.
    E. Reynolds, Liver parenchymal cell injury. IV. Pattern of incorporation of carbon and chlorine from carbon tetrachloride into chemical constituents of liver in vivo, J. Pharmacol. Exp. Ther. 155, 117–126 (1967).PubMedGoogle Scholar
  30. 30.
    K. S. Rao and R. O. Recknagel, Early incorporation of carbon-labeled carbon tetrachloride into rat liver particulate lipids and proteins, Exp. Mol. Pathol. 10, 219–228 (1969).PubMedCrossRefGoogle Scholar
  31. 31.
    E. Gordis, Lipid metabolites of carbon tetrachloride, J. Clin. Invest. 48, 203–209 (1969).PubMedCrossRefGoogle Scholar
  32. 32.
    K. F. Ilett, W. D. Reid, I. G. Sipes, and G. Krishna, Chloroform toxicity in mice: Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules, Exp. Mol. Pathol. 19, 215–229 (1973).PubMedCrossRefGoogle Scholar
  33. 33.
    E. N. Cohen, Metabolism of halothane-2–14 C in the mouse, Anesthesiology 31, 560–565 (1969).PubMedCrossRefGoogle Scholar
  34. 34.
    L. C. Howard, D. R. Brown, and D. A. Blake, Subcellular binding of halothane-1–14 C in mouse liver and brain, J. Pharm. Sci. 62, 1021–1023 (1973).PubMedCrossRefGoogle Scholar
  35. 35.
    F. Schnitger and H. Uehleke, Der Einfluss von Dimethylnitrosamin, Tetrachlorkohlenstoff, Buttergelb and Cyclophosphamid auf den Aminosäureneinbau in Fraktionen von Leberhomogenaten nach metabolischer Aktivierung in vitro, Arch. Toxikol. 25, 169–182 (1969).PubMedCrossRefGoogle Scholar
  36. 36.
    O. Reiner and H. Uehleke, Bindung von Tetrachlorkohlenstoff an reduziertes mikrosomales Cytochrom P-450 and an Häm, Hoppe-Seyler’s Z. Physiol. Chem. 352, 1048–1052 (1971).PubMedCrossRefGoogle Scholar
  37. 37.
    O. Reiner, S. Athanassopoulos, K. H. Hellmer, R. E. Murray, and H. Uehleke, Bildung von Chloroform aus Tetrachlorkohlenstoff in Lebermikrosomen, Lipidperoxidation and Zerstörung von Cytochrom P-450, Arch Toxikol. 29, 219–233 (1972).PubMedCrossRefGoogle Scholar
  38. 38.
    H. Uehleke, K. H. Hellmer, and S. Tabarelli, Binding of 14C-carbon tetrachloride to microsomal proteins in vitro and formation of CHC13 by reduced microsomes, Xenobiotica 3, 1–11 (1973).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Uehleke, K. H. Hellmer, and S. Tabarelli-Poplawski, Metabolic activation of halo-thane and its covalent binding to liver endoplasmic proteins in vitro, Naunyn-Schmiedeberg’s Arch. Pharmacol. 279, 39–52 (1973).PubMedCrossRefGoogle Scholar
  40. 40.
    H. Uehleke, The model system of microsomal drug activation and covalent binding to endoplasmic proteins, in: Experimental Model Systems in Toxicology and Their Significance in Man: Proceedings European Society for the Study of Drug Toxicity, Vol. XV (H. Duncan, ed.), pp. 119–129, Excerpta Medica Foundation, Amsterdam (1974).Google Scholar
  41. 41.
    H. Uehleke and T. Werner, A comparative study on the irreversible binding of labelled halothane, trichlorofluoromethane, chloroform and carbon tetrachloride to hepatic protein and lipids in vitro and in vivo, Arch. Toxikol. 34, 289–308 (1975).CrossRefGoogle Scholar
  42. 42.
    H. Uehleke, F. Schnitger, and K. H. Hellmer, Verhalten verschiedener mikrosomaler Fremdstoff-Oxidationen nach Inaktivierung von Cytochrom P-450 durch UV-Bestrahlung oder durch Desoxycholatbehandlung, Hoppe-Seyler’s Z. Physiol. Chem. 351, 1475–1484 (1970).PubMedCrossRefGoogle Scholar
  43. 43.
    H. Greim, H. Krämer, T. Werner, and H. Uehleke, Metabolic activation of haloalkanes and in vitro tests for mutagenicity, Xenobiotica in press (1976).Google Scholar
  44. 44.
    H. Uehleke, S. Poplawski, G. Bonse, and D. Henschler, Spectral evidence for 2,2,3trichloro-oxirane formation during microsomal trichloroethylene oxidation, Arch. Pharmacol. 293, Suppl. R 64 (1976).Google Scholar
  45. 45.
    R. A. Van Dyke and C. L. Wood, Binding of radioactivity from-labeled halothane in isolated perfused rat livers, Anesthesiology 38, 328–332 (1973).PubMedCrossRefGoogle Scholar
  46. 46.
    B. B. Paul and D. Rubinstein, Metabolism of carbon tetrachloride and chloroform by the rat, J. Pharmacol. Exp. Ther. 141, 141–148 (1963).PubMedGoogle Scholar
  47. 47.
    R. A. Van Dyke and A. J. Gandolfi, Studies on irreversible binding of radioactivity from (14 C) halothane to rat hepatic microsomal lipids and protein, Drug Metab. Dispos. 2, 469–476 (1974).PubMedGoogle Scholar
  48. 48.
    M. M. Airaksinen, P. H. Rosenberg, and T. Tammisto, A possible mechanism of toxicity of trifluoroethanol and other halothane metabolites, Acta Pharmacol. Toxicol. 28, 299–304 (1970).CrossRefGoogle Scholar
  49. 49.
    H. Uehleke and T. Werner, Postnatal development of halothane and other haloalkane metabolism and covalent binding in rat liver microsomes, in: Basic and Therapeutic Aspects of Perinatal Pharmacology (P. L. Morselli, S. Garattini, and F. Sereni, eds.), pp. 277–287, Raven Press, New York (1975).Google Scholar
  50. 50.
    T. Werner and H. Uehleke, Covalent binding of halothane and other haloalkanes to microsomal proteins and lipids in vivo and in vitro, Naunyn-Schmiedeberg’s Arch. Pharmacol. 285, Suppl. R90 (1974).Google Scholar
  51. 51.
    D. M. Brown, P. F. Langley, D. Smith, and D. C. Taylor, Metabolism of chloroform. I. The metabolism of 4C-chloroform by different species, Xenobiotica 3, 151–163 (1974).CrossRefGoogle Scholar
  52. 52.
    B. J. Fry, T. Taylor, and D. E. Hathway, Pulmonary elimination of chloroform and its metabolite in man, Arch. Int. Pharmacodyn. Ther. 196, 98–111 (1972).PubMedGoogle Scholar
  53. 53.
    R. O. Recknagel and E. A. Glende, Carbon tetrachloride hepatotoxicity: An example of lethal cleavage, CRC Critical Reviews in Toxicology 2, 263–297 (1973).CrossRefGoogle Scholar
  54. 54.
    G. J. Traiger and G. L. Plaa, Differences in the potential of carbon tetrachloride in rats by ethanol and isopropanol pretreatment, Toxicol. Appl. Pharmacol. 20, 105–112 (1971).PubMedCrossRefGoogle Scholar
  55. 55.
    H. Uehleke, Age-dependent role of biotransformation in toxic drug action, in: Developmental and Genetic Aspects of Drug and Environmental Toxicity (H. D. Duncan, ed.), pp. 11–21, Excerpta Medica Foundation, Amsterdam (1975).Google Scholar
  56. 56.
    H. Uehleke, The formation and kinetics of reactive drug metabolites in mammals, Mutat. Res. 25, 159–167 (1974).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Hartmut Uehleke
    • 1
  1. 1.Department of ToxicologyBundesgesundheitsamtBerlin 33Germany

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