Skip to main content
SpringerLink
Log in

Investigation of the Immunological Basis of Halothane-Induced Hepatotoxicity

  • Chapter
Biological Reactive Intermediates III

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 197))

Abstract

It is well established that halothane (CF3CHC1Br), an inhalation anesthetic, causes both a mild and a severe form of hepatotoxicity in patients.1 The milder form of hepatotoxicity is characterized by minor elevations in serum transaminase levels and has been reported in about 20% of patients anesthesized with halothane.2,3 The severe form of hepatotoxicity, however, is often fatal and is much rarer.4’5 Most of the patients with the severe disease have high serum transaminase values and massive hepatic necrosis. The necrosis is often çegtrilobular,6 although other histologic lesions have been reported.7,8

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. L. R. Pohl and J. R. Gillette, A perspective on halothane-induced hepatotoxicity, Anesth. Analg. 61: 809 (1982).

    Article  CAS  Google Scholar 

  2. R. Wright, O. E. Eade, M. Chisholm, M. Hawksley, B. Lloyd, T. M. Moles, J. C. Edwards, and M. J. Gardner, Controlled prospective study of the effect on liver function of multiple exposure to halothane, Lancet 1: 817 (1975).

    Article  PubMed  CAS  Google Scholar 

  3. J. Trowell, R. Peto, and A. C. Smith, Controlled trial of repeated halothane anesthetics in patients with carcinoma of the uterine cervix treated with radium, Lancet 1: 821 (1975).

    PubMed  CAS  Google Scholar 

  4. W. W. Mushin, M. Rosen, and E. V. Jones, Post-halothane jaundice in relation to previous administration of halothane, Br. Med. J. 3: 18 (1971).

    Article  CAS  Google Scholar 

  5. H. T. Wark, Postoperative jaundice in children, the influence of halothane, Anesthesia 38: 237 (1983).

    CAS  Google Scholar 

  6. R. L. Peters, H. A. Edmondson, T. B. Reynolds, J. C. Meister, and T. J. Curphey, Hepatic necrosis associated with halothane-induced hepatotoxicity, Am. J. Med. 47: 748 (1969).

    Article  PubMed  CAS  Google Scholar 

  7. E. A. Gall, Report of the pathology panel. National halothane study, Anesthesiology 29: 233 (1968).

    Article  PubMed  CAS  Google Scholar 

  8. D. J. Miller, J. Dwyer, and G. Klatskin, Halothane hepatitis: Benign resolution of severe lesion, Ann. Intern. Med. 89: 212 (1978).

    PubMed  CAS  Google Scholar 

  9. A. J. Gandolfi, R. D. White, I. G. Sipes, and L. R. Pohl, Bioacti-vatio94and covalent binding of halothane invitro: Studies with PHI- and [C]-halothane, J. Pharmacol.Exo. Ther., 214: 721 (1980).

    CAS  Google Scholar 

  10. G., K. Gourlay, J. F. Adams, M. J. Cousins, and P. Hall, Genetic differences in reductive metabolism and hepatotoxicity of halothane in three rat strains, Anesthesiology 55: 90 (1981).

    Article  Google Scholar 

  11. J. R. Trudell, B. Bosterling, and A. J. Trevor, Reductive metabolism of halothane by human and rabbit cytochrome P-450. Binding of 1-chloro-2,2,2-trifluoroethyl radical to phospholipids, Mol. Pharmacol. 21: 710 (1982).

    CAS  Google Scholar 

  12. H. J. Ahr, L. J. King, W. Nastainczyk, and V. Ullrich, The mechanism of reductive dehalogenation of halothane by liver cytochrome P-450, Biochem. Pharmacol. 31: 383 (1982).

    CAS  Google Scholar 

  13. E. N. Cohen, J. R. Trudell, H. N. Edmunds, and E. Watson, Urinary metabolites of halothane in man, Anesthesiology 43: 392 (1975).

    Article  PubMed  CAS  Google Scholar 

  14. D. Karashima, Y. Hirokata, A. Shigematsu, and T. Furukawa, The in vitro metabolism of halothane (2-bromo-2-ehloro-1,1,1-trifluoroethane) by hepatic miorosomal cytochrome P-450, J. Pharmacol. EXD. Ther. 203: 409 (1977).

    CAS  Google Scholar 

  15. L. P. McCarty, R. S. Malek, and E. R. Larsen, The effects of deuteration on the metabolism of halogenated anesthetics in the rat, Auesthesiolomv 51: 106 (1979).

    Article  CAS  Google Scholar 

  16. I. G. Sipes, A. J. Gandolfi, L. R. Pohl, G. Krishna, and B. R. Brown, Comparison of the biotransformation and hepatotoxicity of halothane and deuterated halothane, J. Pharmacol. EXD. Ther. 214: 716 (1980).

    CAS  Google Scholar 

  17. R. Miller and A. Stier, Modification of liver microsomal lipids by halothane metabolites: A multi nuclear NMR spectroscopic study. Naunvn-Sohmiedeberg’s Arch. Pharmaeol. 321: 234 (1982).

    Google Scholar 

  18. L. R. Pohl and J. R. Gillette, Determination of toxic pathways of metabolism by deuterium substitution, Drum Metab. Reviews 15: 1335 (1985).

    CAS  Google Scholar 

  19. J. L. Plummer, P. Hall, M. A. Jenner, and M. J. Cousins, Sex differences in halothane metabolism and hepatotoxicity in a rat model, Anesth. Analg. 64: 563 (1985).

    Article  CAS  Google Scholar 

  20. J. L. Plummer, S. Wanwimolruk, M. A. Jenner, P. Hall, and M. J. Cousins, Effects of cimetidine and ranitidine on halothane metabolism and hepatotoxicity in an animal model, Drum Metab. Disd. 12: 106 (1984).

    CAS  Google Scholar 

  21. C. A. Lunam, M. J. Cousins, and P. Hall, Guinea-Pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia, J. Pharmacol. Exp. Ther. 232: 802 (1985).

    PubMed  CAS  Google Scholar 

  22. S. Belfrage, I. Ahlgren, and S. Axelson, Halothane hepatitis in an anesthetist, Lancet 2: 1466 (1966).

    Article  Google Scholar 

  23. G. Klatskin and D. V. Kimberg, Recurrent hepatitis attributable to halothane sensitization in an anesthetist, N Fngl. J. Med. 280: 515 (1969).

    Article  CAS  Google Scholar 

  24. F. M. T. Carney and R. A. Van Dyke, Halothane hepatitis: A critical review, Anesth. Analg. 51: 135 (1972).

    CAS  Google Scholar 

  25. B. Walton, B. R. Simpson, D. Doniach, J. Perrin, and A. J. Appleyard, Unexplained hepatitis following anesthesia, Br. Med. J. 1: 1171 (1976).

    Article  CAS  Google Scholar 

  26. D. Vergani, D. Tsantoulas, A. L. W. F. Eddleston, M. Davis, and R. Williams, Sensitization to halothane-altered liver components in severe hepatic necrosis after halothane anesthesia, Lancet 2: 801 (1978).

    Article  PubMed  CAS  Google Scholar 

  27. G. Mieli-Vergani, D. Vergani, J. M. Tredger, A. L. W. F. Eddleston, M. Davis, and R. Williams, Lymphocyte cytotoxicity to halothane altered hepatoeytes in patients with severe hepatic necrosis following halothane anesthesia, J. Clin Lab. Immunol. 4: 49 (1980).

    CAS  Google Scholar 

  28. D. Vergani, G. Mieli-Vergani, A. Alberti, J. Neuberger, A. L. W. F. Eddleston, M. Davis, and R. Williams, A.tibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis, N. Engl. J. Med. 303: 66 (1980).

    Google Scholar 

  29. J. Neuberger, G. Mieli-Vergani, J. M. Tredger, M. Davis, and R. Williams, Oxidative metabolism of halothane in the production of altered hepatocyte membrane antigens in acute halothane-induced necrosis, GuI 22: 669 (1981).

    CAS  Google Scholar 

  30. H. Satoh, Y. Fukuda, D. K. Anderson, V. J. Ferrans, J. R. Gillette, and Lance R. Pohl, Immunological studies on the mechanism of halothane-induced hepatotoxicity: Immunohistochemical evidence of trifluoroacetylated hepatoeytes, J. Pharmaeol. Egp. Ther. 233: 857 (1985).

    CAS  Google Scholar 

  31. H. Satoh, J. R. Gillette, H. W. Davies, R. D. Sohuliek, and L. R. Pohl, Immunochemical evidence of trifluoroaoetylated cytochromes P-450 in the liver of halothane treated rats, Mol. Pharmacol. (in press).

    Google Scholar 

  32. Y. Yasukoehi and B. S. S. Masters, Some properties of a detergent-solubilized NADPH cytochrome e (cytochrome P-450) reduotase purified by biospeoific affinity chromatography, J. Biol. Chem. 251: 5337 (1976).

    Google Scholar 

  33. L. Lesko, M. Donlon, G. V. Marinetti, and J. D. Hare, A rapid method for the isolation of rat liver plasma membranes using an aqueous two-phase polymer system, Biochem. Bioohvs. Acta 311: 173 (1973).

    CAS  Google Scholar 

  34. P. E. Thomas, D. Korzeniowski, D. Ryan, and W. Levin, Preparation of monospecific antibodies against two forms of rat liver cytochrome P450 and quantitation of these antigens in microsomes, Arch. Biochem. Bioohvs. 192: 524 (1979).

    Article  CAS  Google Scholar 

  35. S. Avrameas and T. Ternynek, Peroxidase labelled antibody and Fab conjugate with enhanced intracellular penetration, Immunochemistry 8: 1175 (1971).

    Article  PubMed  CAS  Google Scholar 

  36. H. De Groot, U. Harnisch, and T. Noll, Suicidal inactivation of microsomal cytochrome P-450 by halothane under hypoxie conditions, Biochem. Bioohvs. Res. Commun. 107: 885 (1982).

    Article  Google Scholar 

  37. P. A. Krieter and R. A. Van Dyke, Cytochrome P-450 and halothane metabolism. Decrease in rat liver microsomal P-450 in vitro, Chem. Biol. Interact. 44: 219 (1983).

    Article  PubMed  CAS  Google Scholar 

  38. R. V. Branehflower, R. D. Schulick, J. W. George, and L. R. Pohl, Comparison of the effects of methyl-n-butyl ketone and phenobarbital on rat liver cytochromes P-450 and the metabolism of chloroform to phosgene, Toxicol. ADD1. Pharmacol. 71: 414 (1983).

    Google Scholar 

  39. T. Omura and R. Sato, The carbon monoxide binding pigment of liver microsomes. I. Evidence for its hemoprotein nature, J. Biol. Chem. 239: 2370 (1964).

    CAS  Google Scholar 

  40. P. P. Wang, P. Beaune, L. S. Kaminsky, G. A. Dannan, F. F. Kadlubar, D. Larrey, and F. P. Guengerich, Purification and characterization of six cytochrome P-450 isozymes from human liver microsomes, Biochemistry 22: 5375 (1983).

    Article  PubMed  CAS  Google Scholar 

  41. D. E. Ryan, P. E. Thomas, and W. Levin, Purification and characterization of a minor form of hepatic microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, Arch. Biochem. Bioohvs. 216: 272 (1982).

    Article  CAS  Google Scholar 

  42. F. P. Guengerich, G. A. Dannan, S. T. Wright, M. V. Martin, and L. S. Kaminsky, Purification and characterization of liver microsomal cytochromes P-450: Electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or beta-naphthoflavone, Biochemistry 21: 6019 (1982).

    Article  PubMed  CAS  Google Scholar 

  43. D. E. Ryan, P. E. Thomas, D. Korzeniowski, and W. Levin, Separation and characterization of highly purified forms of liver microsomal cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobarbital, and 3-methycholanthrene, J. Biol. Chem. 254: 1365 (1979).

    PubMed  CAS  Google Scholar 

  44. D. J. Waxman, and C. Walsh, Phenobarbital-induced rat liver cytochrome P-450. Purification and characterization of two closely related isozymic forms, J. Biot. Chem. 257: 10446 (1982).

    CAS  Google Scholar 

  45. D. E. Hultquist, D. W. Reed, P. G. Passon, and W. E. Andrews, Purification and properties of S-protein (hemoprotein559) from human erythrocytes, Biochim. Bioohvs. Acta 229: 33 (1971).

    CAS  Google Scholar 

  46. H. Glaumann and J. A. Gustafsson, Subcellular localization of steroid hormone metabolism in rat liver, Exd. Mol. Pathol. 27: 221 (1977).

    Article  CAS  Google Scholar 

  47. G. Bruder, A. Fink, and E. D. Jarasch, The b-type cytochrome in endoplasmic reticulum of mammary gland epithelium and milk fat globule membranes consists of two components, cytochrome b5 and cytochrome P-420, Bxd. Cell Res. 117: 207 (1978).

    Article  CAS  Google Scholar 

  48. E. D. Jarasch, J. Kartenbeck, G. Bruder, A. Fink., D. J. Morre, and W. W. Franke, B-type cytochromes in plasma membranes isolated from rat liver, in comparison with those of endomembranes, J. Cell Biol. 80: 37 (1979).

    Article  PubMed  CAS  Google Scholar 

  49. P. Stasiecki, F. Oesch, G. Bruder, E. D. Jarasch, and W. W. Franke, Distribution of enzymes involved in metabolism of polycyclic aromatic hydrocarbons among rat liver endomembranes and plasma membranes, Eur. J. Cell Biol. 21: 79 (1980).

    PubMed  CAS  Google Scholar 

  50. I. M. Vassiletz, E. F. Derkatchev, and S. A. Neifakh, The electron transfer chain in liver cell plasma membrane, Exd. Cell Res. 46: 419 (1967).

    Article  CAS  Google Scholar 

  51. Y. Ichikawa and T Tamano, Cytochrome b5 and CO-binding cytochromes in the golgi membranes of mammalian livers, Biochem. Bionhvs. Res. Commun. 40: 297 (1970).

    Article  CAS  Google Scholar 

  52. S. Fleischer, B. Fleischer, A. Azzi, and B. Chance, Cytochrome b5 and P-450 in liver cell fractions, Bioohim. Bionhvs. Acta 225: 194 (1971).

    Article  CAS  Google Scholar 

  53. P. Emmelot and C. J. Bos, Studies on plasma membranes. XVII. On the chemical composition of plasma membranes prepared from rat and mouse liver and hepatoma, J. Membrane Biol. 9: 83 (1972).

    Article  CAS  Google Scholar 

  54. P. Emmelot, C. J. Bos, R. P. van Hoeven, and W. J. van Blitterswijk, Isolation of plasma membranes from rat and mouse livers and hepatomas, in: “Methods in Enzymology,” S. Fleischer and L. Packer, eds., Vol. 31, p. 75, Academic Press, New York (1974).

    Google Scholar 

  55. C. von Bahr, E. Hietanen, and H. Glaumann, Oxidation and glucuronidation of certain drugs in various subcellular fractions of rat liver: Binding of desmethylimipramine and hexobarbital to cytochrome P-450 and oxidation and glucuronidation of desmethylimipramine, aminopyrine, p-nitrophenol and 1-naphthol, Acta Pharmacol. Toxicol. 31: 107 (1972).

    Article  Google Scholar 

  56. F. C. Charalampous, N. K. Gonatas, and A. D. Melbourne, Isolation and properties of the plasma membrane of KB cells, J. Cell Biol. 59: 421 (1973).

    Article  PubMed  CAS  Google Scholar 

  57. S. Matsuura, Y. Fujii-Kuriyama, and Y. Tashiro, Immunoelectron microscope localization of cytochrome P-450 on microsomes and other membrane structures of rat hepatocytes, J. Cell Biol. 78: 503 (1978).

    Article  PubMed  CAS  Google Scholar 

  58. P. Emmelot and C. J. Bos, Studies on plasma membranes. XI. Inorganic pyrophosphatase, PPi-glucose phosphotransferase and glucose-6-phosphatase in plasma membranes and microsomes isolated from rat and mouse livers and hepatomas, Biochim. Bionhvs. Acta 211: 169 (1970).

    Article  CAS  Google Scholar 

  59. S. Fleischer and M. Kervina, Subcellular fractionation of rat liver, in: “Methods in Enzymology,” S. Fleischer and L. Packer, eds., Vol. 31, p. 6, Academic Press, New York (1974).

    Google Scholar 

  60. K. E. Howell, A. Ito, and G. E. Palade, Endoplasmic reticulum marker enzymes in golgi fractions-What does this mean ?, J. Cell Biol. 79: 581 (1978).

    Article  PubMed  CAS  Google Scholar 

  61. G. L. Ginsberg and S. D. Cohen, Plasma membrane alterations and covalent binding to organelles after an hepatotoxic dose of paracetamol, The Toxicologist 5: 154 (1985).

    Google Scholar 

  62. K. B. Taylor and H. C. Thomas, Gastrointestinal and liver diseases, in: “Basic and Clinical Immunology,” D. P. Stites, J. D. Stobo, H. H. Fudenberg, and J. V. Wells, eds., p. 518, Lange Medical Publications, Los Altos (1982).

    Google Scholar 

  63. J. V. Wells, Immune mechanisms in tissue damage, in: “Basic and Clinical Immunology,” D. P. Stites, J. D. Stobo, H. H. Fudenberg, and J. V. Wells, eds., p. 136, Lange Medical Publications, Los Altos (1982).

    Google Scholar 

  64. A. H. Callis, S. D. Brooks, S. J. Waters, A. J. Gandolfi, D. O. Lucas, L. R. Pohl, H. Satoh, and I. G. Sipes, Evidence for a role of the immune system in the pathogenesis of halothane hepatitis, in: “Molecular Mechanisms of Anesthesia, Progress in Anesthesiology,” S. H. Roth, ed., Vol. 3, Raven Press (in press).

    Google Scholar 

  65. J. G. Kenna, J. Neuberger, and R. Williams, An enzyme-linked immunosorbent assay for detection of antibodies against halothane-altered hepatocyte antigens, J. Immunol. Method 75: 3 (1984).

    Article  CAS  Google Scholar 

  66. J. G. Kenna, J. Neuberger, and R. Williams, Characterization of halothane-induced antigens by immunoblotting, Biochem. Soc. Trans 13: 910 (1985).

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Chemical Pharmacology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Hiroko Satoh, James R. Gillette & Lance R. Pohl

  2. Pathology Branch, Ultrastructure Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Tamiko Takemura & Victor J. Ferrans

  3. Department of Anesthesiology, Clinical Center, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Sandra E. Jelenich

  4. The Liver Unit, King’s College Hospital and School of Medicine and Dentistry, Denmark Hill, London, SE5 9RS, UK

    John G. Kenna & James Neuberger

Authors
  1. Hiroko Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James R. Gillette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lance R. Pohl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tamiko Takemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Victor J. Ferrans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra E. Jelenich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John G. Kenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James Neuberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    James J. Kocsis

  2. Medical University of South Carolina, Charleston, South Carolina, USA

    David J. Jollow

  3. Rutgers University, Piscataway, New Jersey, USA

    Charlotte M. Witmer  & Robert Snyder  & 

  4. University of Maryland, College Park, Maryland, USA

    Judd O. Nelson

Rights and permissions

Reprints and permissions

Copyright information

© 1986 Plenum Press, New York

About this chapter

Cite this chapter

Satoh, H. et al. (1986). Investigation of the Immunological Basis of Halothane-Induced Hepatotoxicity. In: Kocsis, J.J., Jollow, D.J., Witmer, C.M., Nelson, J.O., Snyder, R. (eds) Biological Reactive Intermediates III. Advances in Experimental Medicine and Biology, vol 197. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5134-4_61

Download citation

  • DOI: https://doi.org/10.1007/978-1-4684-5134-4_61

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-5136-8

  • Online ISBN: 978-1-4684-5134-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation