A model for fatal halothane hepatitis in the guinea pig

R. C. Lind, A. J. Gandolfi, M. P. De la Hall

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background: In the guinea pig, depleting hepatic glutathione before inhaling subanesthetic 0.1% halothane increases covalent binding of halothane biotransformation intermediates to hepatic protein and potentiates resultant liver injury. Because inhalation of a higher concentration of halothane is known to produce greater levels of covalent binding than with subanesthetic halothane, this study was undertaken with 0.25-1.0% halothane concentrations to further examine glutathione depletion as an etiology for halothane hepatitis. Methods: Male Hartley guinea pigs were injected intraperitoneally with either vehicle control solution (Veh) or 1.6 g/kg buthionine sulfoximine (BSO), to decrease hepatic glutathione by >80%, 24 h before a 4-h exposure to 0.25%, 0.5%, or 1.0% (v/v) halothane with 40% O2. Some BSO-pretreated animals also received 2.0 g/kg glutathione monoethyl ester (GEE), intraperitoneally, 2 h before inhaling halothane to replenish hepatic glutathione. Results: Glutathione-depleted animals developed significantly worse hepatic injury with each halothane concentration. One-third to one- half of BSO + halothane-treated animals developed fatal submassive to massive hepatic necrosis. Covalent binding of halothane intermediates to hepatic protein increased by 45% in BSO + 1.0% halothane-treated guinea pigs. Administration of GEE to BSO-pretreated animals before 1.0% halothane decreased binding to protein and blunted development of liver necrosis. Following Veh + 1.0% halothane, hepatic glutathione was found to be decreased by 60%. Conclusions: Glutathione would appear to help protect hepatocytes to some degree from covalent binding by reactive halothane biotransformation intermediates. These studies present the first animal model to produce fatal halothane induced hepatic necrosis.

Original languageEnglish (US)
Pages (from-to)478-487
Number of pages10
JournalAnesthesiology
Volume81
Issue number2
DOIs
StatePublished - 1994

Keywords

  • Anesthetics, volatile; halothane
  • Animals: guinea pig
  • Binding: reactive intermediates
  • Biotransformation: halothane
  • Glutathione: depletion: hepatic
  • Liver: submassive necrosis; massive necrosis

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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