Mechanisms of halothane toxicity: Novel insights

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Abstract

Exposure of individuals to halothane causes, in 20% of patients, a mild form of hepatotoxicity. In contrast, a very small subset of individuals only develops halothane hepatitis, which is thought to have an immunological basis. Sera of halothane hepatitis patients contain antibodies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane and include protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78 and ERp99. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-protein adducts arise in all halothane-exposed individuals. The lack of immunological responsiveness of individuals might be due to tolerance, induced by a presumed repetoire of self-peptides that molecularly mimic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-protein adducts. The 64kDa protein corresponds to the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prosthetic group of the E2 subunit, is involved in the molecular mimicry process. A fraction of halothane hepatitis patients exhibit irregularities in the expression levels of the 52 kDa protein and the E2 subunit protein. Molecular mimicry of TFA-protein adducts by the 52 kDa protein and the E2 subunit protein might play a role in the susceptibility of individuals to development of halothane hepatitis.

References (138)

  • J. Huwyler et al.

    Exposure to the chlorofluorocarbon substitute 2,2-dichloro-1,1,1-trifluoroethane and the anesthetic agent halothane is associated with the transient protein adduct formation in the heart

    Biochem. biophys. Res. Commun.

    (1992)
  • I. Johansson et al.

    Carbon tetrachloride-induced lipid peroxidation dependent on an ethanol-inducible form of rabbit liver microsomal cytochrome P-450

    FEBS Lett.

    (1985)
  • J.W. Kappler et al.

    T-cell tolerance by clonal elimination in the thymus

    Cell

    (1987)
  • J.G. Kenna et al.

    Specific antibodies to halothane-induced liver antigens in halothane-associated hepatitis

    Br. J. Anaesth.

    (1987)
  • J.G. Kenna et al.

    Purification of trifluoroacetylated protein antigens from livers of halothane-treated rats

    Eur. J. Pharmac.

    (1990)
  • J.G. Kenna et al.

    The topography of trifluoroacetylated protein antigens in liver microsomal fractions from halothane treated rats

    Biochem. Pharmac.

    (1992)
  • M. Koponen et al.

    T cell reactivity to penicillin: phenotypic analysis of in vitro activated cell subsets

    J. Allergy clin. Immun.

    (1986)
  • J.L. Martin et al.

    A metabolite of halothane covalently binds to an endoplasmic reticulum protein that is highly homologous to phosphatidylinositol-specific phosphlipase C-α but has no activity

    Biochem. biophys. Res. Commun.

    (1991)
  • S. Matuda et al.

    Molecular cloning of dihydrolipoamide acetyltransferase of the rat pyruvate dehydrogenase complex: sequence comparison and evolutionary relationship to other dihydrolipoamide acetyltransferases

    Biochem. biophys. Acta

    (1992)
  • R.A. Mazzarella et al.

    ERp99, an abundant, conserved glycoprotein of the endoplasmic reticulum, is homologous to the 90-kDa heat shock protein (hsp 90) and the 94-kDa glucose-regulated protein (GRP94)

    J. biol. Chem.

    (1987)
  • P.J. Meier et al.

    Subjects with a genetic defect in drug oxidation

    Gastroenterology

    (1983)
  • A.C. Allison

    Theories of self tolerance and autoimmunity

  • M.W. Anders et al.

    Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites

    CRC Crit. Rev. Toxic.

    (1988)
  • Ph. Beaune et al.

    Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug

  • N. Bloksma et al.

    Basic mechanisms of adaptive immune system functions

  • M. Bourdi et al.

    Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2

    J. clin. Invest.

    (1990)
  • M. Bourdi et al.

    Anti-liver microsomes autoantibodies and dihydralazine-induced hepatitis: specificity of autoantibodies and inductive capacity of the drug

    Molec. Pharmac.

    (1992)
  • E.M. Brunt et al.

    Fulminant hepatic failure after repeated exposure to isoflurane anesthesia: a case report

    Hepatology

    (1991)
  • L.E. Butler et al.

    The calcium-binding protein calreticulin is covalently modified in rat liver by a reactive metabolite of the inhalation anesthetic halothane

    Chem. Res. Toxic.

    (1992)
  • A.H. Callis et al.

    Characterization of a halothane-induced humoral immune response in rabbits

    Clin. exp. Immun.

    (1987)
  • J. Canalese et al.

    Circulating immune complexes in patients with fulminant hepatic failure

    Gut

    (1981)
  • H.F. Casorbi et al.

    Differences in biotransformation of halothane in man

    Anesthesiology

    (1970)
  • D.D. Christ et al.

    Enflurane metabolism produces covalently-bound liver adducts recognized by antibodies from patients with halothane hepatitis

    Anesthesiology

    (1988)
  • D.D. Christ et al.

    Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane

    Drug Metab. Disp.

    (1988)
  • U. Christen et al.

    Halothane metabolism: immunochemical evidence for molecular mimicry of trifluoroacetylated liver protein adducts by constitutive polypeptides

    Molec. Pharmac.

    (1991)
  • U. Christen et al.

    Halothane metabolism: the dihydrolipoamide acetyltransferase subunit of the pyruvate dehydrogenase complex molecularly mimics trifluoroacetyl-protein adducts

    Biochemistry

    (1993)
  • E.N. Cohen et al.

    Urinary metabolites of halothane in man

    Anesthesiology

    (1975)
  • J.W. Coleman et al.

    Drug-specific antibodies in patients receiving captopril

    Br. J. clin. Pharmac.

    (1986)
  • R.L. Coppel et al.

    Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase

  • P. De Haan et al.

    Induction of benzylpenicilloyl specific antibodies including IgE by long-term administration of benzylpenicillin

    Clin. Allergy

    (1983)
  • A.L. deWeck

    Immunopathological mechanisms and clinical aspects of allergic reactions to drugs

  • T. Dyrberg

    Molecular mimicry in autoimmunity

  • H.N. Edmunds et al.

    Low-level binding of halothane metabolites to rat liver histones in vivo

    Anesthesiology

    (1981)
  • M.B. Finkelstein et al.

    Nephrotoxicity of the glutathione and cysteine conjugates of 2-bromo-2-chloro-1,1-difluoroethene

    J. Pharmac. exp. Ther.

    (1992)
  • D.A. Fisher et al.

    Model calculations of the relative effects of CFCs and their replacements on stratospheric ozone

    Nature

    (1990)
  • D.R. Fregeau et al.

    Inhibition of α-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis

    Hepatology

    (1990)
  • S.P.M. Fussey et al.

    Identification and analysis of the major M2 autoantigen in primary biliary cirrhosis

  • A.J. Gandolfi et al.

    Bioactivation and covalent binding of halothane in vitro: studies with 3H- and 14C-halothane

    J. Pharmac. exp. Ther.

    (1980)
  • M.E. Gershwin et al.

    Identification and specificity of a cDNA encoding the 70 kDa mitochondrial antigen recognized in primary biliary cirrhosis

    J. Immun.

    (1987)
  • M.-J. Gething et al.

    Protein folding in the cell

    Nature

    (1992)
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