Halothane hepatitis: Attempt to develop an animal model

Neuberger, James; Kenna, J. Gerry; Williams, Roger

doi:10.1016/0192-0561(87)90086-5

Cited by 21 publications

(6 citation statements)

References 15 publications

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“…The recognition by the serum of patient 11 of the E3 subunit of PDC, a non-lipoylated target antigen the recognition of which was noted with some patients' sera, was not affected by CF3CO-Lys and 6(RS)lipoic acid (Figure 5A). In contrast, as noted in previous experiments (35,54) and demonstrated here with the serum of patient 4 (sera collection 2) and the E2 subunit of OGDC as target antigen, some of the patients' sera recognized lipoylated antigens in a manner not or only marginally sensitive to competition by CF3CO-Lys (25 mM) and 6(RS)-lipoic acid (25 mM (Figure 5B)). These data suggest the occurrence in these sera of higher proportion(s) of autoantibodies recognizing epitopes on native, lipoylated target proteins other than the central lipoic acid motif.…”

Section: Resultscontrasting

confidence: 75%

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The Lipoic Acid Containing Components of the 2-Oxoacid Dehydrogenase Complexes Mimic Trifluoroacetylated Proteins and Are Autoantigens Associated with Halothane Hepatitis

Frey¹,

Christen²,

Jenö³

et al. 1995

Chem. Res. Toxicol.

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Anti-CF3CO antibodies, monospecific toward trifluoroacetylated proteins (CF3CO-proteins), which are elicited in experimental animals and humans exposed to the anesthetic agent halothane, cross-react with an unknown protein of approximately 52 kDa, constitutively expressed in tissues of experimental animals and humans not previously exposed to the agent. Using anti-CF3CO antibody, the protein(s) of 52 kDa could be immunoprecipitated from solubilized rat heart homogenate. Two-dimensional gel electrophoretic analysis revealed the presence of distinct major (P1, P2) and minor (P3, P4, P5) protein components with apparent molecular masses of 52 kDa. From each of the components P1 and P2, the amino acid sequences of three peptides were determined and found to exhibit 100% identity with the corresponding amino acid sequences of the E2 subunit of the rat 2-oxoglutarate dehydrogenase complex (OGDC). Additionally to the E2 subunit of OGDC, anti-CF3CO antibody also recognized on immunoblots the purified E2 subunit of the branched chain 2-oxoacid dehydrogenase complex (BCOADC) and protein X, a constituent of the pyruvate dehydrogenase complex (PDC), in a manner sensitive to competition by N6-(trifluoroacetyl)-L-lysine (CF3CO-Lys), 6(RS)-lipoic acid, and N6-(6(RS)-lipoyl)-L-lysine (lipoyl-Lys). Furthermore, a discrete population of autoantibodies was identified in sera of patients with halothane hepatitis which could not discriminate between the lipoylated target epitope present on the E2 subunit of OGDC and epitopes on CF3CO-RSA, used as model for CF3CO-proteins. These data suggest that the autoantigenicity of these proteins in halothane hepatitis is based on the molecular mimicry of CF3CO-Lys by lipoic acid, the prosthetic group common to protein X and the E2 subunits of OGDC and BCOADC.

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Section: Resultscontrasting

confidence: 75%

“…Current evidence indicates that all halothane-exposed human individuals produce CF3CO-proteins (10,(24)(25)(26). However, it is not understood why, in contrast to the few susceptible individuals afflicted with the disease, the vast majority of individuals appears to immunologically tolerate CF3CO-proteins.…”

Section: Introductionmentioning

confidence: 99%

The Lipoic Acid Containing Components of the 2-Oxoacid Dehydrogenase Complexes Mimic Trifluoroacetylated Proteins and Are Autoantigens Associated with Halothane Hepatitis

Frey¹,

Christen²,

Jenö³

et al. 1995

Chem. Res. Toxicol.

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“…Furthermore, exposure of rats to the newer volatile anesthetics enflurane and isoflurane [18, 191, or to pentahaloethane-based candidate replacements of chlorofluorocarbons such as HCFC 123 [5-71, which are close structural analogues of halothane, has been shown to result in the formation of metabolite-protein adducts not discernible immunochemically from CF,CO-proteins. Based on their reactivity with patients' sera, several discrete CF,CO-proteins have been purified from rat liver and their corresponding native forms identified by amino acid sequencing and/or molecular cloning as protein disulfide isomerase [20] Current evidence indicates that all halothane-exposed human individuals produce CF, 15,25, 261. However, halothane hepatitis is rare; between 1 in 37000 ~4 1 .…”

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confidence: 99%

Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis

Christen

Quinn

Yeaman

et al. 1994

European Journal of Biochemistry

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Trifluoroacetylated (CF,CO-) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti-CF,CO antibody, monospecific for the hapten derivative W-trifluoroacetyl-L-lysine. Anti-CF,CO antibodies cross-reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase, indicating that epitopes on the E2 subunit of pyruvate dehydrogenase molecularly mimic those on CF,CO-proteins. Lipoic acid, the prosthetic group of the E2 subunit of pyruvate dehydrogenase was essential in this process, in that only the lipoylated form of the recombinantly expressed inner lipoyl domain of the human E2 subunit of pyruvate dehydrogenase, but not the unlipoylated form, was recognized by anti-CF,CO antibody. Furthermore, based on a high degree of structural relatedness, both CF,CO-Lys and (6RS)-lipoic acid, as well as the lipoylated peptide ETDKo,,,,,,ATIG specifically inhibited the recognition by anti-CF,CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF,CO-proteins. In sera of patients with halothane hepatitis, autoantibodies with properties identical to those of anti-CF,CO antibody were identified which could not discriminate between CF,CO-proteins and the E2 subunit of pyruvate dehydrogenase. These data suggest that the E2 subunit pyruvate of dehydrogenase is an autoantigen in halothane hepatitis and that molecular mimicry of CF,CO-proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF,CO-Lys and lipoic acid.Halothane hepatitis is a potentially severe and life-threatening form of hepatic damage which may occur in humans exposed to the inhalation anesthetic halothane (CF,CHBrCl) [l, 21. This adverse drug reaction is thought to have an immunological basis ; previous studies have implicated an immune response to trifluoroacetylated hepatic protein antigens [2]. Trifluoroacetyl-protein adducts (CF,CO-proteins) arise through covalent modification of target proteins by the acyl halide intermediate CF,COCl that is elicited upon oxidative, cytochrome-P450-dependent metabolism of halothane and also other structurally closely related compounds [3 -71. In fact, with halothane and 2,2-dichloro-l,l,l-trifluoroethane (HCFC 123) as substrates, the predominant adduct formed in the process has been identified by 19F-NMR as W-trifluoroacetyl-L-lysine (CF,CO-Lys detected in the livers of halothane-exposed rats, rabbits, guinea pigs and mice [6,[8][9][10][11] and also in liver biopsies of halothane-exposed humans [12,13]. In halothane-exposed rats, CF,CO-proteins are found in centrilobular liver sections [6], on the surface of hepatocytes [8], within Kupffer cells [14], in liver microsomal membranes [6, 1.51 and, at low levels, disseminated in the kidneys [6], the heart [16] and the testes [17]. Furthermore, exposure of rats to the newer volatile anesthetics enflurane and isoflurane [18, 191, or to pentahaloethane-based candidate replacements of chlorofluorocarbons such as HCFC 123 [5-71,...

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“…Several attempts have been made previously to generate TFA-specific T cell responses by immunizing various species of animals with TFA modified serum albumin or hepatocytes from halothane-treated animals (Mathieu et al, 1975;Reves and McCracken, Jr., 1976;Neuberger et al, 1987;Chen and Gandolfi, 1997); however, potent immune reactions were not observed. In the hepatocyte preparation, the target antigens may be diluted resulting in reduced immune response.…”

Section: Discussionmentioning

confidence: 99%

Generation of T cell responses targeting the reactive metabolite of halothane in mice

Qin¹,

Cheng²,

Ju³

2010

Toxicology Letters

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Immune-mediated adverse drug reactions (IADRs) represent a significant problem in clinical practice and drug development. Studies of the underlying mechanisms of IADRs have been hampered by the lack of animal models. Halothane causes severe allergic hepatitis with clinical features consistent with an IADR. Our ultimate goal is to develop a mouse model of halothane hepatitis. Evidence suggests that adaptive immune responses targeting liver protein adducts of the reactive metabolite (TFA) play an important role in the pathogenesis. The present study demonstrated that the combination of an anti-CD40 antibody and a Toll-like receptor (TLR) agonist served as a potent adjuvant in generating TFA-specific T cell responses in mice. Both CD4+ and CD8+ subsets of T cells were activated and the TFA-specific responses were detected not only in the spleen but also in the liver of mice immunized with mouse serum albumin adducts of TFA (TFA-MSA) plus the combined CD40/TLR agonist. Whereas all three TLR agonists examined were effective in eliciting TFA-specific immune responses in BALB/cByJ mice, only polyI:C was effective in DBA/1 mice and none of the TLR agonists could aid the generation of TFA-specific T cells in C57BL/6J mice. This result, combined with our previous finding that BALB/cByJ mice were the most susceptible to halothane-induced acute liver injury, provides the basis for employing this strain in future studies. Collectively, our data demonstrated the successful completion of a crucial first step in the development of a murine model of halothane hepatitis.

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Halothane hepatitis: Attempt to develop an animal model

Cited by 21 publications

References 15 publications

The Lipoic Acid Containing Components of the 2-Oxoacid Dehydrogenase Complexes Mimic Trifluoroacetylated Proteins and Are Autoantigens Associated with Halothane Hepatitis

The Lipoic Acid Containing Components of the 2-Oxoacid Dehydrogenase Complexes Mimic Trifluoroacetylated Proteins and Are Autoantigens Associated with Halothane Hepatitis

Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis

Generation of T cell responses targeting the reactive metabolite of halothane in mice

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