Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Satoh, Hiroaki; Martin, Brian M.; Schulick, A H; Christ, David D.; Kenna, J G; Pohl, Lance R.

doi:10.1073/pnas.86.1.322

Cited by 126 publications

(60 citation statements)

References 16 publications

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“…Here, one should note, however, that patients' sera, may contain various discrete populations of antibodies with a multitude of specificities towards epitopes comprising not only the trifluoroacetyl haptenic group but also parts of the carrier molecules. Thus, Satoh et al [21] reported that patients' sera contained discrete populations of antibodies that recognized a purified rat liver CF,CO-protein (i.e. trifluoroacetylated carboxylesterase) in a manner both sensitive and insensitive to competition by CF,CO-Lys.…”

Section: Discussionmentioning

confidence: 99%

“…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 , 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], microsomal carboxylesterase [21], calreticulin [22], ERp72 [23], and ERp99…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…There is already an appreciation that metabolites can contribute to the main component of the pharmacology of a parent molecule [e.g., morphine 6-glucuronide (Hanna et al, 1990)] or be partial contributors [e.g., N-desmethylsertraline (Rudorfer and Potter, 1997)]. Metabolites have also been implicated in adverse effects [e.g., the quinone-imine metabolite of acetaminophen (Manyike et al, 2000) and trifluoroacetyl chloride of halothane (Satoh et al, 1989)]. …”

Section: Introductionmentioning

confidence: 99%

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Tweedie

2012

Drug Metab Dispos

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The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s).When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.

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“…26 It almost never occurs on fi rst exposure, although previous exposures are often associated with fever, and most patients who develop toxicity develop antibodies, both autoantibodies and antibodies against trifl uoroacetylated protein. [27][28][29] This fi nding has led to several attempts to reproduce this syndrome in animals. Although it is possible to induce mild toxicity in rats by a combination of hypoxia, enzyme induction with phenobarbital, and halothane, 30 the toxicity apparently involves the formation of a free radical by a reductive pathway rather than trifl uoroacetyl chloride by an oxidative pathway, and it does not have the characteristics of an immune response similar to the liver toxicity observed in humans.…”

Section: Halothane-induced Hepatotoxicity In Rats and Guinea Pigsmentioning

confidence: 99%

Role of animal models in the study of drug-induced hypersensitivity reactions

Uetrecht

2005

AAPS J

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A BSTRACTDrug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very diffi cult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basic hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ~0.25%, and large-breed dogs are diffi cult to use as an animal model. Two more practical models are penicillamine-induced autoimmunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquineinduced agranulocytosis/hepatotoxicity and halothaneinduced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This fi nding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also signifi cantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow. K EYWORDS: animal models , hypersensitivity reactions , idiosyncratic drug reactions , penicillamine , nevirapine , popliteal lymph node assay INTRODUCTIONTo an immunologist, the term hypersensitivity implies an immune-mediated reaction. The term drug-induced hypersensitivity reaction (DHR) is used to describe a syndrome consisting of fever, rash, and involvement of various organs associated with drugs such as phenytoin, carbamazepine, abacavir, sulfonamides, and allopurinol; however, it is also frequently used to describe any idiosyncratic drug reaction. For many of the adverse reactions to be discussed in this review, it has not been conclusively demonstrated that they are immune mediated, and the term hypersensitivity reaction will be used broadly to refer to any idiosyncratic drug reaction that has features that suggest it is immune mediated. Another working hypothesis for this review, which is supported by a large amount of circumstantial evidence, 1 but in virtually no case proven, is that most DHRs are caused by reactive metabolites. Therefore, a major role of animal models is to test whether reactive metabolites are responsible for hypersensitivity reactions and further to determine how reactive metabolites provoke an immune response.A major characteristic of DHRs is their unpredictable or idiosyncratic nature. This means that at the present time it is impossible to predict which drug candidates will...

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Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase.

Cited by 126 publications

References 16 publications

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

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

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Role of animal models in the study of drug-induced hypersensitivity reactions

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