Immunity to Halothane Metabolite‐Modified Proteins in Halothane Hepatitisa

Kenna, J. Gerry; Knight, T; Pelt, Frank N.A.M. van

doi:10.1111/j.1749-6632.1993.tb35930.x

Cited by 35 publications

(11 citation statements)

References 27 publications

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“…As small molecules, TCE or its metabolites will not be antigenic by themselves, but may haptenize to self-proteins, and thus result in structural modifications that render self-proteins antigenic, potentially leading to autoimmune responses. A trifluoroanalogue of DCAC (trifluoroacylchloride) has been shown to acylate proteins, producing antigens involved in halothane-induced hepatitis Phol et al, 1991;Kenna et al, 1993;Chrsiten et al, 1994) and also, 2,2-dichlorotrifluoroethane-related liver disease (Hoet et al, 1997;White et al 2001). Similarly, covalent binding of TCE in vivo has been observed in rodents Bolt and Filser, 1977;Stot et al, 1982;Mazzullo et al, 1992;Stevens et al, 1992;Kautiainen et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

Cai

König

Boor

et al. 2008

Toxicology and Applied Pharmacology

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Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of antinuclear antibodies increased after 36 and 48 weeks of TCE exposure. Histopathological analyses showed lymphocyte infiltration in the livers of MRL +/+ mice exposed to TCE for 36 or 48 weeks. Lymphocyte infiltration was also apparent in the pancreas, lungs, and kidneys of mice exposed to TCE for 48 weeks. Immunoglobulin deposits in kidney glomeruli were found after 48 weeks of exposure to TCE. Our results suggest that chronic exposure to TCE promotes inflammation in the liver, pancreas, lungs, and kidneys, which may lead to SLE-like disease in MRL +/+ mice.

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Section: Discussionmentioning

confidence: 98%

Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

Cai

König

Boor

et al. 2008

Toxicology and Applied Pharmacology

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“…A number of hepatotoxic drugs have been reported to produce autoantibodies. For example, antiprotein disulfide isomerase, antimicrosomal carboxyesterase, anticalreticulin, anti-ERp72, anti-GRP78, anti-GRP94, and anti-CYP2E1in halothane hepatitis (Bourdi et al 1996;Gut et al 1993;Kenna et al 1993;Pumford et al 1993), anti-CYP2C9 in tienilic acid-induced hepatitis (Homberg et al 1984;Robin et al 1996), anti-CYP1A2 in dihydralazine-induced hepatitis (Bourdi et al 1990), and anti-CYPs in aromatic anticonvulsant-induced hypersensitivities (Leeder et al 1992) have been reported. However, it is not fully understood whether the autoantibodies are the causes or consequences of hepatotoxicity.…”

Section: Hypersensitivity Reaction Associated With Troglitazone Hepatmentioning

confidence: 98%

Troglitazone

Yokoi

2009

Handbook of Experimental Pharmacology

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Troglitazone was the first thiazolidinedione antidiabetic agent approved for clinical use in 1997, but it was withdrawn from the market in 2000 due to serious idiosyncratic hepatotoxicity. Troglitazone contains the structure of a unique chroman ring of vitamin E, and this structure has the potential to undergo metabolic biotransformation to form quinone metabolites, phenoxy radical intermediate, and epoxide species. Although troglitazone has been shown to induce apoptosis in various hepatic and nonhepatic cells, the involvement of reactive metabolites in the troglitazone cytotoxicity is controversial. Numerous toxicological tests, both in vivo and in vitro, have been used to try to predict the toxicity, but no direct mechanism has been demonstrated that can explain the hepatotoxicity that occurred in some individuals. This chapter summarizes the proposed mechanisms of troglitazone hepatotoxicity based in vivo and in vitro studies. Many factors have been proposed to contribute to the mechanism underlying this idiosyncratic toxicity.

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“…Sera from patients with halothane hepatitis have been shown to contain antibodies to novel, halothane metabolite-modified hepatic protein antigens (TFAproteins) which are expressed in livers of halothanetreated animals and humans. The antibodies to the novel antigens are specific to patients with halothane hepatitis, and have been shown to mediate cytotoxic killing in vitro of rabbit isolated hepatocytes which express the TFA-antigens [5][6][7]18]. Immunoblotting studies have indicated that the novel antigens are TFA-modified forms of proteins which are normally situated within hepatocytes, in the endoplasmic reticulum (reviewed by 7,19).…”

Section: Resultsmentioning

confidence: 99%

“…It is is probable immunoblotting have indicated that the novel antithat the mild form of liver damage results from direct gens are trifluoroacetylated proteins, which are proCorrespondence: Dr N. R. Kitteringham, Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool, Merseyside L69 3BX, UK duced via cytochrome P450-mediated metabolism of halothane (CF3CHClBr) to the reactive species trifluoroacetyl chloride (TFA-chloride) [5,6]. Antibodies which recognize these TFA-protein antigens have been detected from immunoblotting in sera from patients with halothane hepatitis, but not in sera from halothane-exposed patients who do not develop the hepatitis, or in other control sera [5][6][7]. During the course of these immunoblotting experiments, it has been noted that sera from patients with halothane hepatitis also contain antibodies which recognize a variety of polypeptide antigens that are present in subcellular fractions prepared from livers of rabbits or rats not previously exposed to halothane [5,6,8,9].…”

Section: Introductionmentioning

confidence: 99%

Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane‐associated hepatitis.

Kitteringham

Kenna

Park

1995

Brit J Clinical Pharma

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1. Previous studies have demonstrated the presence of antibodies to trifluoroacetylated hepatic proteins (TFA‐proteins) in sera from patients with the severe form of halothane‐associated hepatitis (halothane hepatitis). The TFA‐proteins are produced via cytochrome P450‐mediated metabolism of halothane to the reactive species TFA‐ chloride. 2. To investigate the presence of autoantibodies (which recognize various non‐TFA‐modified human hepatic polypeptides) in patients with halothane hepatitis immunoblotting experiments were performed using microsomal fractions prepared freshly from livers of five different (halothane‐free) tissue donors. Blots were developed using 15 well‐characterised sera from patients with halothane hepatitis. 3. Autoantibodies to human hepatic polypeptides were detected in most, but not all, of the patients' sera. The pattern of antibody reactivity varied markedly between sera. Although no common pattern of antibody recognition was observed, polypeptides of molecular mass between 60 and 80 kDa were the predominant targets. A similar protein recognition pattern was seen when each positive serum was tested against the five individual human liver samples. 4. Such autoantibodies were not detected in sera from 16 normal human blood donors, but were detected in three of six sera from patients exposed to halothane without developing hepatitis. 5. The autoantibodies are thought to arise in patients exposed to halothane as a consequence of a halothane‐induced immune response to chemically‐modified proteins. Such antibodies could contribute to the complex pathological processes involved in halothane hepatitis.

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Immunity to Halothane Metabolite‐Modified Proteins in Halothane Hepatitisa

Cited by 35 publications

References 27 publications

Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

Troglitazone

Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane‐associated hepatitis.

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