A number of mechanisms have been proposed to explain the hepatic damage following the administration of the volatile anesthetic, halothane. Although explanations for this hepatotoxicity range from peroxidation, endotoxemia or hypoxia to hyperthyroidism or hypersensitivity, the pathogenetic mechanisms for halothane-induced liver damage are still not well understood. The goal of this study is to demonstrate the presence of and role for an immune component in modulating halothane-induced hepatoxicity. This goal will be accomplished through the following specific aims: (1) To establish the presence of a modified self component in the liver which has been altered by the metabolism of halothane. This modified self component could serve as a potential immunogen in the generation of an immune hypersensitivity response. (2) To detect in halothane-exposed animals the presence of a humoral immune response which cross reacts with synthetic halothane reactive intermediate conjugated proteins. (3) To determine if this humoral immune response plays a role in exacerbating halothane hepatotoxicity. (4) To assess """"""""halothane hepatitis"""""""" patients for the presence of a circulating antibody which cross reacts with halothane reactive intermediate conjugated proteins and (5) To extend this model of hypersensitivity in halothane hepatitis to other volatile anesthetics. The methodology in these investigations will include (1) an enzyme linked immunosorbent assay to detect specific antibodies to modified self or synthetics antigens; (2) indirect immunofluorescence, indirect immunoperoxidase, and complement mediated cytotoxicity to determine the presence of halothane reactive intermediate-modified liver tissue and/or hepatocytes; (3) existing in vivo models of halothane hepatotoxicity to examine the development of a halothane reactive intermediate-induced immune response and any subsequent potentiation of the liver injury by this immune response; (4) collaborative ties with anesthesiologists within and outside the United States to expedite access to """"""""halothane hepatitis"""""""" patient sera. Ultimately, this project will determine if a hypersensitivity immune response is instrumental in the pathogenetic mechanisms of halothane hepatotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034788-03
Application #
3286367
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-06-01
Project End
1988-11-30
Budget Start
1987-06-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Hsieh, Ying-Hsin; Huang, Ying-Ju; Jin, Jin-Shan et al. (2014) Mechanisms of Rose Bengal inhibition on SecA ATPase and ion channel activities. Biochem Biophys Res Commun 454:308-12
Clarke, J B; Thomas, C; Chen, M et al. (1995) Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies. Int Arch Allergy Immunol 108:24-32
Hastings, K L; Thomas, C; Brown, A P et al. (1995) Trifluoroacetylation potentiates the humoral immune response to halothane in the guinea pig. Immunopharmacol Immunotoxicol 17:201-13
Brown, A P; Gandolfi, A J (1994) Glutathione-S-transferase is a target for covalent modification by a halothane reactive intermediate in the guinea pig liver. Toxicology 89:35-47
Hubbard, A K; Lohr, C L; Hastings, K et al. (1993) Immunogenicity studies of a synthetic antigen of alpha methyl dopa. Immunopharmacol Immunotoxicol 15:621-37
Brown, A P; Hastings, K L; Gandolfi, A J et al. (1992) Formation and identification of protein adducts to cytosolic proteins in guinea pig liver slices exposed to halothane. Toxicology 73:281-95
Hastings, K L; Thomas, C; Hubbard, A K et al. (1991) Screening for antibodies associated with halothane hepatitis. Br J Anaesth 67:722-8
Hastings, K L; Schuman, S; Brown, A P et al. (1991) S-ethylthiotrifluoroacetate enhancement of the immune response to halothane in the guinea pig. Adv Exp Med Biol 283:739-44
Hubbard, A K; Levy, J P; Roth, T P et al. (1990) Use of structural alterations in the synthesis of halothane metabolite antigens to mimic halothane-induced immunogen. Drug Chem Toxicol 13:93-112
Hubbard, A K; Roth, T P; Schuman, S et al. (1989) Localization of halothane-induced antigen in situ by specific anti-halothane metabolite antibodies. Clin Exp Immunol 76:422-7

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