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With Halothane-Induced Hepatitis Are Directed Against a Trifluoroacetylated Carboxylesterase (Drug Hypersensitivity/Neoantigens/Metabolism) H

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With Halothane-Induced Hepatitis Are Directed Against a Trifluoroacetylated Carboxylesterase (Drug Hypersensitivity/Neoantigens/Metabolism) H Proc. Natl. Acad. Sci. USA Vol. 86, pp. 322-326, January 1989 Medical Sciences Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase (drug hypersensitivity/neoantigens/metabolism) H. SATOH*, B. M. MARTINt, A. H. SCHULICK*, D. D. CHRIST*, J. G. KENNA*, AND L. R. POHL*t *Laboratory of Chemical Pharmacology, National Heart, Lung and Blood Institute, and tClinical Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892 Communicated by Allan H. Conney, September 28, 1988 (receivedfor review July 5, 1988) ABSTRACT Previous studies have demonstrated that pa- covalently modified by the reactive TFA halide metabolite of tients with halothane-induced hepatitis have serum antibodies halothane (11). that are directed against novel liver microsomal neoantigens To investigate the role of the halothane-induced neoanti- and have suggested that these neoantigens may play an immu- gens in the pathogenesis of halothane hepatitis, a general nopathological role in development of the patients' liver dam- approach for their purification and characterization has been age. These investigations have further revealed that the anti- developed and utilized to identify one of them. bodies are directed against distinct polypeptide fractions (100 kDa, 76 kDa, 59 kDa, 57 kDa, 54 kDa) that have been covalently modified by the reactive trifluoroacetyl halide me- MATERIALS AND METHODS tabolite of halothane. In this paper, the trifluoroacetylated Purification of 59-kDa-TFA Protein from Halothane- (TFA) 59-kDa neoantigen (59-kDa-TFA) recognized by the Treated Rats by Immunoaffmnity and Anion-Exchange HPLC. patients' antibodies was isolated from liver microsomes of Specific anti-TFA IgG (12) was purified from antisera derived halothane-treated rats by chromatography on an immunoaf- from rabbits immunized with TFA rabbit serum albumin (13) finity column of anti-TFA IgG. Antibodies were raised against as described. Anti-TFA IgG (250 mg) was coupled to Affi-Gel the 59-kDa-TFA protein and were used to purify the native 10 (25 ml) according to the manufacturer's instructions protein from liver microsomes ofuntreated rats. Based upon its (Bio-Rad) and packed into a chromatography column (1.6 cm apparent monomeric molecular mass, NH2-terminal amino x 13 cm). acid sequence, catalytic activity, and other physical properties, Male Sprague-Dawley rats were treated with halothane the protein has been identified as a previously characterized and after 12 hr liver microsomes were prepared as described microsomal carboxylesterase (EC 3.1.1.1). A similar strategy elsewhere (12). The microsomes (-3 g) from 20 rats were and characterize neoantigens associated solubilized by stirring gently for 1 hr at 40C in 200 ml of 10 mM may be used to purify potassium phosphate (pH 7.4) containing 0.2 mM EDTA, with other drug toxicities that are believed to have an immu- 0.5% (wt/vol) sodium cholate, 0.2% (vol/vol) Emulgen 911, nopathological basis. 20% (vol/vol) glycerol, and a mixture ofproteinase inhibitors (aprotinin, 87 ,g/ml; leupeptin, 0.7 ,ug/ml; pepstatin A, 0.7 It has been estimated that between 3% and 25% of all drug ,ug/ml; and trypsin inhibitor, 50 ,ug/ml) (buffer A). After toxicities, which can include anaphylaxis, serum sickness, centrifugation at 105,000 x g for 90 min, the supernatant was asthma, urticaria, dermatitis, fever, hemolytic anemia, applied (10 ml/hr) at 4°C to the anti-TFA IgG affinity column, thrombocytopenia, granulocytopenia, hepatitis, nephritis, which had been equilibrated with buffer A. The column was vasculitis, pneumonitis, and lupus-erythematosus-like syn- washed (1 ml/min) with 3 column volumes of 100 mM drome, are due to hypersensitivity (allergic) reactions (1). potassium borate (pH 8.4) containing 1 M KCI, 0.2 mM Although most of these drug-induced hypersensitivities have EDTA, and the proteinase inhibitors (buffer B). The TFA been presumed to be mediated by immunogens formed by the proteins were eluted (1 ml/min) from the column with 200 ml covalent interaction of a reactive drug metabolite with tissue of 20 mM NM-TFA-L-lysine (TFA-Lys) in 10 mM potassium carrier macromolecules (2-6), it is only in the case ofhepatitis phosphate (pH 7.4) containing 0.1 mM EDTA, 20% (vol/vol) caused by the inhalation of anesthetic halothane that this glycerol, and 0.5% (wt/vol) sodium cholate. The eluent was mechanism has been supported substantially by experimental concentrated, dialyzed against 20 mM Tris acetate (pH 7.5) evidence. containing 0.2% (vol/vol) Lubrol PX (buffer C), and injected Previous studies have demonstrated that the majority of onto a Bio-Gel TSK DEAE-5-PW (7.5 mm x 7.5 cm) HPLC halothane hepatitis patients have unique serum antibodies column (Bio-Rad). Elution, monitored at 280 nm, was at a that react with novel neoantigens in livers of animals (1, 7, 8) flow rate of 1 ml/min with a 90-min solvent program con- and humans (9) treated with halothane and have suggested sisting of an initial 60-min linear gradient of buffer C to 35% that these neoantigens may play an immunopathological role buffer D (buffer C containing 0.8 M sodium acetate), followed in development of the patients' liver damage. Characteriza- by a 15-min linear gradient to 100% buffer D, and an tion of these neoantigens by immunoblotting with hapten- additional 15 min at 100%Wo buffer D. The 59-kDa-TFA protein specific anti-trifluoroacetyl (TFA) antibodies and sera from was isolated in the eluent from the HPLC column in a yield several halothane hepatitis patients has revealed that they of 1.3 mg. correspond to distinct liver microsomal protein fractions (100 Purification of 59-kDa Native Protein from Rats by Immu- kDa, 76 kDa, 59 kDa, 57 kDa, 54 kDa) (10, 11) that have been noaffiity and Anion-Exchange HPLC. The purification pro- cedure was similar to that described for the purification ofthe The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviation: TFA, trifluoroacetyl. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 322 Downloaded by guest on September 24, 2021 Medical Sciences: Satoh et al. Proc. Natl. Acad. Sci. USA 86 (1989) 323 59-kDa-TFA protein. In short, antisera were raised against with the hapten derivatives TFA-Lys and N6-acetyl-L-lysine the purified 59-kDa-TFA protein by injecting a female New (Ac-Lys) have been described in detail elsewhere (10-12, 16). Zealand White rabbit with 100 pug of the protein in an equal Comparative TFA Labeling of Liver Microsomal Proteins volume of Freund's complete adjuvant i.m. and s.c. at After the Administration ofHalothane, Ethyl Trifluoroacetate, several sites. After 4 weeks, a booster of 100 ,g ofthe protein Trifluoroethanol, or Sodium Trifluoroacetate. Halothane (10 was administered by i.v. injection and antisera were collected mmol/kg), ethyl trifluoroacetate (5 mmol/kg), or trifluoro- weekly for 5 weeks. Anti-59-kDa-TFA IgG (462 mg) was ethanol (5 mmollkg), dissolved in sesame oil, was adminis- coupled to Affi-Gel 10 and packed into a column. Liver tered i.p. to rats and sodium trifluoroacetate (1.6 mmol/kg, microsomes from 20 untreated male rats were solubilized and dissolved in water) was given by gavage. After 12 hr, rats loaded onto the affinity column. The column was washed were killed and TFA proteins in liver microsomes were with 1 column volume of buffer A and 3 column volumes of detected by immunoblotting as described (12). buffer B containing 0.5% (wt/vol) sodium cholate, and the Other Methods. Carboxylesterase (EC 3.1.1.1) enzyme 59-kDa protein was eluted with 3 column volumes of 2 M activity was determined spectrophotometrically with p- KSCN (pH 7.5). After dialysis and concentration, the 59-kDa nitrophenyl acetate as substrate according to the method of protein was further purified by HPLC on the Bio-Gel TSK McLean et al. (17). Deglycosylation with endoglycosidase H DEAE-5-PW column. A 20-min solvent elution program was was performed as described by Harano et al. (18). Protein used consisting of an initial 9 min with buffer C, followed by was determined according to the method of Lowry et al. (19) a 10-min linear gradient to 12% buffer D. The 59-kDa protein with bovine serum albumin as a standard. was isolated in the eluent from the HPLC column in a yield of 2.7 mg. NH2-Terminal Amino Acid Sequence Analysis. Samples of RESULTS the 59-kDa protein were transblotted to polyvinylidene di- Purification of the 59-kDa-TFA and Native 59-kDa Proteins. fluoride membranes and sequenced as described by Mat- As previously shown (11), 12 hr after the administration of sudaira (14) with modifications as reported by Martin et al. halothane to rats, protein fractions of 100 kDa, 76 kDa, 59 (15). Automated Edman degradation was conducted employ- kDa, 57 kDa, and 54 kDa are among the major TFA labeled ing an Applied Biosystems model 470 A gas-phase sequencer constituents in liver microsomes, with the 59-kDa fraction with an on-line model 120 A phenylthiohydantoin (PTH) being the most prominent TFA component (Fig. 1A, lane 1). amino acid analyzer. Normal program 03R PTH was em- The TFA proteins were separated from other microsomal ployed as provided by Applied Biosystems. proteins (Fig. 1A, lane 2) by binding them selectively to an NaDodSO4/PAGE and Immunoblotting with Anti-TFA IgG affinity column of anti-TFA IgG and then, after thorough and Human Sera. Procedures for polypeptide electrophoretic washing of the column, eluting them selectively with the separation, staining, transfer, and immunoperoxidase detec- hapten derivative TFA-Lys (Fig.
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