Martin J L, Kenna J G, Martin B M, Thomassen D, Reed G F, Pohl L R
Laboratory of Chemical Pharmacology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Hepatology. 1993 Oct;18(4):858-63. doi: 10.1002/hep.1840180417.
Clinical and laboratory evidence suggests that the fulminant liver failure sometimes associated with the inhalation anesthetic halothane may be an immune-mediated toxicity. Most importantly, the vast majority of patients with a clinical diagnosis of halothane hepatitis have serum antibodies, which react with one or more specific liver microsomal proteins that have been covalently altered by the trifluoroacetyl chloride metabolite of halothane. The serum antibodies are specific to halothane hepatitis patients and are not seen in sera of patients with other types of liver pathology. In this study, a 57-kD trifluoroacetylated liver microsomal neoantigen associated with halothane hepatitis and native 57-kD protein were purified from liver microsomes of halothane-treated and -untreated rats, respectively. When the purified trifluoroacetylated 57-kD and native 57-kD proteins were used as test antigens in an enzyme-linked immunosorbent assay, serum antibodies from halothane hepatitis patients (n = 40) reacted with both of these proteins to a significantly greater extent than did serum antibodies from control patients (n = 32). On the basis of its apparent monomeric molecular mass, isoelectric point and NH2-terminal amino acid and tryptic peptide sequences, the 57-kD protein has been identified as rat liver protein disulfide isomerase. Antibodies raised against rat liver protein disulfide isomerase also reacted with a protein of approximately 58-kD in human liver microsomes. The results of this investigation suggest that trifluoroacetylated protein disulfide isomerase is one of the immunogens associated with halothane hepatitis. In certain patients it might lead either to specific antibodies or, possibly, to specific T cells, which could be responsible for halothane hepatitis.
临床和实验室证据表明，有时与吸入性麻醉剂氟烷相关的暴发性肝衰竭可能是一种免疫介导的毒性反应。最重要的是，绝大多数临床诊断为氟烷性肝炎的患者血清中存在抗体，这些抗体与一种或多种特定的肝微粒体蛋白发生反应，这些蛋白已被氟烷的三氟乙酰氯代谢产物共价修饰。血清抗体对氟烷性肝炎患者具有特异性，在其他类型肝病患者的血清中未发现。在本研究中，分别从经氟烷处理和未处理的大鼠肝脏微粒体中纯化出与氟烷性肝炎相关的57-kD三氟乙酰化肝微粒体新抗原和天然57-kD蛋白。当将纯化的三氟乙酰化57-kD和天然57-kD蛋白用作酶联免疫吸附测定中的检测抗原时，氟烷性肝炎患者（n = 40）的血清抗体与这两种蛋白的反应程度明显高于对照患者（n = 32）的血清抗体。根据其明显的单体分子量、等电点、NH2末端氨基酸和胰蛋白酶肽序列，57-kD蛋白已被鉴定为大鼠肝脏蛋白二硫键异构酶。针对大鼠肝脏蛋白二硫键异构酶产生的抗体也与人肝脏微粒体中一种约58-kD的蛋白发生反应。本研究结果表明，三氟乙酰化蛋白二硫键异构酶是与氟烷性肝炎相关的免疫原之一。在某些患者中，它可能导致产生特异性抗体，或者可能导致产生特异性T细胞，这可能是氟烷性肝炎的病因。
