Harris J W, Pohl L R, Martin J L, Anders M W
Department of Pharmacology, University of Rochester, NY 14642.
Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1407-10. doi: 10.1073/pnas.88.4.1407.
Hydrochlorofluorocarbons (HCFCs) are being developed as substitutes for ozone-depleting chlorofluorocarbons (CFCs); because widespread human exposure to HCFCs may be expected, it is important to evaluate their toxicities thoroughly. Here we report studies on the bioactivation of the CFC substitute 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) to an electrophilic intermediate that reacts covalently with liver proteins. HCFC-123 and its analog halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) were studied in rats by 19F NMR spectroscopy, and we found that a trifluoroacetylated lysine adduct was formed with liver proteins. Also, the pattern of proteins immunoreactive with hapten-specific anti-trifluoroacetylprotein antibodies was identical in livers of HCFC-123- and halothane-exposed rats. Because halothane causes an idiosyncratic, and sometimes fatal, hepatitis that is associated with an immune response against several trifluoroacetylated liver proteins, the present findings raise the possibility that humans exposed to HCFC-123 or structurally related HCFCs may be at risk of developing an immunologically mediated hepatitis.
氢氯氟烃（HCFCs）正被开发用作消耗臭氧层的氯氟烃（CFCs）的替代品；由于预计人类会广泛接触HCFCs，因此全面评估它们的毒性很重要。在此，我们报告了关于CFC替代品2,2 - 二氯 - 1,1,1 - 三氟乙烷（HCFC - 123）生物活化成为与肝脏蛋白质发生共价反应的亲电中间体的研究。通过19F核磁共振光谱对大鼠体内的HCFC - 123及其类似物氟烷（2 - 溴 - 2 - 氯 - 1,1,1 - 三氟乙烷）进行了研究，我们发现肝脏蛋白质形成了三氟乙酰化赖氨酸加合物。此外，在暴露于HCFC - 123和氟烷的大鼠肝脏中，与半抗原特异性抗三氟乙酰化蛋白质抗体发生免疫反应的蛋白质模式是相同的。由于氟烷会引发一种特异质性的、有时甚至是致命的肝炎，这种肝炎与针对几种三氟乙酰化肝脏蛋白质的免疫反应有关，目前的研究结果增加了这样一种可能性，即接触HCFC - 123或结构相关的HCFCs的人类可能有发生免疫介导性肝炎的风险。
