METABOLIC BASIS FOR ENFLURANE HEPATOTOXICITY

安氟烷肝毒性的代谢基础

• 批准号: 3920014
• 负责人: D CHRIST
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3920014
• 关键词: adduct; anesthetics; binding proteins; cross immunity; drug hypersensitivity; drug metabolism; enflurane; halothane; hepatitis; hepatotoxin; human subject; human tissue; isoflurane; laboratory rat; microsomes; syndrome

The existence of a rare syndrome of "enflurane hepatitis," similar to that described for halothane and of a cross-sensitization between halothane and enflurane, has been controversial, largely because clinical case reports are equivocal and a plausible molecular mechanism for the hepatotoxicity is lacking. The present study suggests a possible hypersensitivity basis for enflurane hepatitis and the apparent cross-sensitization between halothane and enflurane involving covalently-bound liver microsomal adducts. Immunoblotting studies have revealed that antibodies in the sera of 6 patients with halothane hepatitis recognize liver microsomal antigens of Mr of 100,000, or both 100,000 and 76,000, formed in rats treated with enflurane or halothane. These antigens were not detected in liver microsomes of rats treated with isoflurane or sesame oil. The recognition of these antigens could be abolished by preincubation of the sera with liver microsomes of rats treated with halothane. These data suggest that difluoromethoxydifluoroacetyl halide, a metabolite of enflurane, as well as trifluoroacetyl halide, a metabolite of halothane, covalently bind to similar hepatic proteins, and may become immunogens in susceptible patients. This mechanism may also account for the apparent cross-sensitization between halothane and enflurane anesthesia, and the development of hepatic necrosis.

存在一种罕见的综合征“安氟醚肝炎”，类似 与氟烷所述的相同， 氟烷和安氟醚之间的区别一直存在争议， 因为临床病例报告模棱两可， 缺乏肝毒性的分子机制。 本 研究表明安氟烷可能存在超敏反应基础 肝炎和氟烷之间的明显交叉致敏 和涉及共价结合的肝微粒体加合物的安氟醚。 免疫印迹研究表明，血清中的抗体 6例氟烷性肝炎患者肝微粒体识别率为 抗原的Mr为100，000，或同时为100，000和76，000， 用安氟醚或氟烷处理的大鼠。 这些抗原不是 在接受异氟烷或 香油 这些抗原的识别可以被取消 通过将血清与处理的大鼠肝微粒体预孵育 用氟烷。 这些数据表明 二氟甲氧基二氟乙酰卤，安氟醚的代谢物， 以及三氟乙酰卤，氟烷的代谢物， 共价结合类似的肝蛋白，并可能成为 易感患者的免疫原。 该机制还可以 解释了氟烷和 安氟醚麻醉和肝坏死的发展。