METABOLIC BASIS FOR ENFLURANE HEPATOTOXICITY

安氟烷肝毒性的代谢基础

• 批准号: 3942798
• 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/3942798
• 关键词: acylating agent; anesthetics; chemical addition; drug hypersensitivity; drug metabolism; enflurane; enzyme linked immunosorbent assay; halothane; hepatitis; hepatotoxin; human subject; microsomes

Case reports of idiosyncratic enflurane hepatitis and an apparent cross-sensitization between halothane and enflurane exposure have suggested to us that the oxidative metabolism of enflurane to a reactive acylating intermediate might produce covalently bound protein adducts which act as antigens, similar to those implicated in the genesis of halothane hepatitis. Use of immunoblotting and enzyme linked immunosorbent assay techniques revealed that several microsomal protein adducts that react with an anti-trifluoroacetyl (TFA) hapten antibody were formed in rat liver after halothane, enflurane, or isoflurane administration. The relative extents of adduct formation were halothane much greater than enflurane much greater than isoflurane and correlated with the relative rates of metabolism of these drugs. Moreover, antibodies found in the serum of patients with fulminant hepatic necrosis induced by halothane, recognized these adducts. These studies indicate that a common molecular mechanism involving potentially immunogenic, covalently bound metabolites may be responsible for the idiosyncratic hepatitis seen after enflurane in patients sensitized to halothane. Moreover, they also suggest that the relatively safe inhalation anesthetic, enflurane, probably should not be administered to patients that have been sensitized previously to halothane or enflurane.

特异质型安氟醚肝炎病例报告和明显的 氟烷和安氟醚暴露之间的交叉致敏作用 已经向我们表明安氟醚的氧化代谢 反应性酰化中间体可能共价产生 作为抗原的结合蛋白加合物，类似于那些 与氟烷肝炎的发生有关。 使用 免疫印迹和酶联免疫吸附测定 技术显示，几种微粒体蛋白加合物， 与抗三氟乙酰（TFA）半抗原抗体反应， 氟烷、安氟醚或异氟醚后在大鼠肝脏中形成 局 加合物形成的相对程度为 氟烷比安氟醚大得多 异氟烷的相对代谢率相关 这些药物。 此外，在患者血清中发现的抗体 氟烷引起的暴发性肝坏死， 这些加合物 这些研究表明，一种常见的分子 涉及潜在免疫原性、共价结合 代谢物可能是导致特异质肝炎的原因 在氟烷致敏的患者中观察到安氟醚后。 此外，他们还建议，相对安全的吸入 麻醉剂，安氟醚，可能不应该给予 既往对氟烷过敏的患者，或 安氟醚