HEPATIC MICROSOMAL ENZYME METABOLISM OF ANESTHETICS

麻醉药的肝微粒体酶代谢

• 批准号: 3271470
• 负责人: LAURENCE S KAMINSKY
• 金额: $ 6.21万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-05-01 至 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3271470
• 关键词: NAD(H) phosphate; anesthetics; barbiturates; benzopyrenes; catalyst; chemical binding; cytochrome P450; cytochrome b2; drug adverse effect; drug metabolism; electron transport; environmental contamination; inhalation anesthesia; liver pharmacology; methylcholanthrene; microsomes; oxidation; phenobarbital; pollutant interaction; superoxides; tissue /cell culture

The overall aim of this investigation is to determine the manner in which microsomal metabolism of clinically used, volatile, fluorinated ether, anesthetics contributes to their potential toxicity. Studies will be performed with rats and mice in vivo, and rat, mouse and human tissue in vitro. Studies will continue with the anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) and its ethyl and allyl analogs and will be initiated with the recently introduced anesthetics sevoflurane (fluoromethyl 2, 2, 2-trifluoro-1- trifluoromethyl -ethyl ether) and isoflurane (1-chloro-2,2,2-trifluoro-ethyl difluoromethyl ether). Specific aims are: (1) To determine the metabolic pathways of these anesthetics using in vitro microsomal and a variety of reconstituted purified cytochrome P-450 isozyme systems, and by molecular orbital calculations, and to compare metabolism by variously-induced rat and human hepatic microsomal and purified isozyme systems; by rat renal, hepatic and pulmonary microsomes to gain insight into anesthetic substrate specificity differences of the cytochromes P-450 from different organs; and by oxidative and reductive pathways. The ability of the various anesthetics to affect the suicide inactivation of cytochromes P-450 will be investigated. (2) To determine the toxicity of the anesthetics following administration to untreated or variously-induced rats. Rates of exhalation and blood concentrations of anesthetics and metabolites will be determined. Toxicity will be assessed by observations of lethality, clinical symptoms, histopathology, SGPT activities, kidney p-aminohippuric acid uptake, destruction of cytochrome P-450, and the potential of anesthetics and metabolites to produce immune dysfunction. The Ames test will be used to make in vitro assessments of the mutagenic potential of the anesthetic agents. (3) To determine the role of Ah locus gene products including cytochromes P-450, in mediating the toxicity of anesthetics in Beta-naphthoflavone induced mice. Ah responsive and non-responsive mice will be used. These studies will provide insight into the relationship between biotransformation and toxicity of anesthetics as an assessment of their safety, and for the design of better and more safe anesthetics. Comparisons of the data from rat and human hepatic tissue will provide a basis for assessing the potential toxicity of the anesthetic agents to humans, and to drug-anesthetic and environmental pollutant-anesthetic interactions.

本次调查的总体目标是确定 临床使用的挥发性氟化醚的微粒体代谢， 麻醉剂有助于它们的潜在毒性。 研究将 用大鼠和小鼠在体内进行，以及用大鼠、小鼠和人组织在体内进行。 体外 将继续对麻醉剂Fluroxene进行研究 （2，2，2-三氟乙基乙烯基醚）及其乙基和烯丙基类似物， 开始使用最近引入的麻醉剂七氟烷 （氟甲基2，2，2-三氟-1-三氟甲基-乙基醚）和 异氟烷（1-氯-2，2，2-三氟乙基二氟甲基醚）。 具体 目的：（1）确定这些麻醉药的代谢途径 使用体外微粒体和各种重组纯化的 细胞色素P-450同工酶系统，并通过分子轨道计算， 并通过各种诱导的大鼠和人肝脏比较代谢 微粒体和纯化的同工酶系统;通过大鼠肾、肝和 肺微粒体以了解麻醉底物特异性 来自不同器官的细胞色素P-450的差异; 氧化和还原途径。 各种麻醉剂 为了影响细胞色素P-450的自杀失活， 研究了 (2)为了确定麻醉剂的毒性， 给药至未处理的或各种诱导的大鼠。 呼气率 麻醉剂和代谢物的血液浓度 测定 将通过观察致死率评估毒性， 临床症状，组织病理学，SGPT活性，肾对氨基马尿酸 酸摄取，细胞色素P-450的破坏，以及 麻醉剂和代谢物产生免疫功能障碍。 艾姆斯试验 将用于体外评估 麻醉剂 (3)确定Ah位点基因产物的作用 包括细胞色素P-450，在介导麻醉剂的毒性， β-萘酚酮诱导小鼠。 Ah反应性和非反应性小鼠 将用于 这些研究将为深入了解 生物转化和麻醉剂毒性之间的关系， 他们的安全性，以及设计更好更安全的麻醉剂。 大鼠和人肝组织数据的比较将提供一个 评估麻醉剂潜在毒性的依据， 人类，以及药物麻醉剂和环境污染物麻醉剂 交互.