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HEPATIC MICROSOMAL ENZYME METABOLISM OF ANESTHETICS

麻醉药的肝微粒体酶代谢

基本信息

批准号：
3271472
负责人：
LAURENCE S KAMINSKY
金额：
$ 5.72万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-05-01 至 1991-03-31
项目状态：
已结题

项目摘要

The key role of cytochromes P-450 in the metabolism and toxicity of volatile anesthetic agents and the ready inducibility of these enzymes provides for potentially hazardous drug-anesthetic interactions. The overall aims of this investigation are to determine microsomal metabolism of volatile, halogenated anesthetics and the contribution of this metabolism to the potential toxicity of the anesthetic agents under the influence of inducing xenobiotics. We propose to complete studies of the toxicity and metabolism of the anesthetic fluroxene and to initiate studies of the recently introduced anesthetics isoflurane and sevoflurane and their metabolites, 2,2,2-trifluoroethanol (TFE), trifluoroacetaldehyde, and trifluoroacetic acid. Metabolic pathways will be determined by combining data from in vitro microsomal systems, isolated hepatocyte cultures, reconstituted cytochrome P-450 systems, and in vivo experiments. Additional specific aims are: to determine the molecular mechanism of TFE-induced bone marrow depression using in vivo and in vitro determinations of the effects of TFE and TFE metabolites on protein synthesis, DNA synthesis, RNA synthesis, and covalent binding of reactive metabolites to cellular macromolecules; to determine the mechanisms of synergistic toxic interactions of endotoxin and TFE, and of endotoxin and isoflurane and to compare them to that of halothane and endotoxin, which also leads to increased toxicity; and to determine the reason for the observed sex differences in sensitivity to the toxicity of anesthetics and metabolites. The effect of sex specific steroids on cytochrome P-450 metabolism of anesthetics and metabolites will be determined. Toxicity will be assessed by observations of lethality, serum glutamate-pyruvate transaminase activity, blood urea nitrogen, serum cholinesterase, white blood cell count, and histopathology. The role of specific cytochrome P-450 isozymes will be assessed with the use of a variety of inducing agents including ethanol, phenobarbital, and beta-naphthoflavone. An understanding of the influence of inducing agents of cytochrome P-450 on anesthetic metabolism/toxicity, particularly on tissue growth and the hemopoietic system, will provide the basis for evaluating drug-anesthetic interactions for which there is such a rich potential in the surgical environment, where infection control and tissue growth are very important. The data will also provide insight into the potential toxic interactions of the anesthetics with concomitant bacterial infections.

细胞色素P-450在代谢和毒性中的关键作用挥发性麻醉剂和容易诱导这些酶提供了潜在的危险药物麻醉剂交互. 本次调查的总体目标是测定挥发性、卤化麻醉剂和这种代谢的贡献麻醉剂在以下因素影响下的潜在毒性诱导异生物质。我们建议完成对麻醉剂Fluroxene的毒性和代谢，开始研究最近引进的麻醉剂异氟烷和七氟烷及其代谢产物，2，2，2-三氟乙醇 (TFE)三氟乙醛和三氟乙酸。代谢将通过结合来自体外的数据来确定途径。微粒体系统，分离的肝细胞培养物，复溶细胞色素P-450系统和体内实验。额外具体目标是：确定体内和体外研究TFE诱导的骨髓抑制测定TFE和TFE代谢物对蛋白质合成、DNA合成、RNA合成和共价键反应性代谢物与细胞大分子的结合; 确定协同毒性相互作用的机制内毒素和TFE，内毒素和异氟烷，与氟烷和内毒素相比，导致毒性增加;并确定观察到的对毒性敏感性的性别差异麻醉剂和代谢物。性别特异性类固醇的作用对麻醉药及代谢物细胞色素P-450代谢的影响将被确定。将通过观察以下指标评估毒性：致死率，血清谷丙转氨酶活性，血液尿素氮、血清胆碱酯酶、白色血细胞计数，以及组织病理学特异性细胞色素P-450同工酶的作用将使用各种诱导剂进行评估包括乙醇、苯巴比妥和β-萘酚酮。一个对细胞色素诱导剂影响的认识 P-450对麻醉剂代谢/毒性的影响，尤其是对组织的影响生长和造血系统，将提供基础评价药物-麻醉剂相互作用，在感染控制的手术环境中具有丰富的潜力和组织生长是非常重要的。数据还将提供深入了解麻醉剂的潜在毒性相互作用伴随细菌感染。