POLYMORPHIC DRUG OXIDATION--THE HUMAN AND RAT DEBRISOQUINE 4-HYDROXYLASE GENES

多态性药物氧化--人和大鼠去溴异喹4-羟化酶基因

• 批准号: 3916876
• 负责人: F J GONZALEZ
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/3916876
• 关键词: Europe; antibody; biological polymorphism; cancer risk; chemical carcinogenesis; cytochrome P450; drug metabolism; gene expression; gene mutation; genetic manipulation; genetic mapping; human population genetics; isoquinolines; laboratory rat; liver metabolism; molecular cloning; nucleic acid probes; nucleic acid sequence; oxidation reduction reaction; toxin metabolism; unspecific monooxygenase

Individual subjects vary considerably in their abilities to metabolize drugs. In addition, genetic influences are thought to govern individual susceptibility to chemically-induced cancers. The mixed function monooxygenase system is composed of multiple forms of P450s that are the principle enzymes associated with drug and carcinogen metabolism. These enzymes can serve to detoxify and hasten the elimination of foreign agents or they can activate inert chemicals to harmful electrophilic metabolites that damage DNA and initiate the carcinogenic process. We have begun to study polymorphic drug oxidation in humans by establishing the mechanism of the debrisoquine 4-hydroxylase polymorphism. This polymorphism effects from 5% to 10% of the North American and European Caucasian population. These individuals, referred to as poor metabolizers, or PMs, cannot metabolize debrisoquine and many other related drugs, while the rest of the population, called extensive metabolizers, or EMs, rapidly hydroxylate this drug resulting in the inactivation of its therapeutic form. To examine the mechanism of this defect we have isolated the rat P450 that metabolizes debrisoquine, designated IIDI, and prepared a specific antibody that reacts with both the rat and human IIDI protein. We also isolated the human IIDI genes. By analysis of lymphocyte DNA we are able to phenotype PMs using Southern blots and the IIDI cDNA. The human IIDI locus contains three related genes and is located on the long arm of chromosome 22.

个别受试者的能力有很大的不同 代谢药物。此外，基因影响被认为是 管理个人对化学诱发癌症的易感性。 该混合功能单加氧酶系统由多个 与药物相关的主要酶P450的形式 和致癌物新陈代谢。这些酶可以用于解毒和 加快消灭外国特工，否则他们会激活惰性 化学物质到有害的亲电代谢产物，破坏DNA和 启动致癌过程。我们已经开始研究 多形药物在人体内氧化作用机制的建立 Debrisquine 4-羟基酶的多态。这种多态 对北美和欧洲高加索人的影响为5%到10% 人口。这些个体被称为不良代谢者， 或PM，不能代谢Debrisquine和许多其他相关的 毒品，而其他人则称之为广泛的 代谢物，或EM，迅速羟化这种药物，导致 其治疗形式的失活。来研究这个机制 在这个缺陷中，我们已经分离出了代谢的大鼠P450 Debrisquine，命名为IIDI，并制备了特异性抗体 它可以与大鼠和人类的IIDI蛋白发生反应。我们也 分离出人类IIDI基因。通过对淋巴细胞DNA的分析 能够利用Southern blotts和IIDI基因对PM进行表型。 人类IIDI基因座包含三个相关基因，位于 在22号染色体的长臂上。