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

个体受试者的能力差异很大， 代谢药物。 此外，遗传影响被认为 控制着个体对化学诱发癌症的易感性。 混合功能单加氧酶系统由多个 P450是与药物相关的主要酶， 和致癌物质代谢。 这些酶可以解毒， 加速消除外国代理人或他们可以激活惰性 有害的亲电代谢物，破坏DNA， 启动致癌过程。 我们已经开始研究 通过建立机制， 异喹胍4-羟化酶多态性 该多态性 影响5%至10%的北美和欧洲高加索人 人口 这些人，被称为弱代谢者， 或PM，不能代谢异喹和许多其他相关的 药物，而其余的人口，所谓的广泛 代谢者或EM迅速使这种药物羟基化， 其治疗形式的失活。 为了检查机制， 我们分离出了大鼠P450， 并制备了特异性抗体 能与大鼠和人类的IIDI蛋白反应 我们也 分离出人类IIDI基因。 通过淋巴细胞DNA分析， 能够使用Southern印迹和IIDI cDNA对PM进行表型分析。 人IIDI基因座包含三个相关基因，位于 在22号染色体的长臂上

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.