INTERRACIAL DIFFERENCES IN CYTOCHROME P450 MEDIATED METABOLISM

细胞色素 P450 介导的代谢的种族差异

• 批准号: 6107499
• 负责人: grant R. wilkinson
• 金额: $ 26.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107499
• 关键词: African American; Asian Americans; East Indian; Japanese; Mexican Americans; caucasian American; clearance rate; clinical research; cytochrome P450; debrisoquin; drug metabolism; enzyme activity; gas chromatography; gastrointestinal drug absorption; genetic polymorphism; high performance liquid chromatography; human subject; liver metabolism; midazolam; muscle relaxants; nortriptyline; pharmacogenetics; phenytoin; polymerase chain reaction; racial /ethnic difference; restriction fragment length polymorphism; single strand conformation polymorphism

The U.S. population is becoming more ethnically and racially diverse. At the same time, globalization of drug development and the international marketing of new therapeutic agents have increased significantly. As a result, drugs are now regularly administered to populations that are distinctly different from those in whom they were originally evaluated. The working hypothesis of this Project is that racial differences in drug metabolism, especially those mediated by cytochrome P450 (CYP) enzymes, is an important determinant of interindividual variability in drug responsiveness. This will be tested with respect to 4 different CYP isoforms using appropriate in vivo probes that measure their activity in individual subjects of different racial origin. CYP3A is of interest because it is the predominant CYP enzyme in human liver and is also localized in the intestinal epithelium. Accordingly, it is an important determinant of first-pass metabolism and the bioavailability of orally administered drugs. Also, CYP3A's broad substrate specificity results in it being involved in the metabolism of a very large number of drugs and also some environmental procarcinogens. Midazolam will be used as the in vivo probe for CYP3A using a protocol that permits estimation of the separate contributions of its hepatic and intestinal activities. Similar studies will also be undertaken using chlorzoxazone as an in vivo probe for CYP2E1; this isoform is importantly involved in the activation of many dietary and environmental procarcinogens. The purpose of these studies is to compare the enzymes' activities in Caucasians, African-Americans, Mexican-Americans, Japanese and Asia- Indians. In the case of CYP2E1, where an inter-racial difference has already been demonstrated, studies will also be undertaken to determine the mechanism(s) of the substantially lower level of activity present in Japanese compared to Caucasians. Investigations will also focus on two enzymes with genetic polymorphisms (CYP2D6 and CYP2C19), in order to determine in extensive metabolizers the relationship between different genotypes and catalytic activity (phenotype) for the prototypic substrates; debrisoquine and mephenytoin, respectively. Because these studies will be performed in both Caucasians and Southeast Asians, it will be possible to test the hypothesis that inter-racial differences are also present in these gene products.

美国人口正变得更加人种和种族 多种多样。与此同时，药物开发和全球化 新的治疗药物的国际市场营销增加了 意义重大。因此，现在定期给药 与他们所在的人口明显不同的人口 最初是经过评估的。本项目的工作假设 药物新陈代谢的种族差异，特别是那些 由细胞色素P450(CYP)酶介导，是一种重要的 药物反应性个体间变异性的决定因素。 这将针对4种不同的CYP亚型进行测试，使用 适当的体内探针，测量它们在个体中的活性 不同种族的受试者。CyP3A之所以令人感兴趣，是因为它 人体肝脏中主要的CYP酶，也定位于 在肠道上皮细胞中。因此，它是一个重要的 首过代谢的决定因素和口服的生物利用度 施以毒品。此外，CYP3A广泛的底物专一性 导致它参与了一种非常大的 一些药物和一些环境致癌物。 咪达唑仑将被用作CYP3A的体内探针，使用 一种允许估计其各自贡献的议定书 肝脏和肠道活动。类似的研究也将在 使用氯唑沙宗作为CYP2E1的体内探针； 这种异构体重要地参与了许多 饮食和环境致癌物质。这些活动的目的是 研究是比较高加索人的酶活性， 非洲裔美国人、墨西哥裔美国人、日本人和亚洲人- 印第安人。以CYP2E1为例，不同种族之间的差异 已经证明，还将进行研究，以 确定大幅降低水平的机制(S) 与高加索人相比，日语中存在的活动。调查 还将重点介绍两种具有遗传多态的酶 (CYP2D6和CYP2C19)，以确定在广泛的 代谢物不同基因型间的关系及 原型底物的催化活性(表型)； 去甲异喹和甲苯妥因。因为这些研究 将在高加索人和东南亚人中演出，它将 有可能检验这样一个假设：种族间的差异 也存在于这些基因产品中。