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: 6325863
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325863
• 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.

美国人口在种族和种族上变得越来越多 各种各样的。 同时，药物开发全球化和 新治疗剂的国际营销增加了 显著地。 结果，现在定期服用药物 与他们的人群明显不同 最初评估。 该项目的工作假设 是药物代谢的种族差异，尤其是那些 由细胞色素P450（CYP）酶介导的是重要的 确定药物反应性差异的决定因素。 这将对使用4种不同的CYP同工型进行测试 适当的体内探针，以测量其在个体中的活性 不同种族来源的主题。 CYP3A很感兴趣，因为它是 人肝脏中主要的CYP酶，也被定位 在肠上皮中。 因此，这是一个重要的 第一通代谢的决定因素和口服的生物利用度 管理药物。 此外，CYP3A的广泛底物特异性 导致它参与了非常大的代谢 药物的数量以及一些环境促促药物。 咪达唑仑将使用A用作CYP3A的体内探针 允许估算其单独贡献的协议 肝和肠活动。 类似的研究也将是 使用氯唑唑酮作为CYP2E1的体内探针进行； 这种同工型重要地参与了许多 饮食和环境procarcinogens。 这些目的 研究是为了比较高加索人的酶活性， 非裔美国人，墨西哥裔美国人，日本和亚洲 - 印第安人。 在cyp2e1的情况下，那里是种族间差异 已经证明了 确定基本较低水平的机制 与高加索人相比，日语中存在的活动。 调查 还将专注于两个具有遗传多态性的酶 （CYP2D6和CYP2C19），以确定广泛 代谢物不同基因型与 原型底物的催化活性（表型）； 碎屑和梅菲托因。 因为这些研究 将在高加索人和东南亚人进行 可以测试种族间差异的假设是 这些基因产品也存在。