INTERRACIAL DIFFERENCES IN CYTOCHROME P450 MEDIATED METABOLISM

美国人口在民族和种族上变得更加多元化 多样化。 与此同时，药物开发的全球化和 新的治疗剂的国际销售已经增加 显著 因此，药物现在定期给予 那些与他们所处的环境截然不同的人， 最初被评估。 本项目的工作假设 药物代谢的种族差异，特别是那些 由细胞色素P450（CYP）酶介导，是一种重要的 药物反应性个体间差异的决定因素。 将使用以下方法对4种不同的β-内酰胺酶亚型进行检测： 合适的体内探针，其测量它们在个体中的活性 不同种族出身的人。CYP 3A之所以受关注，是因为它 人肝脏中的主要酶， 在肠上皮中。 因此，这是一个重要的 首过代谢和口服生物利用度的决定因素 管理药物。 此外，CYP 3A具有广泛的底物特异性 导致它参与了一个非常大的 一些药物和一些环境原致癌物。 咪达唑仑将用作CYP 3A的体内探针，使用 协议，允许估计其单独的贡献， 肝脏和肠道活动。 类似的研究也将在 使用氯唑沙宗作为CYP 2 E1的体内探针进行; 这种同种型重要地参与许多 饮食和环境原致癌物。 施行本 研究的目的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 在CYP 2 E1的情况下，种族间差异 已经证明，还将进行研究， 确定实质上较低水平的 与高加索人相比，日本人中存在的活性。 调查 还将关注两种具有遗传多态性的酶 （CYP 2D 6和CYP 2C 19），以确定广泛的 不同基因型之间的关系， 原型底物的催化活性（表型）; 异喹胍和美芬妥英。 因为这些研究 将在高加索人和东南亚人中进行， 可以检验种族间差异是 也存在于这些基因产物中。

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.