THE CYP2D6 GENETIC POLYMORPHISM

CYP2D6 基因多态性

• 批准号: 3774831
• 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/3774831
• 关键词: Chinese; Japanese; alleles; caucasian American; cytochrome P450; debrisoquin; drug metabolism; enzyme activity; enzyme substrate; gene mutation; genetic polymorphism; human genetic material tag; human population genetics; human tissue; linkage mapping; molecular weight; polymerase chain reaction; racial /ethnic difference

The debrisoquine/sparteine genetic polymorphism is due to mutant or null alleles encoding the cytochrome P450 CYP2D6. This polymorphism is most prevalent in Caucasians in which 7 to 10% possess two null alleles and are incapable of metabolizing a large number of therapeutically-important drugs. Several null alleles have been sequenced and PCR assays developed for diagnostic purposes. Over 95% of deficient metabolizers can be diagnosed by PCR. Interethnic variation of drug metabolism has also been described and detailed studies have been conducted comparing a number of enzymes. The debrisoquine/sparteine polymorphism exhibits markedly different characteristics in Oriental subjects. In Japanese and Chinese, the frequency of deficient individuals ranges from 0 to a maximum of 2.3%, depending on the target population and the drug used for phenotyping. A most intriguing observation is that the average rate of metabolism among the normal metabolizers differ between ethnic groups; Oriental subjects have, on average, a slower metabolism than Caucasians when sparteine, a CYP2D6 substrate, was used as the probe drug to investigate this difference. Several CYP2D6 alleles were sequenced from a population of Japanese subjects and a new variant allele, designated CYP2D6v1 was uncovered that contains two amino acid changes that might confer lower rates of metabolism. In addition several CYP2D6D null alleles and two CYP2D6B mutants were found. The latter finding indicates that the CYP2D6B allele is not exclusive to Caucasians.

异喹啉/金豆碱遗传多态性是由于突变或无效 编码细胞色素 P450 CYP2D6 的等位基因。 这种多态性是最 普遍存在于白种人中，其中 7% 至 10% 拥有两个无效等位基因，并且 无法代谢大量具有治疗意义的物质 药物。 几个无效等位基因已被测序并开发了 PCR 检测方法 用于诊断目的。 超过 95% 的代谢缺陷者可以 通过PCR诊断。 药物代谢的种族间差异也已被证实 已经进行了描述和详细的研究，比较了一些 酶。 异喹啉/金豆碱多态性表现出显着的 东方学科的不同特点。 在日语和中文中， 缺陷个体的频率范围从 0 到最大 2.3%， 取决于目标人群和用于表型分析的药物。 一个 最有趣的观察是，人的平均新陈代谢率 不同种族的正常代谢者有所不同； 东方科目 平均而言，当金雀花（一种 CYP2D6底物，被用作探针药物来研究这一点 不同之处。 从人群中对几个 CYP2D6 等位基因进行了测序 日本受试者和一个新的变异等位基因，指定为 CYP2D6v1 发现含有两个氨基酸变化，可能会降低 新陈代谢率。 此外还有几个 CYP2D6D 无效等位基因和两个 发现了 CYP2D6B 突变体。 后一个发现表明 CYP2D6B 等位基因并非白种人所独有。