POLYMORPHIC DRUG OXIDATION--THE HUMAN CYP2D6 GENE

异喹胍/鹰爪豆碱的遗传多态性是由于许多 CYP 2D 6基因的突变等位基因。 这种多态性，它影响了大约 7.5%的白种人，导致大量无法代谢 毒品 最严重的临床重要性是抗心律失常 毒品 通过分析确定了命名为CYP 2D 6（C）的变异等位基因 特征为丁呋洛尔代谢缺陷的人肝脏。 用该肝脏克隆CYP 2D 6（C）cDNA。 该变异cDNA编码一个 缺少氨基酸但具有催化活性的蛋白质。 该蛋白质在SDS上具有不同的相对分子量- 聚丙烯酰胺凝胶，并且可能在细胞中不稳定。 分析 使用特异性PCR检测的白细胞DNA显示，CYP 2D 6（C） 一种罕见的等位基因，占所有突变等位基因的不到1.5%。 在亚洲受试者中，异喹胍/鹰爪豆碱多态性非常罕见， 影响不到0.5%的人口。 少数代谢不良者 在日本人群中发现的一种具有独特的等位基因， Bam H1限制性片段长度多态性不平衡， 在高加索人身上发现的。 这个等位基因可能有缺陷。 以确定 为了了解这种缺陷等位基因的性质，我们从人的肝脏中克隆了CYP 2D 6基因。 日本低金雀花碱代谢白细胞DNA及其外显子 进行了测序。 一个G到A的突变被确定在交界处， 内含子4和外显子5，导致缺陷的3'剪接识别位点。 该突变与CYP 2C 6（B）主要等位基因突变相同， 白种人 然而，在突变的日本人中发现了另一个碱基变化 在CYP 2C 6（B）中未观察到的等位基因。

The debrisoquine/sparteine genetic polymorphism is due to a number of mutant alleles of the CYP2D6 gene. This polymorphism, which affects about 7.5% of Caucasians, results in the inability to metabolize a large number of drugs. Of most serious clinical importance are the antiarrythmic drugs. A variant allele designated CYP2D6(C) was identified by analysis of a human liver characterized as being deficient in bufuralol metabolism. This liver was used to clone CYP2D6(C) cDNA. The variant cDNA encoded a protein that lacked an amino acid but otherwise was catalytically active. This protein had a different relative molecular weight on SDS- polyacrylamide gels and may be unstable in the cell. Analysis of leukocyte DNAs using a specific PCR test revealed that the CYP2D6(C) was a rare allele representing less than 1.5% of all mutant alleles. In Asian subjects, the debrisoquine/sparteine polymorphism is very rare, afflicting less than 0.5% of the population. The few poor metabolizers found in a Japanese population possess a unique allele that is in linkage disequilibrium with a Bam H1 restriction fragment length polymorphism not found in Caucasians. This allele is presumably defective. To determine the nature of this defective allele, the CYP2D6 gene was cloned from the leukocyte DNA of Japanese having low sparteine metabolism and its exons were sequenced. A G to A mutation was identified at the junction of intron 4 and exon 5, resulting in a defective 3' splice recognition site. This mutation is identical to the major CYP2C6(B) allele mutation in Caucasians. However, another base change was found in the mutant Japanese allele that was not seen in CYP2C6(B).