Dahl M L, Johansson I, Bertilsson L, Ingelman-Sundberg M, Sjöqvist F
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, Sweden.
J Pharmacol Exp Ther. 1995 Jul;274(1):516-20.
Hydroxylation of debrisoquine, catalyzed by the cytochrome P450 CYP2D6 exhibits genetic polymorphism, with large inter-individual differences in metabolic capacity. About 7% of Caucasians carry deficient CYP2D6 alleles and lack the CYP2D6 enzyme (poor metabolizers). We have shown in two Swedish families, individuals carrying duplicated or amplified functional CYP2D6L-genes (CYP2D6L2), causing the opposite phenomenon, ultrarapid metabolism of debrisoquine. In the present study, the occurrence of extra copies of CYP2D6L-alleles was studied in relation to debrisoquine metabolic ratio (MR) in 270 Swedish Caucasians including 64 selected subjects with very rapid metabolism (MR < or = 0.2). Thirteen of the 64 subjects carried a duplicated CYP2D6-gene as identified by EcoRI and XbaI restriction fragment length polymorphism and allele-specific polymerase chain reaction-amplification of genomic DNA. A new allele with three active CYP2D6L-genes was identified, characterized by an XbaI 54 kilobase fragment. This indicates a preference of the CYP2D6L-gene to be amplified compared to other CYP2D6 genes. Only one subject with an MR higher than 0.2 carried the duplicated CYP2D6L-allele, also being heterozygous for the defect CYP2D6B-allele. The overall frequency of the duplicated/amplified CYP2D6-allele was about 1%, and was present in 40% of subjects with MRs < or = 0.1. Thus, other variant CYP2D6-genes may exist that cause increased CYP2D6 activity. In conclusion, a haplotype with duplicated or amplified functional CYP2D6 genes predicts, with high accuracy, ultrarapid metabolism of debrisoquine. Genotyping for this CYP2D locus variant might be of value in patients not responding to generally recommended doses of CYP2D6 substrates, to distinguish between high metabolic capacity and noncompliance.
由细胞色素P450 CYP2D6催化的异喹胍羟基化表现出遗传多态性，个体间代谢能力存在很大差异。约7%的高加索人携带缺陷型CYP2D6等位基因且缺乏CYP2D6酶（代谢缓慢者）。我们在两个瑞典家族中发现，携带重复或扩增功能性CYP2D6L基因（CYP2D6L2）的个体出现了相反的现象，即异喹胍代谢超快。在本研究中，我们在270名瑞典高加索人中研究了CYP2D6L等位基因额外拷贝的出现情况与异喹胍代谢率（MR）的关系，其中包括64名代谢非常快（MR≤0.2）的选定受试者。通过EcoRI和XbaI限制性片段长度多态性以及基因组DNA的等位基因特异性聚合酶链反应扩增，在64名受试者中的13名中鉴定出携带重复的CYP2D6基因。鉴定出一个具有三个活性CYP2D6L基因的新等位基因，其特征是XbaI 54千碱基片段。这表明与其他CYP2D6基因相比，CYP2D6L基因更倾向于被扩增。只有一名MR高于0.2的受试者携带重复的CYP2D6L等位基因，同时该受试者也是缺陷型CYP2D6B等位基因的杂合子。重复/扩增的CYP2D6等位基因的总体频率约为1%，在MR≤0.1的受试者中占40%。因此，可能存在其他导致CYP2D6活性增加的CYP2D6基因变体。总之，具有重复或扩增功能性CYP2D6基因的单倍型可高度准确地预测异喹胍代谢超快。对于对一般推荐剂量的CYP2D6底物无反应的患者，对该CYP2D基因座变体进行基因分型可能有助于区分高代谢能力和不依从性。
