Dahl M L, Johansson I, Palmertz M P, Ingelman-Sundberg M, Sjöqvist F
Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
Clin Pharmacol Ther. 1992 Jan;51(1):12-7. doi: 10.1038/clpt.1992.2.
The molecular basis of polymorphic debrisoquin hydroxylation was studied in 223 Swedish white subjects, 187 extensive metabolizers and 36 poor metabolizers phenotyped with debrisoquin and desipramine. Restriction fragment length polymorphism (RFLP) analysis of the CYP2D6 gene revealed that 52% of unrelated poor metabolizers were homozygous for Xba I 29 kb fragment, and only 8% had two mutant alleles detected with RFLP. Allele-specific polymerase chain reaction (PCR)-based DNA amplification, however, revealed that all but one of the poor metabolizers had two mutant alleles of the CYP2D6A or CYP2D6B type or both. Extensive metabolizers who were heterozygous for wild-type and CYP2D6B genes had metabolic ratios for debrisoquin and desipramine that were higher than those of subjects who were homozygous for the wild-type gene. The 16 + 9 kb Xba I RFLP pattern was associated with the poor metabolizer phenotype and CYP2D6B mutations. Three extremely rapid metabolizers of debrisoquin had a 44 kb Xba I fragment that did not carry either CYP2D6A or CYP2D6B mutations. In conclusion, in the Swedish population studied, allele-specific PCR amplification allowed prediction of the debrisoquin hydroxylation phenotype with 99% accuracy.
在223名瑞典白人受试者中研究了多态性异喹胍羟化的分子基础，其中187名是快代谢者，36名是慢代谢者，通过异喹胍和地昔帕明进行表型分析。对CYP2D6基因的限制性片段长度多态性（RFLP）分析显示，52%的无关慢代谢者对于Xba I 29 kb片段是纯合子，只有8%通过RFLP检测到有两个突变等位基因。然而，基于等位基因特异性聚合酶链反应（PCR）的DNA扩增显示，除一名慢代谢者外，所有慢代谢者都有两个CYP2D6A或CYP2D6B类型的突变等位基因，或两者皆有。对于野生型和CYP2D6B基因杂合的快代谢者，异喹胍和地昔帕明的代谢率高于野生型基因纯合的受试者。16 + 9 kb Xba I RFLP模式与慢代谢者表型和CYP2D6B突变相关。三名异喹胍极快代谢者有一个44 kb Xba I片段，该片段未携带CYP2D6A或CYP2D6B突变。总之，在所研究的瑞典人群中，等位基因特异性PCR扩增能够以99%的准确率预测异喹胍羟化表型。
