Tsuneoka Y, Matsuo Y, Ichikawa Y, Watanabe Y
Department of Pharmacology, National Defense Medical College, Namiki, Tokorozawa, Japan.
Metabolism. 1998 Jan;47(1):94-6. doi: 10.1016/s0026-0495(98)90199-8.
To further investigate the association between Parkinson's disease (PD) and genetic polymorphism of the CYP2D6 gene, a mutant allele (CVP2D6J) frequently observed in the Japanese population and related to EM/PM polymorphism (phenotypically, individuals are either extensive metabolizers [EM] or poor metabolizers [PM] of debrisoquine) was investigated. The CYP2D6J gene with a nucleotide substitution from C to T at position 188 (the HphI site in exon 1), which reduces CYP2D6 enzyme activity, was analyzed by polymerase chain reaction (PCR) and by digestion with HphI. No significant relationship was observed between PD patients and controls for this mutation. This suggests that the EM/PM polymorphism of CYP2D6 contributes little to the pathogenesis of PD. To further study the molecular basis for the relationship between PD and CYP2D6, the heterogeneity of CYP2D6 was investigated by combined genotype analysis of the two mutant CYP2D6 genes (ie, CYP2D6J, the HphI site mutation in exon 1, and CYP2D6L, the HhaI site mutation in exon 6). Although some characteristic patterns of the combined genotypes were observed in both PD patients and controls, a strong association between the heterogeneity of the CYP2D6 gene and PD was not shown by combined genotype analysis.
为了进一步研究帕金森病（PD）与细胞色素P450 2D6（CYP2D6）基因多态性之间的关联，我们对在日本人群中经常观察到的一种突变等位基因（CYP2D6J）进行了研究，该基因与异喹胍的代谢酶/代谢酶多态性（从表型上看，个体对异喹胍的代谢要么是快代谢型[EM]，要么是慢代谢型[PM]）有关。通过聚合酶链反应（PCR）和HphI酶切分析了位于188位核苷酸由C突变为T的CYP2D6J基因（外显子1中的HphI位点），该突变会降低CYP2D6酶的活性。在PD患者和对照组之间未观察到该突变的显著相关性。这表明CYP2D6的代谢酶/代谢酶多态性对PD的发病机制贡献不大。为了进一步研究PD与CYP2D6之间关系的分子基础，通过对两个突变的CYP2D6基因（即外显子1中HphI位点突变的CYP2D6J和外显子6中HhaI位点突变的CYP2D6L）进行联合基因型分析，研究了CYP2D6的异质性。尽管在PD患者和对照组中都观察到了一些联合基因型的特征模式，但联合基因型分析并未显示CYP2D6基因的异质性与PD之间存在强关联。
