GENETIC POLYMORPHISM OF DRUG METABOLIZING-ENZYME ; ANALYSIS OF NOVEL POLYMORPHISM AND DEVELOPMENT OF GENOTYPING METHOD

细胞色素P450是细胞色素P450的一种形式，参与了40多种临床重要药物的代谢，包括一些三环类抗抑郁药、抗心律失常药、b-肾上腺素能阻滞剂和组胺H_1拮抗剂。这种形式的CYP在人群中呈多态表达，并表现为两种表型，广泛代谢物和不良代谢物(PM)。推测东方人可能存在一些未知的多态，因为高加索人的主要变异不能完全解释日语PM的频率。对两例经脱氢异喹表型鉴定的日本PM进行了CYP2D6基因分析。结果，发现了两个新的突变。是外显子5的一碱基插入，导致在下游的11DP处产生一个终止密码子。这个变异体被命名为CYP2D6^*21。另一例为非激活基因的串联重复序列，位于CYP2D基因座上。针对每个变异等位基因建立了基因分型方法。由于受试者人数较少，本研究不能确定CYP2D6^*36-^*36的频率。另一方面，CYP2D6^*21似乎是导致日本人PM表型的主要变异之一。

CYP2D6 is a form of cytochrome P450(CYP)involved in the metabolism of more than 40 clinically important drugs including some tricyclic antidepressants, antiarrhythmics, b-adrenergic blockers and histamin H_1 antagonists. This form of CYP is polymorphically expressed in a population and characterized as two phenotypes, extensive metabolizers and poor metabolizers(PM). It was assumed that there may be some unknown polymorphisms in Orientals, because major variants in Caucasians could not fully account for the frequency of the PM in Japanese. Analysis of the CYP2D6 gene in two Japanese PMs identified by phenotyping using debrisoquine was performed. As a result, novel two mutations were discovered. was one-base insertion in exon 5, leading to generation a stop codon at 11 dp downstream. This variant was designated as the CYP2D6^*21. The other one was tandem repeat of inactive gene, CYP2D6^*36, at regions of the CYP2D locus. Genotyping method was established against each of the variant allele. The frequency of the CYP2D6^*36-^*36 could not be determined in this study due to small sise of subjects. On the other hand, the CYP2D6^*21 appeared to be one of the major variant causing PM phenotype in Japanese.