Zimmermann T, Schlenk R, Pfaff G, Lach P, Wildfeuer A
Forschung und Entwicklung, Pfizer/Mack, Illertissen, Fed. Rep. of Germany.
Arzneimittelforschung. 1995 Jan;45(1):41-3.
The polymorphism of dextromethorphan (CAS 125-71-3) metabolism is dependent on hepatic cytochrom P4502D6 (CYP2D6) activity. The relationship between the CYP2D6 genotype and the dextromethorphan phenotype was studied in 83 healthy unrelated subjects. Genotype was determined by allele-specific polymerase chain reaction (PCR). Phenotyping was performed by administration of 25 mg dextromethorphan hydrobromide and determination of the urinary metabolic ratio of dextromethorphan and its O-demethylated metabolite dextrorphan (DEM/DOR). Six subjects (7.2%) were homozygous for mutant alleles (95% confidence interval 2.7%-14.7%), 18 subjects (22%) were heterozygous carriers, and 59 were homozygous for the wild-type allele. Six subjects were classified as poor metabolizers (PM) of dextromethorphan, 77 as extensive metabolizers (EM). Genotyping correctly predicted all PMs and EMs. The CYP2D6-B mutation was most frequently found, being present in 83% of PM and 8% of EM alleles. Heterozygous EMs (22% of the total population studied) were significantly underrepresented compared to the expected genotype frequency of 31% (p < 0.05). The extensive metabolizers who were heterozygous for the wild-type allele had a significantly higher metabolic ratio, compared to the homozygous EMs (log10DEM/DOR [95% = -1.99 [(-2.30)-(-1.69)] vs. -2.55 [(-2.67)-(-2.43)]; p < 0.001), indicating a gene-dose effect for CYP2D6.
右美沙芬（化学物质登记号125 - 71 - 3）代谢的多态性取决于肝脏细胞色素P4502D6（CYP2D6）的活性。在83名健康无亲缘关系的受试者中研究了CYP2D6基因型与右美沙芬表型之间的关系。通过等位基因特异性聚合酶链反应（PCR）确定基因型。通过给予25mg氢溴酸右美沙芬并测定右美沙芬及其O - 去甲基代谢物右啡烷的尿代谢比（DEM/DOR）来进行表型分析。6名受试者（7.2%）为突变等位基因纯合子（95%置信区间2.7% - 14.7%），18名受试者（22%）为杂合携带者，59名受试者为野生型等位基因纯合子。6名受试者被归类为右美沙芬慢代谢者（PM），77名受试者为快代谢者（EM）。基因分型正确预测了所有的慢代谢者和快代谢者。最常发现的是CYP2D6 - B突变，存在于83%的慢代谢者等位基因和8%的快代谢者等位基因中。与预期基因型频率31%相比，杂合快代谢者（占所研究总人群的22%）明显比例偏低（p < 0.05）。与野生型等位基因杂合的快代谢者相比，野生型等位基因纯合的快代谢者代谢比显著更高（log10DEM/DOR [95% = - 1.99 [(-2.30)-(-1.69)] 对比 - 2.55 [(-2.67)-(-2.43)]；p < 0.001），表明CYP2D6存在基因剂量效应。
