Stubbins M J, Harries L W, Smith G, Tarbit M H, Wolf C R
Biomedical Research Centre, University of Dundee, Ninewells Hospital, Tayside, UK.
Pharmacogenetics. 1996 Oct;6(5):429-39. doi: 10.1097/00008571-199610000-00007.
Cytochrome P450 CYP2C9 metabolizes a wide variety of clinically important drugs, including phenytoin, tolbutamide, warfarin and a large number of non-steroidal anti-inflammatory drugs. Previous studies have shown that even relatively conservative changes in the amino acid composition of this enzyme can affect both its activity and substrate specificity. To date six different human CYP2C9 cDNA sequences, as well as the highly homologous CYP2C10 sequence have been reported suggesting that the CYP2C9 gene is polymorphic. Only nine single base substitutions in the coding region of CYP2C9 account for the differences seen between the CYP2C9 proteins. In this report we have developed polymerase chain reaction (PCR)-based assays to distinguish all seven sequences, and have determined their allele frequencies in the Caucasian population. Of the seven sequences studied in one hundred individuals only three appeared to be CYP2C9 alleles. These alleles termed CYP2C91, CYP2C92 and CYP2C9*3 had allele frequencies of 0.79, 0.125 and 0.085 respectively. The CYP2C10 gene could not be found in any of the samples studied. The assays developed here will allow the prediction of CYP2C9 phenotype, thus identifying those individuals who may exhibit different drug pharmacokinetics for CYP2C9 substrates.
细胞色素P450 CYP2C9可代谢多种临床上重要的药物，包括苯妥英、甲苯磺丁脲、华法林以及大量非甾体抗炎药。先前的研究表明，即使该酶氨基酸组成发生相对保守的变化，也会影响其活性和底物特异性。迄今为止，已报道了六种不同的人类CYP2C9 cDNA序列以及高度同源的CYP2C10序列，这表明CYP2C9基因具有多态性。CYP2C9编码区仅九个单碱基替换就导致了CYP2C9蛋白之间的差异。在本报告中，我们开发了基于聚合酶链反应（PCR）的检测方法来区分所有七种序列，并确定了它们在白种人群体中的等位基因频率。在对100个人研究的七种序列中，只有三种似乎是CYP2C9等位基因。这些等位基因分别称为CYP2C91、CYP2C92和CYP2C9*3，其等位基因频率分别为0.79、0.125和0.085。在所研究的任何样本中均未发现CYP2C10基因。这里开发的检测方法将有助于预测CYP2C9表型，从而识别那些可能对CYP2C9底物表现出不同药物药代动力学的个体。
