Department of Pediatrics, Guangdong Women and Children's Hospital, 13 Guangyuanxi Road, Guangzhou 510010, China.
Curr Drug Metab. 2009 Sep;10(7):781-834. doi: 10.2174/138920009789895480.
Human cytochrome P450 2C9 (CYP2C9) accounts for approximately 20% of total hepatic CYP content and metabolizes approximately 15% clinically used drugs including S-warfarin, tolbutamide, phenytoin, losartan, diclofenac, and celecoxib. To date, there are at least 33 variants of CYP2C9 (1B through to 34) being identified. CYP2C92 and CYP2C93 differ from the wild-type CYP2C91 by a single point mutation: CYP2C92 is characterised by a 430C>T exchange in exon 3 resulting in an Arg144Cys amino acid substitution, whereas CYP2C93 shows an exchange of 1075A>C in exon 7 causing an Ile359Leu substitution in the catalytic site of the enzyme. CYP2C92 is frequent among Caucasians with approximately 1% of the population being homozygous carriers and 22% heterozygous. The corresponding figures for the CYP2C93 allele are 0.4% and 15%, respectively. Worldwide, a number of other variants have also to be considered. The CYP2C9 polymorphisms are relevant for the efficacy and adverse effects of numerous nonsteroidal anti-inflammatory agents, sulfonylurea antidiabetic drugs and, most critically, oral anticoagulants belonging to the class of vitamin K epoxide reductase inhibitors. Numerous clinical studies have shown that the CYP2C9 polymorphism should be considered in warfarin therapy and practical algorithms how to consider it in therapy are available. These studies have highlighted the importance of the CYP2C92 and *3 alleles. Warfarin has served as a practical example of how pharmacogenetics can be utilized to achieve maximum efficacy and minimum toxicity. Polymorphisms in CYP2C9 have the potential to affect the toxicity of CYP2C9 drugs with somewhat lower therapeutic indices such as warfarin, phenytoin, and certain antidiabetic drugs. CYP2C9 is one of the clinically significant drug metabolising enzymes that demonstrates genetic variants with significant phenotype and clinical outcomes. Genetic testing of CYP2C9 is expected to have a role in predicting drug clearance and implementing individualized pharmacotherapy. Prospective clinical studies with large samples are required to establish gene-dose and gene-effect relatiohsips for CYP2C9.
人细胞色素 P450 2C9（CYP2C9）约占总肝 CYP 含量的 20%，代谢约 15%的临床用药，包括 S-华法林、甲苯磺丁脲、苯妥英、氯沙坦、双氯芬酸和塞来昔布。迄今为止，已经发现至少有 33 种 CYP2C9（1B 到34）的变体。CYP2C92 和 CYP2C93 与野生型 CYP2C91 仅存在一个点突变的差异：CYP2C92 特征是 3 号外显子中的 430C>T 交换，导致精氨酸 144 取代为半胱氨酸，而 CYP2C93 则在外显子 7 中发生 1075A>C 的交换，导致酶的催化部位的异亮氨酸 359 取代为亮氨酸。CYP2C92 在白种人中较为常见，约有 1%的人群为纯合子携带者，22%为杂合子。相应的 CYP2C93 等位基因的数字分别为 0.4%和 15%。在全球范围内，还需要考虑其他一些变体。CYP2C9 多态性与许多非甾体抗炎药、磺酰脲类抗糖尿病药物以及最重要的维生素 K 环氧化物还原酶抑制剂类口服抗凝剂的疗效和不良反应有关。许多临床研究表明，在华法林治疗中应考虑 CYP2C9 多态性，并且有可用的实际算法来考虑治疗中的多态性。这些研究强调了 CYP2C92 和*3 等位基因的重要性。华法林已成为药理学如何用于实现最大疗效和最小毒性的实际范例。CYP2C9 中的多态性有可能影响华法林、苯妥英和某些抗糖尿病药物等治疗指数较低的 CYP2C9 药物的毒性。CYP2C9 是具有显著表型和临床结果的具有临床意义的药物代谢酶之一。预计 CYP2C9 的基因检测将在预测药物清除率和实施个体化药物治疗方面发挥作用。需要进行具有大量样本的前瞻性临床研究，以确定 CYP2C9 的基因剂量和基因效应关系。
