Clinical relevance of genetic polymorphisms in the human CYP2C subfamily
Clinical relevance of genetic polymorphisms in the human CYP2C subfamily
复制标题
DOI：
10.1046/j.0306-5251.2001.01499.x
复制
发表时间：
2001-10-01
影响因子：
3.4
通讯作者：
Goldstein, JA
中科院分区：
文献类型：
--
作者：
Goldstein, JA
人类细胞色素P450酶是一个重要的P450酶家族，可代谢约20%的临床用药。该亚家族有四个成员，分别是：CYP2C8、CYP2C9、CYP2C19和CYP2C18。其中，具有重要临床意义的是细胞色素P450 2 C8、细胞色素P4 2 9和细胞色素P4 2 C19。细胞色素PY2Cs还代谢一些内源化合物，如花生四烯酸。这个亚家族的每个成员都被发现具有遗传多态。这些多态中最广为人知的是细胞色素P4502C19。在高加索人、非裔美国人和亚洲人群体中，约有3%-5%的人是CYP2C19的代谢不良者，12%-100%是非裔美国人。该基因多态性影响抗癫痫药美苯妥因、质子泵抑制剂如奥美拉唑、抗焦虑药安定、某些抗抑郁药和抗疟疾药物普罗瓜尼的代谢。暴露于安定的PM可发生毒性效应，在低剂量的这些药物中，某些质子泵抑制剂对PM的疗效可能比EM更强。存在一些可以通过基因测试检测到的突变等位基因。CYP2C9代谢多种药物，包括抗凝剂华法林、抗糖尿病药物(如甲苯丁胺)、抗惊厥药物(如苯妥英钠)和非类固醇抗炎药。功能多态的发生率要低得多，估计在高加索人为1/250，在亚洲人更低。然而，这些罕见的基因多态的临床后果可能是严重的。据报道，接触华法林的CYP2C9 PM发生了严重的和危及生命的出血事件。苯妥英已被报道在PM中引起严重毒性。在代谢紫杉醇(紫杉醇)的细胞色素PYP2C8中发现了新的多态。对于已知的CYP2C变异等位基因疾病，基因检测是可用的。
The human CYP2Cs are an important subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs. There are four members of the subfamily, CYP2C8, CYP2C9, CYP2C19, and CYP2C18. Of these CYP2C8, CYP2C9, and CYP2C19 are of clinical importance. The CYP2Cs also metabolize some endogenous compounds such as arachidonic acid. Each member of this subfamily has been found to be genetically polymorphic. The most well-known of these polymorphisms is in CYP2C19. Poor metabolizers (PMs) of CYP2C19 represent approximately 3-5% of Caucasians, a similar percentage of African-Americans and 12-100% of Asian groups. The polymorphism affects metabolism of the anticonvulsant agent mephenytoin, proton pump inhibitors such as omeprazole, the anxiolytic agent diazepam, certain antidepressants, and the antimalarial drug proguanil. Toxic effects can occur in PMs exposed to diazepam, and the efficacy of some proton pump inhibitors may be greater in PMs than EMs at low doses of these drugs. A number of mutant alleles exist that can be detected by genetic testing. CYP2C9 metabolizes a wide variety of drugs including the anticoagulant warfarin, antidiabetic agents such as tolbutamide, anticonvulsants such as phenytoin, and nonsteroidal anti-inflammatory drugs. The incidence of functional polymorphisms is much lower, estimated to be 1/250 in Caucasians and lower in Asians. However, the clinical consequences of these rarer polymorphisms can be severe. Severe and life-threatening bleeding episodes have been reported in CYP2C9 PMs exposed to warfarin. Phenytoin has been reported to cause severe toxicity in PMs. New polymorphisms have been discovered in CYP2C8, which metabolizes taxol (paclitaxel). Genetic testing is available for ill of the known CYP2C variant alleles.