Genetic association between sensitivity to warfarin and expression of CYP2C9*3.
Genetic association between sensitivity to warfarin and expression of CYP2C9*3.
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DOI：
10.1097/00008571-199710000-00004
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发表时间：
1997-10
期刊：
影响因子：
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通讯作者：
D. J. Steward;R. Haining;K. Henne;G. Davis;T. Rushmore;W. Trager;A. Rettie
中科院分区：
文献类型：
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作者：
D. J. Steward;R. Haining;K. Henne;G. Davis;T. Rushmore;W. Trager;A. Rettie
细胞色素P4502C9 （CYP2C9）主要负责终止外消旋华法林的抗凝作用，通过将药理学上更有效的s -对映体羟基化到无活性代谢产物。CYP2C9基因突变导致三种等位基因变异CYP2C9*1、CYP2C9*2和CYP2C9*3的表达。与野生型酶相比，CYP2C9*2和CYP2C9*3在体外均表现出不同的催化性能。在目前的研究中，一名患者被证明对华法林治疗异常敏感，并且能够耐受不超过0.5 mg /天的外消旋药物。对CYP2C9基因外显子3和7进行pcr扩增，然后进行限制性酶切或序列分析，表明该个体CYP2C9*3为纯合子。此外，通过手性相高效液相色谱法测定患者血浆华法林对映体比例和尿7-羟基华法林对映体比例，以研究这两种参数是否可以代替基因型检测具有诊断价值。对照组接受4- 8mg /天华法林治疗的患者血浆S:R比为0.50 +/- 0.25:1，而接受极低剂量华法林治疗的患者血浆S:R比为3.9:1。相比之下，尿7-羟基华法林S:R比为4:1，与对照患者的立体选择性相同。因此，CYP2C9*3的表达与s -华法林清除率降低和正常剂量外消旋药物治疗反应危险加剧有关。血浆S:R华法林比值分析可作为一种有用的替代测试基因分型这一遗传缺陷。
Cytochrome P4502C9 (CYP2C9) is largely responsible for terminating the anticoagulant effect of racemic warfarin via hydroxylation of the pharmacologically more potent S-enantiomer to inactive metabolites. Mutations in the CYP2C9 gene result in the expression of three allelic variants, CYP2C9*1, CYP2C9*2 and CYP2C9*3. Both CYP2C9*2 and CYP2C9*3 exhibit altered catalytic properties in vitro relative to the wild-type enzyme. In the present study, a patient was genotyped who had proven unusually sensitive to warfarin therapy and could tolerate no more than 0.5 mg of the racemic drug/day. PCR-amplification of exons 3 and 7 of the CYP2C9 gene, followed by restriction digest or sequence analysis, showed that this individual was homozygous for CYP2C9*3. In addition, patient plasma warfarin enantiomer ratios and urinary 7-hydroxywarfarin enantiomer ratios were determined by chiral-phase high performance liquid chromotography in order to investigate whether either parameter might be of diagnostic value in place of a genotypic test. Control patients receiving 4-8 mg warfarin/day exhibited plasma S:R ratios of 0.50 +/- 0.25:1, whereas the patient on very low-dose warfarin exhibited an S:R ratio of 3.9:1. In contrast, the urinary 7-hydroxywarfarin S:R ratio of 4:1 showed the same stereoselectivity as that reported for control patients. Therefore, expression of CYP2C9*3 is associated with diminished clearance of S-warfarin and a dangerously exacerbated therapeutic response to normal doses of the racemic drug. Analysis of the plasma S:R warfarin ratio may serve as a useful alternative test to genotyping for this genetic defect.