Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy
Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy
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DOI：
10.1097/00008571-199512000-00008
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发表时间：
1995-12-01
期刊：
影响因子：
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通讯作者：
Idle, JR
中科院分区：
文献类型：
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作者：
Furuya, H;FernandezSalguero, P;Idle, JR
在英国和其他许多国家，华法林是口服抗凝剂的首选药物。作为外消旋体给药，(R)-和(S)-对映体都是活性的。(S)-华法林的效力大约是(R)-华法林的三倍，尽管它的清除度更高(Choonara等人，1986年)。一种高亲和力的肝脏(S)-华法林7-羟基酶似乎主要负责最有效的对映体的代谢清除，最近这种活性被归因于一种特定的细胞色素P450同工酶，即细胞色素P450同工酶，负责(S)-华法林的区域和立体选择性代谢(Rettie等，1992)。显然，CYP2C9基因内的遗传多态导致了不同的蛋白质对(S)-华法林的7-羟化反应具有不同的催化活性，这可能对潜在的对映体清除有重要影响，从而对口服药物的体内反应有重要影响。由于C，-T碱基替代，蛋白质中第144位的半胱氨酸被精氨酸取代(Kimura等人，1987年)，产生了CYP2C9的一个等位变异，由Rettie等人(1994)命名为R144C。虽然Kaminsky等人(1993)使用在酵母中表达的定点突变体发现Arg-144-Cys突变既不显著影响华法林羟化的区域选择性也不影响华法林羟化的立体选择性，Rettie等人(1994)表达了CYP2C9和
Warfarin is the oral anticoagulant drug of choice in the UK and in many other countries. Administered as a racemate, both the (R)-and (S)-enantiomers are active.(S)-warfarin being about three-times as potent as (R)-warfarin, despite its higher clearance (Choonara et al., 1986). A high affinity hepatic (S)-warfarin 7-hydroxylase appears to be principally responsible for the metabolic clearance of the most potent enantiomer and recently this activity has been ascribed to a specific cytochrome P450 isozyme, CYP2C9, responsible for both the regioselective and stereoselective metabolism of (S)-warfarin (Rettie et al., 1992). Clearly, genetic polymorphism within the CYP2C9 gene, which gave rise to qualitatively different proteins with differing catalytic activities with respect to the 7-hydroxylation of (S)-warfarin, might have a major effect upon the clearance of the potentenantiomer and thus the in vivo response to orally administered drug. A single amino acid substitution of cysteine for arginine at position 144 in the protein, arising from C,–T base substitution (Kimura et al., 1987) gives rise to an allelic variant of CYP2C9, termed R144C by Rettie et al.(1994). Although Kaminsky et al.(1993), using site directed mutants expressed in yeast, found that the Arg-144-Cys mutation markedly affected neither the regio-nor the stereoselectivity of warfarin hydroxylation, Rettie et al.(1994), who expressed CYP2C9 and