Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8
首发时间:2011-10-06
Abstract:The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication.
keywords: Structure-function relationship Polymorphism CYP2C8 Drug metabolism Individualized medication
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细胞色素P450 2C8的多态性酶结构以及功能
摘要:细胞色素P450氧化一系列各种临床药物和外源性化学物质的代谢。细胞色素CYP 2C8 主要存在于肝脏中并且可以代谢抗癌药物紫杉醇。以前关于细胞色素CYP 2C8 的多态性的研究几乎都采用不纯的蛋白质,或者在细胞中或者从微粒体中。因此,他们的机构以及功能的关系并不是很明确。在本文的研究中, 两种细胞色素CYP 2C8 的多态性被表达并纯化,并且采用了圆二色谱,紫外,截流光谱仪等手段来研究其性质。
关键词: 构效关系 多态性 细胞色素CYP2C8 药物代谢 个体化用药
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