人CYP2C8多态性功能及CYP2C8基因依赖性药物相互作用的体外研究
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摘要
目的：CYP2C8基因多态性是造成个体间CYP2C8的药物代谢能力产生巨大差异的因素之一。主要CYP2C8基因多态性功能的系统性研究,具有重要的药理学和毒理学意义,可为CYP2C8代谢表型预测和经CYP2C8代谢药物的个体化用药提供数据和信息。但目前仍缺乏在统一的CYP表达体系和相同的检测系统中,研究CYP2C8重要等位基因功能的相关报道。CYP2C8药物代谢能力的个体差异可能会导致携带CYP2C8多态性基因型的患者,对CYP2C8介导的代谢性药物相互作用的敏感性增加,而导致恶性药物毒副作用。现阶段,尚未有研究证明CYP2C8基因多态性是否会影响药物间相互作用的发生和机制,以及能否会引起药物相互作用的个体差异。本课题研究中,我们针对CYP2C8主要基因多态性功能改变,以及CYP2C8基因型依赖的药物相互作用等尚未解决的科学问题展开系统研究和分析。
方法：首先,选取野生型CYP2C8(CYP2C8.1),3个重要的CYP2C8等位基因(CYP2C8.2,CYP2C8.3,CYP2C8.4)以及CYP2C8.3携带的两个重要SNPs(R139和K399R),应用体外重组和蛋白表达技术,将CYP2C8.1和5种CYP2C8变异体于相同的表达体系中进行表达,构建涵盖主要CYP2C8多态性的CYP2C8多态性基因文库和蛋白文库；利用已构建成功的CYP2C8多态性蛋白文库,研究体外重组CYP2C8.1和5种重要CYP2C8突变体对抗肿瘤药物(紫杉醇)和抗疟疾药物(阿莫地奎)代谢功能的差异,在此基础上系统性分析CYP2C8基因多态性对CYP2C8酶学性质改变的效应关系。在系统性分析了CYP2C8多态性功能的基础上,我们评估了10类共27种临床常用药物对CYP2C8.1和5种CYP2C8突变体紫杉醇催化活性的抑制程度,并根据体外抑制数据预测受测药物和紫杉醇,在不同CYP2C8基因型中,体内药物间相互作用的发生风险。其次,我们初步建立了一种基于荧光底物的,针对于CYP2C8介导的代谢性药物相互作用的高通量检测方法,用于快速评估药物或新药候选化合物对不同CYP2C8多态性的体外抑制程
结果：对CYP2C8野生型及其5种突变体的功能研究表明：1、CYPs体外重组技术可应用于CYP多态性功能研究和体外药物代谢机制研究；2、CYP2C8体外代谢紫杉醇和阿莫地奎的研究显示,本系统表达纯化的CYP2C8.1具有正常的药物催化活性,获得的酶动力学参数Km与已有报道数据相近。3、与CYP2C8.1相比,R139K的药物代谢能力无显著变化,CYP2C8.2,CYP2C8.3,CYP2C8.4和K399R的药物代谢能力有不同程度的降低,其中K399R的代谢能力最低。药物相互作用研究表明：1、紫杉醇和受测药物的体外药物相互作用研究结果显示,受测药物对CYP2C8突变体的半数抑制常数(IC50),与CYP2C8.1相比存在明显差异,CYP2C8基因多态性可能对CYP2C8介导的代谢性药物相互作用产生影响；2、紫杉醇和受测药物间体内相互作用的预测结果显示,不同CYP2C8基因型可能导致体内相互作用性质的改变。3、基于体外重组CYPs和荧光底物的高通量药物抑制检测方法可以用于体外药物相互作用的快速检测和初步研究；
总结：本研究从CYP2C8药物代谢功能和CYP2C8抑制介导的代谢性药物相互作用两方面,研究了CYP2C8基因多态性的影响效应。系统性分析CYP2C8多态性功能将为CYP2C8表型预测,为经CYP2C8代谢的药物,尤其是紫杉醇和阿莫地奎的个体化用药提供更加均一化的数据和信息。紫杉醇和27种临床常用药物相互作用研究将为临床药理学研究人员提供体内和体外药物代谢抑制数据,以进一步评估和解决临床中CYP2C8基因型依赖的代谢性药物相互作用。同时也为根据体外抑制数据预测体内药物相互作用提供了新的思路。另外,以荧光底物为基础的药物抑制检测平台,将为药物和新药化合物体外抑制检测提供快速、灵敏、高通量的分析方法和手段。
Aim:The interin-dividual difference on the catalytic capacity of CYP2C8 is likely to be the result of CYP2C8 genetic polymorphisms. Systematic study on the enzymatic functional variations of important allelic CYP2C8 is significant to pharmacology and toxicology, and it can provide useful information and in vitro data to the personal therapy of clinical CYP2C8-metabolizing drugs. However, there has been no systematic analysis of the catalytic properties of the main CYP2C8 variants in the same expression system and under identical assay conditions. Moreover, the patients carrying CYP2C8 polymorphic genotype may be at increasing risk to CYP2C8-metabolic DDIs due to the interindividual difference of CYP2C8 catalytic properties. However, no report has been able to show whether and how CYP2C8 genetic variants affect the occurrence and the individual differences in the in vitro and in vivo DDIs with CYP2C8-cleared drugs. In this study, we systematically analysed these scientific problems on CYP2C8 genetic polymorphisms, their functional variations and CYP2C8 genotype-dependent DDIs, which have not been worked out.
Method:Firstly, wild-type CYP2C8 (CYP2C8.1), three allelic CYP2C8s (CYP2C8.2, CYP2C8.3, CYP2C8.4) and two important CYP2C8 SNPs (R139K and K399R, carried by CYP2C8.3) were chosen, and then were expressed in the same expression system using in vitro recombinant and protein expression technology. We constructed the comprehensive CYP2C8 polymorphic gene library and protein library. Secondly, we investigated the difference on the catalytic properties of wild-type and variants CYP2C8s to the metabolism of anticancer drug (paclitaxel) and antimalaria drug (amodiaquine), using the constructed CYP2C8 polymorphic protein library, and systematically analysed the relationship between CYP2C8 genetic polymorphisms effects and the alteration on CYP2C8 enzymatic property. Thirdly, we evaluated in vitro inhibitory potency of 27 clinical drugs to the metabolism of paclitaxel by wild-type and 5 variant CYP2C8s. Fourthly, in vivo paclitaxel-detected drugs DDIs in different CYP2C8 genotype were predicted via in vitro inhibition data. Fifthly, we primarily developed a high-throughput fluorescent-based detection method for CYP2C8-mediated metabolic DDIs, which can detect the inhibitory potency of durgs or new chemical candidates to wild-type and variant CYP2C8 activities,
Results:The investigation on function of wild-type and variant CYP2C8s indicated: 1. in vitro CYPs recombinant technology can be applied in characterization of CYP polymorphic function and in mechanistic study of in vitro drug metabolisms; 2. the fluorogenic substrate-based detection showed that all enzymes expressed in this system possess robust activity; 3. the investigation on in vitro metabolism of paclitaxel and amodiaquine by CYP2C8s showed that CYP2C8.1 has a normal Km value which is comparable to previous data and possesses normal catalytic property; 4. it reveales similar enzymatic activity in R139K and low activity in CYP2C8.2, CYP2C8.3, CYP2C8.4 and K399R compared with CYP2C8.1 and K399R shows the lowest enzymatic activity. The evaluation on DDIs indicated:1. the evaluation on the paclitaxel-detected drugs DDIs showed that IC50 values of the detected drugs to the metabolism of paclitaxel by CYP2C8 variants are significantly different from that of CYP2C8.1. CYP2C8-medicated metabolic DDIs may be affected by CYP2C8 genetic polymorphisms; 2. in vivo DDIs indices [I]/Ki which were calculated via IC50 values and their pharmacokinetic data showed CYP2C8 genotype may change the quality of in vivo DDIs, and we must pay attention to the CYP2C8 genotype effects on DDIs prediction; 3. in vitro recombinant CYPs and fluorogenic substrate-based high-throughput drug screening platform can be primarily applied in the in vitro DDIs study;
Conclusions:This study systematically analysed the relationship between CYP2C8 genetic polymorphisms and CYP2C8 catalytic property from the pharmacogenomic and drug-drug interaction perspectives. Systematical analysis on the function of CYP2C8 variants can provide more homogeneous data for predicting CYP2C8 phenotypes and could be applied to personalised drug therapy, especially for paclitaxel and amodiaquine. The evaluation on DDIs between paclitaxel and 27 significantly clinical drugs can be used by pharmacologists in the design of in vivo studies to further assess and address the potential role of CYP2C8 genotype-dependent inhibition in clinical DDIs, and offers a new thinking to prediction on in vivo DDIs via in vitro inhibition data. We constructed a fluorogenic substrate-based CYP2C8 enzymatic-activity detecting and drug screening platform, which can provide a quick, sensitive and high-throughput method to detect CYP2C8 polymorphic activities and drug inhibition;
方法：首先,选取野生型CYP2C8(CYP2C8.1),3个重要的CYP2C8等位基因(CYP2C8.2,CYP2C8.3,CYP2C8.4)以及CYP2C8.3携带的两个重要SNPs(R139和K399R),应用体外重组和蛋白表达技术,将CYP2C8.1和5种CYP2C8变异体于相同的表达体系中进行表达,构建涵盖主要CYP2C8多态性的CYP2C8多态性基因文库和蛋白文库；利用已构建成功的CYP2C8多态性蛋白文库,研究体外重组CYP2C8.1和5种重要CYP2C8突变体对抗肿瘤药物(紫杉醇)和抗疟疾药物(阿莫地奎)代谢功能的差异,在此基础上系统性分析CYP2C8基因多态性对CYP2C8酶学性质改变的效应关系。在系统性分析了CYP2C8多态性功能的基础上,我们评估了10类共27种临床常用药物对CYP2C8.1和5种CYP2C8突变体紫杉醇催化活性的抑制程度,并根据体外抑制数据预测受测药物和紫杉醇,在不同CYP2C8基因型中,体内药物间相互作用的发生风险。其次,我们初步建立了一种基于荧光底物的,针对于CYP2C8介导的代谢性药物相互作用的高通量检测方法,用于快速评估药物或新药候选化合物对不同CYP2C8多态性的体外抑制程
结果：对CYP2C8野生型及其5种突变体的功能研究表明：1、CYPs体外重组技术可应用于CYP多态性功能研究和体外药物代谢机制研究；2、CYP2C8体外代谢紫杉醇和阿莫地奎的研究显示,本系统表达纯化的CYP2C8.1具有正常的药物催化活性,获得的酶动力学参数Km与已有报道数据相近。3、与CYP2C8.1相比,R139K的药物代谢能力无显著变化,CYP2C8.2,CYP2C8.3,CYP2C8.4和K399R的药物代谢能力有不同程度的降低,其中K399R的代谢能力最低。药物相互作用研究表明：1、紫杉醇和受测药物的体外药物相互作用研究结果显示,受测药物对CYP2C8突变体的半数抑制常数(IC50),与CYP2C8.1相比存在明显差异,CYP2C8基因多态性可能对CYP2C8介导的代谢性药物相互作用产生影响；2、紫杉醇和受测药物间体内相互作用的预测结果显示,不同CYP2C8基因型可能导致体内相互作用性质的改变。3、基于体外重组CYPs和荧光底物的高通量药物抑制检测方法可以用于体外药物相互作用的快速检测和初步研究；
总结：本研究从CYP2C8药物代谢功能和CYP2C8抑制介导的代谢性药物相互作用两方面,研究了CYP2C8基因多态性的影响效应。系统性分析CYP2C8多态性功能将为CYP2C8表型预测,为经CYP2C8代谢的药物,尤其是紫杉醇和阿莫地奎的个体化用药提供更加均一化的数据和信息。紫杉醇和27种临床常用药物相互作用研究将为临床药理学研究人员提供体内和体外药物代谢抑制数据,以进一步评估和解决临床中CYP2C8基因型依赖的代谢性药物相互作用。同时也为根据体外抑制数据预测体内药物相互作用提供了新的思路。另外,以荧光底物为基础的药物抑制检测平台,将为药物和新药化合物体外抑制检测提供快速、灵敏、高通量的分析方法和手段。
Aim:The interin-dividual difference on the catalytic capacity of CYP2C8 is likely to be the result of CYP2C8 genetic polymorphisms. Systematic study on the enzymatic functional variations of important allelic CYP2C8 is significant to pharmacology and toxicology, and it can provide useful information and in vitro data to the personal therapy of clinical CYP2C8-metabolizing drugs. However, there has been no systematic analysis of the catalytic properties of the main CYP2C8 variants in the same expression system and under identical assay conditions. Moreover, the patients carrying CYP2C8 polymorphic genotype may be at increasing risk to CYP2C8-metabolic DDIs due to the interindividual difference of CYP2C8 catalytic properties. However, no report has been able to show whether and how CYP2C8 genetic variants affect the occurrence and the individual differences in the in vitro and in vivo DDIs with CYP2C8-cleared drugs. In this study, we systematically analysed these scientific problems on CYP2C8 genetic polymorphisms, their functional variations and CYP2C8 genotype-dependent DDIs, which have not been worked out.
Method:Firstly, wild-type CYP2C8 (CYP2C8.1), three allelic CYP2C8s (CYP2C8.2, CYP2C8.3, CYP2C8.4) and two important CYP2C8 SNPs (R139K and K399R, carried by CYP2C8.3) were chosen, and then were expressed in the same expression system using in vitro recombinant and protein expression technology. We constructed the comprehensive CYP2C8 polymorphic gene library and protein library. Secondly, we investigated the difference on the catalytic properties of wild-type and variants CYP2C8s to the metabolism of anticancer drug (paclitaxel) and antimalaria drug (amodiaquine), using the constructed CYP2C8 polymorphic protein library, and systematically analysed the relationship between CYP2C8 genetic polymorphisms effects and the alteration on CYP2C8 enzymatic property. Thirdly, we evaluated in vitro inhibitory potency of 27 clinical drugs to the metabolism of paclitaxel by wild-type and 5 variant CYP2C8s. Fourthly, in vivo paclitaxel-detected drugs DDIs in different CYP2C8 genotype were predicted via in vitro inhibition data. Fifthly, we primarily developed a high-throughput fluorescent-based detection method for CYP2C8-mediated metabolic DDIs, which can detect the inhibitory potency of durgs or new chemical candidates to wild-type and variant CYP2C8 activities,
Results:The investigation on function of wild-type and variant CYP2C8s indicated: 1. in vitro CYPs recombinant technology can be applied in characterization of CYP polymorphic function and in mechanistic study of in vitro drug metabolisms; 2. the fluorogenic substrate-based detection showed that all enzymes expressed in this system possess robust activity; 3. the investigation on in vitro metabolism of paclitaxel and amodiaquine by CYP2C8s showed that CYP2C8.1 has a normal Km value which is comparable to previous data and possesses normal catalytic property; 4. it reveales similar enzymatic activity in R139K and low activity in CYP2C8.2, CYP2C8.3, CYP2C8.4 and K399R compared with CYP2C8.1 and K399R shows the lowest enzymatic activity. The evaluation on DDIs indicated:1. the evaluation on the paclitaxel-detected drugs DDIs showed that IC50 values of the detected drugs to the metabolism of paclitaxel by CYP2C8 variants are significantly different from that of CYP2C8.1. CYP2C8-medicated metabolic DDIs may be affected by CYP2C8 genetic polymorphisms; 2. in vivo DDIs indices [I]/Ki which were calculated via IC50 values and their pharmacokinetic data showed CYP2C8 genotype may change the quality of in vivo DDIs, and we must pay attention to the CYP2C8 genotype effects on DDIs prediction; 3. in vitro recombinant CYPs and fluorogenic substrate-based high-throughput drug screening platform can be primarily applied in the in vitro DDIs study;
Conclusions:This study systematically analysed the relationship between CYP2C8 genetic polymorphisms and CYP2C8 catalytic property from the pharmacogenomic and drug-drug interaction perspectives. Systematical analysis on the function of CYP2C8 variants can provide more homogeneous data for predicting CYP2C8 phenotypes and could be applied to personalised drug therapy, especially for paclitaxel and amodiaquine. The evaluation on DDIs between paclitaxel and 27 significantly clinical drugs can be used by pharmacologists in the design of in vivo studies to further assess and address the potential role of CYP2C8 genotype-dependent inhibition in clinical DDIs, and offers a new thinking to prediction on in vivo DDIs via in vitro inhibition data. We constructed a fluorogenic substrate-based CYP2C8 enzymatic-activity detecting and drug screening platform, which can provide a quick, sensitive and high-throughput method to detect CYP2C8 polymorphic activities and drug inhibition;
引文
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