抗癫痫药物卡马西平代谢个体差异的遗传分析

发布时间：2018-01-30 02:34

  本文关键词： 癫痫病 卡马西平 基因多态性 代谢 血药浓度 药物耐受性　出处：《吉林大学》2015年硕士论文　论文类型：学位论文

【摘要】：癫痫是一种常见的慢性神经系统疾病，目前药物治疗是控制癫痫的主要手段。卡马西平（carbamazepine，CBZ）是最常用的抗癫痫药物之一，但在治疗过程中存在血药浓度个体差异大，，有效性和安全性难于预测的特点，约有1/3的患者出现药物耐受性，因此需要监测患者的血药浓度，实行个体化治疗。 大量的研究证实，药物代谢酶，转运体和靶蛋白的基因多态性是导致不同个体间药物反应差异的主要因素。卡马西平主要通过抑制兴奋性电压依赖性钠通道，如Nav1.1,1.2（SCN1A,SCN2A）,稳定神经细胞膜和减少兴奋性氨基酸-谷氨酸的释放而发挥抗癫痫作用。在体内它首先经肝脏的细胞色素氧化酶P450酶(cytochrome p450,CYP450)3A4转化为有活性的CBZ-10，11-环氧化物（CBZE），然后被微粒体环氧化物水解酶(microsomal epoxide hydrolase,EPHX1)代谢为无活性的CBZ-10,11二氢二醇（CBZD）从肾脏排出。其中细胞色素P450氧化还原酶(P450oxidoreductase,POR)是CYP450同工酶唯一的电子供体，协助CYP3A4完成催化活性。由ABCB1和ABCC2编码的MDR1和MPR2是CBZ的细胞外排转运体，阻碍CBZ的肠吸收和通过血脑屏障。因此负责CBZ代谢、转运的酶或蛋白的基因多态性可能通过改变其功能影响CBZ在体内的血药浓度和疗效。 本课题首先分析了在83名中国成年癫痫患者中CYP3A4*1G、EPHX1T337C/A416G、ABCC2-24CT/1249GA/3972CT和SCN1A IVS5-91GA基因多态性对CBZ血药浓度和药物耐受性的影响。结果表明携带变异的EPHX1A416G基因型的癫痫患者血清中CBZ浓度显著地高于野生型基因的携带者（AG+GG vs AA, P=0.005）。携带EPHX1337TC/CC基因型的患者易产生药物的耐受性（odds ratio≥4.0）。 进一步我们分析了在210名中国儿童癫痫患者中CYP3A4*1G、POR*28和ABCB1C1236T、G2677T/A、C3435T基因多态性对CBZ及其代谢产物CBZE、CBZD的影响。结果表明与3435CT基因型携带者相比，携带3435CC基因型的患者具有较高的剂量调整的CBZ及其两个代谢产物CBZE和CBZD浓度（P 0.05），CYP3A4*1G突变体携带者具有较低的剂量调整的CBZ和CBZE浓度。 以上数据表明CBZ的主要转运体和代谢酶的基因多态性是CBZ代谢的个体差异的影响因素之一，也是导致药物产生耐受性的原因。这些结果将为CBZ实现个体化治疗，增加药物疗效提供重要的理论依据。
[Abstract]:Epilepsy is a common chronic nervous system disease. At present, drug therapy is the main means to control epilepsy. Carbamazepine CBZ is one of the most commonly used antiepileptic drugs. However, in the course of treatment, there is a large individual difference in blood drug concentration, the effectiveness and safety of the characteristics of difficult to predict, about 1/3 patients have drug tolerance, so we need to monitor the blood drug concentration of patients. Individualized treatment was carried out. A large number of studies have confirmed that gene polymorphisms of drug metabolizing enzymes, transporters and target proteins are the main factors leading to the difference of drug reactions among individuals. Carbamazepine mainly inhibits excitatory voltage-dependent sodium channels. For example, Nav1.1 1. 1 + 1. 2% SCN1A (SCN2A). It plays an antiepileptic effect by stabilizing the membrane of nerve cells and reducing the release of excitatory amino acid-glutamic acid. In vivo, it first passes through the cytochrome oxidase P450 enzyme of the liver. Cytochrome p450. CYP450)3A4 was transformed into active CBZ-10O11-epoxide (CBZE). Then the microsomal epoxide hydrolase EPHX1 was metabolized into inactive CBZ-10. The cytochrome P450 redox enzyme P450 oxidoreductase was excreted from the kidney. POR) is the only electron donor of CYP450 isozyme. MDR1 and MPR2 encoded by ABCB1 and ABCC2 are the extracellular efflux transporters of CBZ. Therefore, gene polymorphisms of enzymes or proteins responsible for CBZ metabolism and transport may affect the concentration and efficacy of CBZ in vivo by altering its function. In this study, we first analyzed the CYP3A41G EPHX1T337C / A416G in 83 Chinese adult epileptic patients. ABCC2-24CT/1249GA/3972CT and SCN1A. The effect of IVS5-91GA gene polymorphism on serum drug concentration and drug tolerance of CBZ. The results showed that the serum CBZ concentration in epileptic patients with variant EPHX1A416G genotype was significant. Carriers with higher than wild-type genes (. AG GG vs AA. Patients with EPHX1337TC/CC genotype were likely to develop drug tolerance and odds of ratio 鈮

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