Chinese Journal of Tissue Engineering Research ›› 2014, Vol. 18 ›› Issue (46): 7509-7514.doi: 10.3969/j.issn.2095-4344.2014.46.026
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Yu Li-chong1, 2, Qian Ye-yong2, Shi Bing-yi2, Fan Yu2, Liu Lu-peng2, Yu Fei2
Revised:
2014-10-30
Online:
2014-11-12
Published:
2014-11-12
Contact:
Qian Ye-yong, Chief physician, Master’s supervisor, Second Department of Urology, Institute of Organ Transplantation, the 309th Hospital of PLA, Beijing 100091, China
About author:
Yu Li-chong, Studying for master’s degree, Physician, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; Second Department of Urology, Institute of Organ Transplantation, the 309th Hospital of PLA, Beijing 100091, China
Supported by:
the Capital Clinical Application Research, No. Z13110700220000
CLC Number:
Yu Li-chong, Qian Ye-yong, Shi Bing-yi, Fan Yu, Liu Lu-peng, Yu Fei. Genomics and gene polymorphism of immunosuppressive drugs after kidney transplantation[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(46): 7509-7514.
2.1 钙调神经蛋白抑制剂类药物相关的药物基因组学与基因多态性 钙调神经蛋白抑制剂类免疫抑制药物主要包括环孢素A和他克莫司两大类,是当前联合免疫抑制方案的主要组成部分。由于基因的不同可能改变酶的活性影响药物清除率,使得同种群的不同个体即使给予相同剂量的免疫抑制剂,药物代谢也会有所差异。钙调神经蛋白抑制剂类药物的治疗窗相对较窄,个体间的差异给临床治疗带来更多困难,术后严密监测血药浓度是必要措施。研究显示,环孢素A和他克莫司的药代动力学相似,都是通过CYP3A酶在肠腔内进行首过代谢[1]。此类药物的清除和代谢很大程度上依赖CYP3A尤其是CYP3A4和CYP3A5 酶[2]。进一步相关研究表明,CYP3A4在环孢素A的代谢中起主要作用,CYP3A5在他克莫司的代谢中起主要作 用[3]。 环孢素A是钙调神经蛋白抑制剂类药物最早的成员,是免疫抑制药物发展的奠基石,它通过与环菲林(cyclophilin)相结合从而抑制钙调磷酸酶,抑制活化T细胞核因子去磷酸化,致使包括白细胞介素2、白细胞介素4、Y-干扰素等T细胞活化方面有重要作用的细胞因子合成进一步减少,从而达到抑制T细胞活化的免疫抑制作用。环孢素A药物的毒副作用主要是肾毒性和肝毒性,其中肝脏对环孢素A比肾脏更加敏感,文献报道肝毒性的发生率为49%,主要表现为低蛋白血症、高胆红素血症、胆汁淤积和转氨酶升高,其次是胃肠道不良反应和神经系统不良反应,主要包括恶心、呕吐、厌食、肠胀气和震颤、刺痛、麻木等感觉异常等;其他的不良反应为不伴有酮症以及酮尿症的高血糖症、轻中度高血压、多毛、齿龈肥大等。 关于环孢素A药物浓度与CYP3A基因多态性的研究结果不尽相同。胡永芳等[4]回顾性分析了肾移植术后1月内环孢素A药物浓度的变化,结果发现在63例肾移植受者中,CYP3A5*3和CYP3A4*18B突变等位基因发生频率分别为0.770(95 CI:0.767-0.773)和0.235(95 CI:0.235-0.241)。在移植后1个月内,携带CYP3A4*1/*1野生型纯合子受者的药物血浓度谷值(C0)以及剂量校正血浓度谷值(C0/D)均明显高于携带CYP3A4*1/*18B杂合子和CYP3A4*18B/*18B突变型纯合子受者,CYP3A5*1/*1基因型组的给药剂量明显高于CYP3A5*1/*3或CYF3A5*3/*3基因型组,CYP3A5*3和(或)CYP3A4*18B基因多态性对肾移植后1个月环孢素A药代动力学有一定影响。而Kreutz等[5]的回顾性分析399例肾移植后受者CYP3A5基因多态性与环孢素A的药代动力学及受者预后相关性的研究显示,未发现携带CYP3A5*1等位基因的受者与环孢素A的药物血浓度谷值有相关性。Amundsen 等[6]的研究也认为环孢素A的药物浓度只与CYP3A4的基因多态性有关,而与CYP3A5的基因多态性无关。关于CYP3A4*1B(A392G)的研究,由于亚洲人携带这一基因的人数很少[7],临床意义不大,国内关于它的研究不多。Elens等[8]对最近发现的CYP3A4*22进行了研究,结果发现对于接受环孢素A治疗的肾移植受者,CYP3A4*22是移植肾功能延迟恢复的危险因素,而且可能会导致肌酐清除率下降。Meng等[9]对126例肾移植受者进行研究,认为CYP3A5*3C在肾移植后第7天与剂量校正血浓度谷值(C0/D)值有关,可以作为术后早期优化环孢素使用剂量的潜在参考因素。关于环孢素A药代动力学与ABCB1基因多态性之间的研究结果呈现明显的两极化,Bouamar等[10]的研究认为两者之间没有联系,Singh等[11]的研究结果恰恰相反。可能受限于纳入实验的人数不足以及随访时间节点不一导致结果出现明显差异。而辛华雯等[12]的研究随访了339例服用环孢素A的肾移植受者,结果表明ABCB1基因1236C>T,2677G>T/A,3435C>T多态性对极少数时间点的环孢素A浓度有影响,但对绝大多数时间点的环孢素浓度无影响。 他克莫司是通过与胞浆结合蛋白-FKBP-12特异性结合,抑制钙调磷酸酶,进一步抑制活化T细胞核因子(NF-AT)的转录活化,最终抑制T淋巴细胞的活化从而达到与环孢素A相类似的免疫抑制作用。他克莫司的药物毒副作用主要是肾毒性,肾移植受者服用他克莫司的群体中,肌酐升高发生率为35%,其肝毒性发生率较环孢素A明显减少;其次是血糖代谢紊乱,术后新发糖尿病的发生率较高,约为8.2%;其他常见的不良反应主要是神经系统异常,其中震颤反应发生率最高,占34.7%。 目前的研究文献表明,影响他克莫司利用率和药物清除的酶主要是CYP3A,尤其是CYP3A4以及CYP3A5。相关研究证实CYP3A4和CYP3A5同时表达时,这两种亚型在他克莫司药物代谢中所起的作用几乎相当[13]。 CYP3A5基因位于人类第7号染色体,全长31.8 kb,有13个外显子,编码502个氨基酸[14]。CYP3A4基因位于人类第7号染色体,全长27 kb,有13个外显子12个内含子的编码区域。CYP3A5野生型基因片段是CYP3A5*1,突变型基因片段是CYP3A5*3。研究显示,CYP3A5*1的基因分布频率具有明显的种族差异性[15],高加索人占5%-15%,非洲裔美国人占45%-73%,亚洲人占15%-35%,墨西哥人约占25%。何霞等[16]的研究表明汉族肾移植后受者CYP3A5*1等位基因的频率约占25.85%。 CYP3A5基因多态性的机制主要是其转录和翻译产生CYP3A5酶的不同从而影响他克莫司的代谢。携带CYP3A5*1基因片段的纯合型或者杂合型可以通过转录并翻译产生大量有功能的CYP3A5酶,而携带CYP3A5*3基因片段的纯合型几乎不产生CYP3A5酶[17]。Zhang等[18]的一项对118例中国肾移植受者的研究表明,表达CYP3A5酶组受者他克莫司的C0/D值是不表达组的2.2-4.3倍。徐芳等[19]的研究结果相似,即肾移植后他克莫司C2/D的个体化差异与受者CYP 3A5*3基因型密切相关。Roy等[20]的研究显示肾移植后表达CYP3A5酶的移植受者达到理想的他克莫司药物浓度需要更长的时间(超过2周)。丰贵文等[21]随访172例肾移植的受者,观察了术后12个月CYP3A5基因分型对他克莫司的浓度和剂量的影响,研究表明CYP3A5*1/*1型受者对他克莫司的代谢快,术后早期应适当加大他克莫司的剂量以达到目标浓度;*1/*3型受者对他克莫司的代谢先慢后快,早期剂量应加大,后期控制减量速度,3个月后可适当加快减量速度;*3/*3型受者对他克莫司的代谢慢,早期应给予低剂量,后期药物减量速度应适当加快。 CYP3A4联合CYP3A5可以解释60%的个体因为剂量调整而造成的他克莫司血药浓度波动[22-23]。CYP3A4*18B(20070T>C;rs2242480)等位基因是目前所知的CYP3A4 SNPs突变频率最高的一个位点,在黄种人中突变频率高达24.5%[24]。Shi等[25]发现CYP3A4*18B和CYP3A5*3基因型可以解释28.4%的中国汉族个体他克莫司的清除率差异。de Jonge等[26]的研究也得出相似结论,认为CYP3A4和CYP3A5介导的他克莫司代谢是影响其体内代谢的主要因素。李丹滢等[27]对46例中国汉族肾移植受者术后1个月内他克莫司浓度谷值(C0/D)进行了研究,结果表明46例患者CYP3A4*18B和CYP3A5*3等位基因频率分别为0.304和0.707。术后1个月内,CYP3A4 *1/*1型受者C0/D值分别为*1/*18B和*18B/*18B型受者的1.38和2.43倍。CYP3A5*3/*3型受者C/D值分别为*1/*3和*1/*1型受者的1.73和2.53倍。因此研究认为CYP3A4/5单倍型与他克莫司C0/D值显著相关,移植前检测CYP3A4/5单倍型将有利于他克莫司给药剂量的调整。何霞等[28]的研究结果相似,他们对101例健康志愿者和56例亲体肾移植受者随访6个月,测定移植后7 d、14 d、1个月、3个月和6个月时血药浓度,比较不同基因型间他克莫司C/D值之间的差异,结果表明受者术后服用他克莫司C/D值与CYP3A4、CYP3A5基因多态性具有显著相关性。林玲 等[29]对61例肾移植受者进行了研究,比较术后14 d和 1,2,3个月时不同基因型受者间他克莫司浓度谷值(C0)、他克莫司剂量(D)和浓度/剂量(C0/D)的差异,结果认为肾移植受者CYP3A5*3和CYP3A4*18B基因多态性对他克莫司的药代动学有显著影响,对CYP3A5联合CYP3A4 (CYP3A5-CYP3A4)单倍型的分析比单独考虑一种基因型影响更为显著。值得关注的是,迄今为止尚无联合应用CYP3A5和CYP3A4基因多态性临床指导的他克莫司个体化用药的前瞻性随机对照研究。 尽管CYP3A对他克莫司的血药浓度和药物代谢的影响最大,其他一些酶对他克莫司的代谢也有一定的影响。研究证实,氧化还原酶*28(POR*28)与他克莫司的谷值浓度有关,表达POR*28的个体需要较高剂量的他克莫 司[30]。此外,孕烷X受体(PXR)是由NR1I2编码的细胞核受体,PXR是CYP3A4表达的主要转录激活因子,进而参与药物代谢相关酶和转运蛋白的诱导表达,且可以通过与其他核受体相互作用,调控多种靶基因的表达,实现机体内环境的稳态平衡[31]。在一篇回顾性的研究中,这一基因的多态性,尤其是PXR-28385 C>T以及NR1I28055T的表达者需要较高剂量的他克莫司,同时发现其感染BK病毒血症的几率较高[32]。 ABCB1编码P蛋白,有可能影响他克莫司的吸收以及体内分布。然而,他克莫司药代动力学与ABCB1基因多态性之间的关系存在争议,一些研究证明ABCB1的基因多态性对于他克莫司的药物浓度有影响[33-34],而另一些的结果恰恰相反[35-36]。另外,ABCB1基因也可能与钙调神经蛋白抑制剂类药物的不良反应有关,这些不良反应包括中毒性肾损害[37]、神经毒性[38]、移植肾功能延迟恢复、肾移植术后糖尿病等[39]。 2.2 mTOR抑制剂相关的药物基因组学与基因多态性 西罗莫司和依维莫司是大环内酯类抗生素,它们在结构上与他克莫司相似,并且都与FKBP蛋白相结合,通过抑制丝氨酸/苏氨酸蛋白激酶活性,影响核糖体功能,从而抑制蛋白质合成,阻止T细胞的G1-S期过渡,对G0期B细胞也有抑制作用,通过阻止细胞因子介导的T、B细胞的活化、增殖,从而达到抑制免疫的目的[40]。该类药物的不良反应主要包括血脂升高、血红蛋白水平降低、关节疼痛、外周性水肿、胃肠道不适、皮肤病、口腔炎、电解质紊乱(如低钾血症和低磷血症)、呼吸困难、咳嗽、感染和淋巴囊肿等[41]。有报道称,mTOR抑制剂会引起伤口难以愈合以及伤口开裂的情况,尤其是在肾移植术后早期更易发 生[42]。CYP3A和P蛋白影响了西罗莫司和依维莫司的吸收,而CYP3A4和CYP3A5则在该类药物代谢及清除过程中起重要作用。关于mTOR抑制剂的药代动力学的基因多态性的研究很少。国外一项研究表明CYP3A5的基因型可能与西罗莫司的药代动力学有关[43],而依维莫司并未发现相似情况[44]。廖珂等[45]调查了112例中国汉族稳定期肾移植受者,结果发现汉族稳定期肾移植受者的CYP3A5*3基因多态性是影响西罗莫司浓度的主要因素,MDRlC3435T基因多态性则对其无影响。研究还表明,与CYP3A5*3/*3型受者相比较,CYP3A5*1/*1和*1/*3型受者为达到目标血药浓度需服用更高剂量的西罗莫司。 2.3 霉酚酸酯类药物相关的药物基因组学与基因多态性 霉酚酸酯类药物被迅速水解成活性代谢物—霉酚酸,其作用机制是可选择性、非竞争性、可逆性的抑制次黄嘌呤核苷酸脱氢酶(IMPDH),抑制鸟嘌呤核苷的经典合成途径,可特异性抑制T淋巴细胞增殖,从而到达免疫抑制的效果。此类药物的副作用主要是胃肠道反应,包括腹泻(最常见的不良反应)、腹痛、恶心和呕吐,其次是血液系统的不良反应,包括贫血、白细胞减少症和血小板减少症,还有一些包括感染、头痛和震颤等其他不良反应[46]。 霉酚酸主要经肝脏内代谢酶UGTIA9作用生成无活性的代谢产物霉酚酸葡萄糖苷酸,同时部分经UGT287酶作用形成霉酚酸酰基葡萄糖苷酸[47]。张伟霞等[47]对中国成年肾和肝移植受者口服霉酚酸酯后霉酚酸及其代谢产物的药动学和药效学进行了研究,研究收集了98例肾移植和79例肝移植受者的558份和479份霉酚酸血样和移植受者的临床资料,结果表明UGTIA9*1b的基因变异可以影响到霉酚酸和霉酚酸葡萄糖苷酸的曲线下面积(AUC),参与霉酚酸葡萄糖苷酸肝脏排泄转运蛋白ABCC2的1249 G>A单核苷酸突变与霉酚酸酰基葡萄糖苷酸的AUC升高有关。但没有发现UGT287和其他相关酶和转运体基因多态性对霉酚酸及其代谢物药代动力学的影响。国外相关研究表明SLCO1B1521T>C(*5)可能改变肝脏生成霉酚酸葡萄糖苷酸的能力,从而减少进入肝脏循环的霉酚酸,减少霉酚酸的蓄积,最终减轻肾毒性[48]。研究表明携带至少一个SLCO1B3334T基因的受者较携带334G基因的受者需要更大剂量的霉酚酸,但尚未有证据表明和安全性以及远期预后有关[49]。此外,Pazik等[50]的研究表明UGT1A9 98C可能在肾移植后1年内与肾小球滤过率下降有关。"
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