细胞色素 P4503 A4与 P4503 A5及多药耐药基因多态性对氨氯地平降压疗效影响研究

目的：探讨细胞色素 P450（ CYP）3A4倡1G、CYP3A5倡3及多药耐药（MDR1） C1236T、MDR1 G2677T／A和MDR1 C3435T基因多态性对氨氯地平降压疗效的影响。方法纳入159名原发性高血压患者,予氨氯地平5 mg· d－1干预4周,检测相关基因型,分析不同个体CYP3A4、3A5及MDR1相关基因型分布特征,考察不同单核苷酸多态性（ SNP）及MDR1单倍体对氨氯地平降压疗效的影响。结果 CYP3A4倡1G倡1G 基因型舒张压（ DBP）下降幅度显著低于CYP3A4倡1G倡1和CYP3A4倡1倡1（P＜0.05）;CYP3A5倡3倡3基因型DBP下降幅度显著高于CYP3A5倡1倡3和CYP3A5倡1倡1（P＜0.05）;MDR1 C1236T CC、MDR1 G2677T／A AA基因型收缩压（SBP）下降幅度显著高于其他基因型（P＜0.05）;MDR1 C3435T各基因型治疗前后SBP、DBP下降幅度差异均无统计学意义（P＞0.05）。携带MDR1 C3435T CC、MDR1 C3435T CT基因型的患者的DBP下降幅度,女性显著高于男性（ P＜0.05）。对MDR1单倍体分析,各组单倍体治疗前后 SBP、DBP 下降幅度差异均无统计学意义（ P ＞0.05）。结论CYP3A5倡3、CYP3A4倡1G基因多态性可影响氨氯地平降压疗效,MDR1各单倍体未发现与氨氯地平降压疗效相关。     

细胞色素P4503A5~*3基因多态性与环孢素所致肝损伤相关性的评价

目的系统评价细胞色素P450 3A5*3(CYP3A5*3)基因多态性与环孢素所致的肝损伤的相关性。方法系统检索Pub Med、MedLine、EMbase、Cochrane图书馆、维普数据库、中国知网和万方数据库,查找CYP3A5*3基因多态性与环孢素致患者肝损伤相关性的研究,检索时间自各数据库建库至2016年3月。试验组为环孢素致肝损伤患者,对照组为无肝损伤患者或其他原因致肝损伤患者。用Rev Man 5. 2. 0软件进行Meta分析。结果共纳入病例对照研究3篇(包括英文1篇和中文2篇),患者807名。患者的基因型分布均符合Hardy-Weinberg平衡定律。试验组和对照组CYP3A5*3AA型的分布率分别为21. 70%(87例/401例)和22. 36%(91例/407例),差异有统计学意义(P <0. 01)。试验组和对照组中携带等位基因A的分布率分别为21. 20%和32. 89%,携带等位基因G的分布率分别为78. 80%和67. 11%,差异均无统计学意义(均P> 0. 05)。结论 CYP3A5*3基因多态性与环孢素致患者肝损伤相关,其中携带CYP3A5*3AA基因型的患者服用环孢素所致肝损伤的发生率较低,而此发生率与等位基因A和G的分布无关。     

没食子酸对细胞色素P4503 A4介导的硝苯地平代谢的影响

目的 体外研究没食子酸对细胞色素P4503A4(CYP3A4)介导的硝苯地平代谢的影响.方法 将不同浓度没食子酸、人肝微粒体(HLM)与硝苯地平孵育,测定硝苯地平的减少率并计算其半抑制浓度IC50值.将没食子酸与HLM预孵育0 min和30 min后作为干预1组和干预2组;将不加入没食子酸、HLM预孵育0 min设为空...     

细胞色素P_(450)3A5基因多态性的研究进展

细胞色素P4503A5（Cytochrome P4503A5，CYP3A5）是CYP3A亚族中的一种重要的同工酶。其遗传多态性影响着许多经CYP3A介导的药物，如地尔硫革、阿芬太尼等在肝微粒体中的氧化代谢，该酶的活性存在明显的个体差异，对不同个体的药物治疗作用和不良反应及药物的毒性产生重要影响，是引起个体及种族间对同一底物代谢能力不同的原因之一。本文主要对CYP3A5基因多态性及其种族差异，CYP3A5基因多态性对药物处置、药动学、药效学及疾病风险等影响进行综述如下。     

合心爽对肾移植受者环孢素A血药浓度的影响

以荧光偏振免疫分析法测定肾移植受者环孢素A(CSA)的血药浓度。对20例CsA血药浓度谷值偏低的患者，加服合心爽(地尔硫卓)，结果表明：2周后CsA血药浓度明显升高，而CsA对肾功能的损害明显降低。     

细胞色素P450 3A5基因多态性及其对药物代谢影响的研究进展

细胞色素P450 3A5是细胞色素P450亚家族CYP3A的成员之一,对CYP3A底物的代谢清除率有明显的作用,与CYIY3A4等共同或独立催化或影响药物代谢,具有种族差异的遗传多态性.研究CYP3A5多态性及其对药物代谢的影响,对于临床上个体化用药具有积极的意义.     

细胞色素P450(CYP)3A5与CYP2C19基因多态性对伏立康唑在健康人体的药代动力学特征的影响

目的研究中国健康人体内细胞色素P450(CYP)3A5、CYP2C19基因多态性对伏立康唑药代动力学的影响。方法用RFLP-PCR法对受试者进行全血CYP3A5、CYP2C19基因分型;建立人血浆中伏立康唑的LC-MS测定方法,检测血药浓度;并对受试者单次口服伏立康唑200 mg后的系列血药浓度进行测定。结果伏立康唑200 mg,CYP2C19突变纯合子的AUC0-36、AUC0-∞值均显著高于野生组;也显著高于突变杂合组;而CL/F值则明显低于野生组。T1/2﹑Cmax等在各组间无统计学差异;伏立康唑各药代动力学参数在CYP3A5各组间均无统计学差异。结论中国人体内CYP2C19基因多态性对伏立康唑的药代动力学过程有显著影响;而CYP3A5基因多态性对伏立康唑的药代动力学过程无明显影响。     

肾移植病人中CYP3A4基因多态性对环孢素A代谢的影响

目的 用基因分析技术对CsA代谢酶CYP3A4进行基因分型,以阐述CYP3A4基因多态性对环孢素A代谢的影响及相互关系,从而预测血药浓度及安全性。方法 用聚合酶链反应结合限制性片段长度多态性分析法分别建立了CYP3A的CYP3A4基因亚型3个新突变点(CYP3A4~*4,~*5,~*6)的基因分型方法,并对中国肾移植人群进行基因分型,同时测定CsA及其代谢物浓度,以原形药与代谢物浓度的比值MR作为表型验证指标。结果CYP3A4~*4,*~5,*~6等位基因在中国肾移植人群中的突变率为:2/133,3/197,3/200。野生型病人中肝肾功能正常和异常者测得MR均值分别为0.47±0.13和0.82±0.21。3种突变型病人MR均值为0.90±0.30。结论CYP3A4~*4,~*5,~*6等位基因的存在有可能降低了药物代谢酶CYP3A4的活性,从而使环孢素A的代谢减慢。     

橙皮苷对辛伐他汀调脂作用及细胞色素P4503A mRNA表达的影响

目的　研究橙皮苷对辛伐他汀 (simvastatingroup ,SV)调脂作用及CYP450 3AmRNA表达的影响。方法　将Wistar大鼠随机分为 :对照组 (controlgroup)、高脂血症模型组 (modelgroup)、辛伐他汀组 (simvastatingroup ,SVgroup)、低剂量橙皮苷 +辛伐他汀组 (lowdosehesperidin +SV group ,LDHS)、高剂量橙皮苷 +辛伐他汀组 (highdosehesperidin +SV group ,HDHS)。除对照组外 ,余组均饲喂高脂饮食 ,各实验组按 5mg·kg- 1SV灌胃 ,并分别加用不同剂量的橙皮苷。实验 8wk后 ,检测各组大鼠血脂水平 ,肝脏及小肠CYP450 3A基因表达水平。结果　高脂饲养 8wk后 ,模型组TC、TG和LDL C均升高 (P <0 0 1) ;SV组TC、TG和LDL C较模型组降低 (P <0 0 1或P <0 0 5) ;加用橙皮苷后 ,TC和TG均较SV组呈剂量依赖性降低。模型组肝脏CYP450 3AmRNA表达量与对照组比较无统计学意义 (P >0 0 5) ,小肠CYP450 3AmRNA表达量较对照组升高 (P <0 0 5)。使用SV后 ,肝脏CYP450 3AmRNA表达量较模型组有增加趋势 ,小肠表达量增加 (P <0 0 5)。SV与橙皮苷合用后 ,随橙皮苷剂量的加大 ,肝脏及小肠CYP450 3AmR NA的表达呈下降趋势 ,以HDHS组明显 (P <0 0 5)。结论　橙皮苷能增加SV的调脂作用 ,其机制可能与橙皮苷抑制了CYP450 3A基因表达?     

卡瓦胡椒提取物和卡瓦内酯对细胞色素P4503A4的抑制作用

由于卡瓦胡椒Piper methysticaum存在肝毒性,该植物制品最近已从德国市场撤消,但其肝毒性的原因尚不清楚。鉴于细胞色素P450酶在肝代谢和清除外来抗生素中起重要作用,作者研究了该植物提取物对细胞色素P450 3A4(CYP3A4)的影响。     

Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients

AIM: To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. METHODS: The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. RESULTS: The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. CONCLUSION: The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.     

CYP3A基因多态性与心脏移植术后环孢素肾毒性的相关性

目的：探讨心脏移植受者CYP3A基因多态性与环孢素（CsA）所致肾毒性易感性的关系。方法：应用飞行时间质谱技术分析66例CsA免疫抑制治疗发生肾毒性（20例）和未发生肾毒性（46例）心脏移植术后患者的CYP3A基因多态性,并通过统计学分析CYP3A各单核苷酸多态性（SNP）位点基因型与CsA所致肾毒性之间的关系。结果：筛选出8个标签位点的等位基因在肾毒性和非肾毒性组间的分布差异均无统计学意义。经非条件性二元Logistic回归分析,在AIC定义的共显性和显性遗传模型下,未发现CYP3A基因8个SNP位点与CsA肾毒性的发生有显著性关联。结论：本研究显示心脏移植受者本次调查的CYP3A基因位点与CsA所致肾毒性无显著性关联。     

CYP3A5~*3和CYP3A4~*18B基因多态性对肾移植患者环孢素药代动力学的影响

目的回顾性研究肾脏移植后1mon,CYP3A5*3和CYP3A4*18B基因多态性对CsA药代动力学参数的影响。方法采用PCR-RFLP方法分析了63名肾脏移植患者CYP3A5*3和CYP3A4*18B基因型;荧光偏正免疫法用于检测肾移植患者静脉全血中的CsA浓度。结果在63名肾移植患者中,CYP3A5*3和CYP3A4*18B突变等位基因发生频率分别为0.770(95CI:0.767～0.773),0.235(95CI:0.235～0.241),而且这些等位基因表现出完全连锁不平衡。在移植术后1mon内,携带CYP3A4*1/*1野生型纯合子患者的C0以及剂量校正谷血浓度(C0/D)均明显高于携带CYP3A4*1/*18B杂合子或CYP3A4*18B/*18B突变型纯合子患者(P<0.05,Mann-WhitneyUtest);CYP3A5*1/*1基因型组的给药剂量明显高于CYP3A5*1/*3或CYP3A5*3/*3基因型组(P=0.004<0.01,Kruakal-Wallistest);CYP34*18B和CYP3A5*3联合考虑,对于CYP3A5表达组,同样发现C0、C0/D在CYP3A4*1/*1组C0以及C0/D均明显高于CYP3A4*1/*18B或CYP3A4*18B/*18B组(P<0.05,Mann-WhitneyUtest);而其他药动学参数在CYP3A5*3及CYP3A4*18B各组间相比差异则没有统计学意义。结论CYP3A5*3和(或)CYP3A4*18B基因多态性对肾移植后1monCsA药代动力学有一定影响,移植前CYP3A5*3基因型的分析仍需进一步研究。     

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

Objective  The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation. Methods  A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C₀ and C₂, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated. Results  Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C₂, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C₀, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C₀ was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C₀ in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C₀ was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C_2. Conclusion  The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.     

Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients

The objective of this study was to investigate the possible association of the ABCB1 gene C3435 T polymorphism and the CYP3A5 gene A6986G polymorphism with sirolimus (SRL) trough concentration and dose requirements in Chinese stable renal transplant recipients. Blood samples were collected from 105 healthy volunteers and 50 renal transplant patients, whose polymorphisms of the ABCB1 and CYP3A5 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Plasma concentrations of SRL were determined with HPLC. The allele frequencies of the ABCB1 mutation in Chinese healthy volunteers and renal transplant recipients were 51.0% and 44.0% (p>0.05), while the allele frequencies of the CYP3A5 mutation were 72.9% and 71.0% (p>0.05). The SRL concentration/dose ratio (C/D) in patients with CYP3A5 (*)3/(*)3 were significantly higher than that of those with (*)1 allele (p<0.05). However, no significant differences were observed between C/D and ABCB1 SNPs (p>0.05). These results confirm that when treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A5(*)1 allele required significantly more SRL to achieve adequate blood trough concentrations. In patients with SRL-based therapy, genotyping of the CYP3A5 genes may help to optimize the SRL management in renal transplant recipients.     

Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients

OBJECTIVE: The expression on lymphocytes of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene, might influence cyclosporine intracellular concentration. METHODS: ABCB1 genotypes, cyclosporine intracellular and blood concentrations were determined in 64 stable renal, liver or lung transplant recipients. RESULTS: Cyclosporine intracellular concentration correlated moderately with blood concentration (r=0.30, P<0.00005). The ABCB1 1199A carriers presented a 1.8-fold decreased cyclosporine intracellular concentration (P=0.04), whereas the 3435T carriers presented a 1.7-fold increase (P=0.02) as well as a 1.2-fold increased blood concentration (P=0.04). In contrast, ABCB1 61A>G, 1236C>T and 2677G>T polymorphisms did not influence cyclosporine intracellular and blood concentrations. CONCLUSION: This is the first report demonstrating that ABCB1 polymorphisms influence cyclosporine intracellular concentration. Interestingly, its influence on intracellular concentration is significantly higher than on blood concentration (P<0.002). This may therefore modulate cyclosporine immunosuppressive activity.     

CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响

目的研究CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响。方法采用化学发光免疫法检测20例肾移植术后患者在服用缓释(10例)和普通剂型(10例)他克莫司后的全血浓度;采用聚合酶链反应-限制性片段长度多态法检测服用缓释剂型他克莫司患者的CYP3A5基因型;缓释剂型组检测0~24 h的11个时间点的血药浓度,而普通剂型检测0~12 h内的10个时间点的血药浓度。结果无剂量校正的缓释剂型组的AUC_(0~24 h)为普通剂型组AUC_(0~12 h)的1.78倍,有剂量校正的缓释剂型组的C_0为普通剂型的60%,其余药动学参数差异无显著性;缓释剂型中慢代谢型组的C_(max)、AUC_(0~24 h)和C_0分别为快代谢型组的1.75、1.96、2.49倍(无剂量校正)以及1.80、2.34和2.64倍(有剂量校正);缓释剂型组的C_0与AUC_(0~24 h)的相关性良好。结论他克莫司普通剂型转换至缓释剂型时应该注意上调给药剂量,同时缓释剂型应结合CYP3A5的基因型检测,确保C_0值在治疗窗范围内。     

肾移植受者CYP3A5基因多态性对他可莫司代谢的影响

目的研究CYP3A基因多态性对肾移植受者他可莫司代谢的影响。方法50例肾移植受者采用FK506＋霉酚酸酯＋强的松三联免疫抑制方案,FK506起始剂量0．15mg／（kg·d）,1w后根据目标血药浓度调整。CYP3A5基因多态性检测采用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）方法,50例肾移植受者分为＊1／＊1型（12例）、＊1／＊3型（16例）、＊3／＊3型（22例）共3组。比较6个月内FK506的血药浓度／剂量比。结果 肾移植术后7天、1月、3月、6月＊3／＊3型患者FK506的血药浓度／剂量比显著高于＊1／＊1型和＊1／＊3型（P〈0．05）。结论由于CYP3A5基因多态性影响,＊1／＊1型组的患者早期难以达到有效FK506目标血药浓度,应该提高该组患者的起始用药剂量,根据CYP3A5基因多态性作为FK506个体化用药的依据,可以减少早期急性排斥反应,提高肾移植的临床效果。