细胞色素P450 2C19基因多态性对雷贝拉唑抑酸效应的影响

背景:研究表明细胞色素P4502C19(CYP2C19)参与质子泵抑制剂(PPIs)的代谢,是奥美拉唑、兰索拉唑和泮托拉唑的主要代谢途径。而雷贝拉唑主要经非酶途径代谢,只有一小部分经CYP2C19途径代谢。目的:研究CYP2C19基因多态性(表型多态性)对雷贝拉唑抑酸效应的影响,阐明用雷贝拉唑治疗酸相关疾病时区分CYP2C19基因型的必要性。方法:36名健康志愿者参与本研究。采用聚合酶链反应鄄限制性片段长度多态性(PCR鄄RFLP)方法确定CYP2C19基因型,据此将志愿者分为CYP2C19强代谢型组(n=24)和弱代谢型组(n=12)。给予两组志愿者雷贝拉唑20mg单剂量口服,动态监测24h胃内pH。结果:CYP2C19强代谢型组与弱代谢型组胃内pH>3的抑酸起效时间无显著差异(177.50min±20.09min对146.65min±12.30min,P>0.05)。强代谢型组24h胃内pH>4的总时间(769.67min±107.50min)和时间百分比(61.6%±9.4%)与弱代谢型组(912.00min±87.67min和65.7%±6.4%)相比差异无显著性(P>0.05);两组24h胃内pH的中位数和均值差异亦无显著性(4.92±1.53对5.30±0.33和4.97±0.72对4.97±0.21,P>0.05)。结论:雷贝拉唑在不同CYP2C19基因型志愿者中的抑酸效应相同,提示雷贝拉唑治疗酸相关疾病的疗效不依赖于CYP2C19基因多态性。     

细胞色素P4502C19基因多态性与肺癌易感性的关系

研究证明致癌物代谢酶的遗传多态性在决定环境致癌物的效应时起着关键性的作用,ＣＹＰ酶体系中许多酶参与致癌物的代谢,其基因的多态性与肿瘤的易感性有关,如ＣＹＰ２Ｄ６、ＣＹＰ１Ａ１、ＣＹＰ２Ｅ１等。１９９４年,ｄｅＭｏｒａｉｓ等发现细胞色素Ｐ４５０２Ｃ１９（ＣＹＰ２Ｃ１９）等位基因的两个突变位点：ＣＹＰ２Ｃ１９ｍ１和ＣＹＰ２Ｃ１９ｍ２,并证明ＣＹＰ２Ｃ１９基因的多态性与ＣＹＰ２Ｃ１９酶活性的多态性有关［１］。我们应用等位基因特异扩增法（ＡＳＡ）原理,建立了ＣＹＰ２Ｃ１９等位基因分型法［２,３］,并对７…     

根除幽门螺杆菌疗效与细胞色素氧化酶P450 2C19基因多态性的关系

目的 比较雷贝拉唑与奥美拉唑三联疗法根除幽门螺杆菌（Hp）的疗效与细胞色素氧化酶P4502 C19（CYP 2C19）基因多态性的关系。方法 采用随机、对照研究方法，将169例因消化不良症状接受常规胃镜检查确诊为慢性胃炎且Hp阳性的连续患者分人两组：雷贝拉唑三联疗法组（RAC组85例）和奥美拉唑三联疗法组（OAC组84例）。Hp诊断依靠组织病理学检查并参考快速尿素酶试验、血清Hp抗体检测结果。RAC组、OAC组均给予三联治疗：RAC组：雷贝拉唑10mg，OAC组：奥美拉唑20mg，两组均联用羟氨苄青霉素1000mg和克拉霉素500mg，全部药物每日2次，疗程7d。采用聚合酶链式反应结合限制性内切酶技术（PCR-RFLP），进行CYP 2C19基因型分析，治疗结束后第28天用^14C尿素呼气实验检测Hp根除疗效。结果 160例完成治疗方案，RAC组及OAC组的Hp根除率按PP分析及ITT分析均无统计学差异（P〉0．05）。根据CYP 2C19基因型分析，160例中，弱代谢型（PM）、中间代谢型（IM）及强代谢型（EM）的Hp根除率分别为95．5%（21／22）、85．9％（73／85）和67．9％（36／53）。PM型及IM型的Hp根除率均显著高于EM型（P〈0．05），而PM型与IM型间差异无统计学意义（P〉0．05）。RAC组中，各基因型的Hp根除率差异无统计学意义（P〉0．05）。OAC组中。IM型与EM型间（P〈0．01）及EM型与PM型间（P〈0．05）差异均有统计学意义。结论 雷贝拉唑与奥美拉唑两种三联疗法均能有效根除Hp。总疗效差异无统计学意义。雷贝拉唑三联疗法疗效较稳定，个体间差异小。PM型及IM型的Hp根除率均较EM型为高。     

CYP2C19与质子泵抑制剂

随着对肝脏微粒体细胞色素P450(CYP)基因变异研究的不断深入，人们发现CYP2C19基因多态性与质子泵抑制剂的药动学、药效学等方面密切相关，并影响临床治疗，此文对两者之间的关系作一综述。     

细胞色素P450 2C19多态性与对氯吡格雷的反应性研究进展

氯吡格雷是一种无活性的前体药物,进入体内后需要通过细胞色素P450（主要是细胞色素P450 2C19即CYP2C19）氧化为活性代谢物而发挥其抗血小板作用。越来越多的研究发现CYP2C19某些基因多态性（主要是细胞色素P450＊2）与氯吡格雷的活性代谢产物减少,血小板抑制程度减轻,及主要不良心血管事件及支架内血栓增加有关。现就细胞色素P450多态性对氯吡格雷的药代动力学、药效动力学与临床终点事件的影响,及对细胞色素P450等位基因携带者的处理最新研究进展进行综述。     

细胞色素P450基因多态性与宫颈癌易感性关系的研究进展

在宫颈癌的发生过程中,人乳头瘤病毒感染宫颈是必要的条件。对肿瘤的易感性则影响最终的疾病结局。细胞色素P450(CYP450)是体内重要的代谢酶,与许多前致癌物和致癌物的活化有关,是目前肿瘤研究的热点之一。基因多态性是遗传易感性的物质基础,深入研究CYP450在宫颈癌肿瘤发生、发展的机制及遗传多态性与肿瘤易感性的关系,使易感患者脱离不良环境因素,可将宫颈癌控制在预防阶段。     

细胞色素P450 2C19*2基因多态性联合钙通道阻滞剂与冠状动脉支架内血栓形成的相关性

目的:探讨经皮冠状动脉介入术(PCI)后接受氯吡格雷治疗的患者中,细胞色素P450 2C19(CYP2C19)*2基因多态性(681A)与支架内血栓形成的相关性,以及服用钙通道阻滞剂(CCBs)与支架内血栓形成的相关性。方法:检测1 738例冠心病PCI术后患者的CYP2C19基因多态性,并将这些患者分为CCBs组和非CCBs组,采用比浊法检测二磷酸腺苷(ADP)途径诱导的血小板最大聚集率(MPAR),比较两组患者MPAR及支架内血栓形成率的差异。结果:19例(2.4%)CYP2C19*2基因型的患者(包括CYP2C19*2/*2或*1/*2)和7例(0.75%)基因型为CYP2C19*1/*1的患者发生了明确的支架内血栓形成;CYP2C19*2基因型患者支架内血栓形成的发生率明显高于CYP2C19野生型纯合子患者(CYP2C19*1/*1)(风险比为4.26,95%可信区间为1.28～9.22,P<0.05);基因型为CYP2C19*1/*1的患者发生支架内血栓形成的风险最低,而基因型为CYP2C19*2/*2的患者支架内血栓形成的风险最高(风险比为0.568,95%可信区间为0.308～2.070,P<0.01);CCBs组和非CCBs组MPAR及支架内血栓形成率差异无统计学意义。结论:PCI术后接受氯吡格雷治疗的冠心病患者中,CYP2C19*2基因型患者支架内血栓形成的风险增加,而服用CCBs不会导致氯吡格雷抗血小板聚集作用减弱以及支架内血栓形成事件增加。     

细胞色素P450 2E1基因多态性与食管癌的易感性

细胞色素。P450 2E1(CYP2E1)基因编码的氧化酶是环境前致癌物活化的关键酶之一。研究表明，CYP2E1基因RsaI、DraI位点的多态性可影响该基因的表达，从而影响肿瘤的发生。为此，我们用PCR-限制性片段长度多态性法研究食管癌非高发区CYP2E1基因RsaI、DraI位点的基因型，并探讨各基因型、吸烟、饮酒以及各基因型与吸烟和饮酒的交互作用与食管癌易感性的关系。     

精神药物与细胞色素P450 2C酶

阿米替林、氯丙咪嗪、西酞普兰、艾司西酞普兰、度洛西汀、吗氯贝胺和苯妥英经2C19酶代谢,氟伏沙明、氟西汀、帕罗西汀和丙戊酸钠抑制2C19酶,理论上升高这些药物血浓度,而卡马西平和苯妥英抑制2C19酶,理论上降低这些药物血浓度。丙戊酸钠、苯妥英、阿戈美拉汀经2C9酶代谢,氟西汀、氟伏沙明、帕罗西汀和丙戊酸钠抑制2C9酶,理论上增加这些药物血浓度,而卡马西平和巴比妥酸盐诱导2C9酶,降低这些药物血浓度。     

细胞色素P4502C19基因多态性对NSTE-ACS患者血小板反应性及临床预后的影响

目的探讨细胞色素P450 2C19(CYP2C19)基因多态性与非ST段抬高急性冠脉综合征(NSTE-ACS)患者服用氯吡格雷后血小板反应性的关系,并评价不同基因型对NSTE-ACS患者预后的影响。方法连续纳入接受PCI治疗的NSTE-ACS患者462例,依据CYP2C19基因型,分为快代谢型(CYP2C19*1/*1)、中间代谢型(CYP2C19*1/*2、CYP2C19*1/*3)和慢代谢型(CYP2C19*2/*2、CYP2C19*2/*3)。采用流式细胞术测定的血小板反应指数(PRI)和光比浊法测定的血小板聚集率(PAG)两种方法来评价患者在服用氯吡格雷后的血小板反应性。全部患者随访2年,以全因死亡、支架内再狭窄、急性支架内血栓形成、再发急性心肌梗死定义为主要不良心血管事件(MACE),采用Cox回归分析评价CYP2C19基因型、PRI、PAG等指标对MACE的预测能力。结果快代谢型158例、中间代谢型246例、慢代谢型58例。快代谢型、中间代谢型、慢代谢型PRI分别为48.6±10.5、56.7±12.6、65.3±11.4,PAG分别为67.4±8.5、71.9±8.2、7...     

Influence of cytochrome P450 2C19 genetic polymorphism and dosage of rabeprazole on accuracy of proton-pump inhibitor testing in Chinese patients with gastroesophageal reflux disease

BACKGROUND AND AIM: To evaluate the optimal dosage of rabeprazole for proton-pump inhibitor (PPI) testing of gastroesophageal reflux disease (GERD) and to test the influence of cytochrome P450 (CYP) 2C19 polymorphism in a population with a high prevalence of people who metabolize PPI poorly. METHODS: In this randomized, open-label trial, patients with symptoms suggestive of GERD were randomized to receive a 2-week test with 20- or 40-mg rabeprazole after diagnostic endoscopy. Symptom response was assessed with a four-grade daily record; in addition, DNA from peripheral blood leukocytes was genotyped for CYP2C19 polymorphism with the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Of the 164 patients who completed the study, 69 (42.1%) were endoscopically positive for esophagitis; the remaining 95 (57.9%) were diagnosed with endoscopy-negative reflux disease. Based on the best cut-off value for 50% symptom reduction, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detecting erosive esophagitis were 68%, 70%, 66%, 72%, and 69%, respectively, for the 20-mg regimen, and 84%, 71%, 64%, 88%, and 76%, respectively, for the 40-mg regimen, a non-significant difference. Regarding the genotype, 60 (39%) patients had two wild-type alleles, 63 (40.9%) had one variant allele, and 31 (20.1%) had two variant CYP2C19 alleles. The presence of a variant allele did not alter the diagnostic efficacy of PPI testing. CONCLUSIONS: Both dose levels of rabeprazole proved efficacious in the diagnosis of GERD. Various measures of test accuracy were unrelated to the status of the CYP2C19 genotype.     

Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans

AIM: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups. METHODS: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography. RESULTS: The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole. CONCLUSION: In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.     

细胞色素P450 2E1基因与胃癌易感性关系

目的：探讨与致癌物亚硝胺代谢激活有关的细胞色素P450（CYP）2E1基因多型性与胃癌易感性关系。方法：采用病例对照分子流行病学研究方法，以聚合酶链反应－限制性片段长度多态性（PCR－RFLP）技术，对福建省长乐市92例胃癌病例和92例正常对照的CYP2E1基因型进行检测。结果：在病例组和对照组中，RsaI识别的野生型（C1／C1）基因频率分别为66．3％和48．89％；DraI识别的野生型（CC）基因频率分别为57．6％和41．3％，差异均具有显著性（P＜0．05），即具有RsaI识别的C1／C1基因型或DraI识别的CC基因型个体，患胃癌的危险性大（OR值分别为2．06和1．93）。联合分析表明，这两个位点的基因型存在某种程度的联合作用（P＜0．05）。结论：CYP2E1基因多型性可能与胃癌易感性有关。     

细胞色素P4502C9-Leu359基因变异与华法林抗凝治疗研究

目的　研究细胞色素 P45 0 2 C9-Leu3 5 9基因变异与华法林耐量和抗凝出血并发症的关系。方法　对5 5例心脏瓣膜置换术后长期服用华法林的病人 ,根据华法林用量大小分组 :华法林用量 /体表面积≤ 1 .5 mgm2 -1为 G1组 ,>1 .5 mgm2 -1为 G2组。利用 PCR-RFLP法进行 CYP2 C9Leu3 5 9基因测定 ,同时随访出血并发症 ,进行比较分析。结果　G1组 CYP2 C9Leu3 5 9突变明显高于 G2组 (P<0 .0 5 ) ;G1组出血发生率明显高于 G2组 (P<0 .0 5 )。结论CYP2 C9Leu3 5 9突变者 ,华法林耐受剂量小 ;华法林耐量小者 ,容易出血。选择 CYP2 C9Leu3 5 9作为基因监测有助于预测华法林的用量     

Cytochrome P450 2C19 enzyme,Cytochrome P450 2C9 enzyme,and Cytochrome P450 2D6 enzyme allelic variants and its possible effect on drug metabolism: A retrospective study

The objective of the present study was to assess the allelic variations of Cytochrome P450 (CYP) enzymes Cytochrome P450 2C19 (CYP2C19), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) as they play a major role in drug metabolism. The interindividual genetic variabilities of these enzymes can account for different responsiveness as well as concentration fluctuations for a particular drug.During the period of 2017 to 2018 a total of 54 patients have received pharmacogenetic testing at the Department of Genetics and Molecular Medicine at Kaunas Clinics. According to the genotype-metabolic phenotypes of CYP2C19, CYP2D6, CYP2C9 enzymes patients were classified according to the guidelines by Clinical Pharmacogenetics Implementation Consortium (CPIC): normal metabolizers (NMs), intermediate metabolizers (IMs), rapid metabolizers (RMs), ultrarapid metabolizers (UMs), and poor metabolizers (PMs).CYP2C19 enzyme allelic distribution: 18 patients (33.33%) with ∗1/∗1 genotype were NMs; 14 patients (25.93%) with ∗1/∗2; ∗2/∗17 genotypes were classified as IMs; 15 patients (27.78%) possessed ∗1/∗17 genotype and were RMs; 4 patients (7.4%) had ∗17/∗17 genotype with increased enzyme activity compared with RMs, were classified as UMs; 3 patients (5.56%) had ∗2/∗2 genotype and were marked as PMs. CYP2D6 enzyme allelic distribution: 26 patients (48.148%) contained ∗1/∗1,∗2/∗2,∗1/∗2,∗1/∗41,∗2/∗41 genotypes with normal enzymatic function so were accounted as NMs; 21 patients (38.89%) with ∗1/∗5, ∗2/∗4, ∗10/∗41, ∗1/∗4, ∗1/∗3, ∗2/∗5, ∗2/∗4, ∗2/∗6 genotypes were accounted as IMs; 2 patients (3.7%) possessed ∗2XN genotype and were accounted as UMs and 5 patients (9.26%) possessed ∗4/∗5,∗4/∗10,∗4/∗9,∗4/∗41 genotypes and had non-functional enzymatic activity so were accounted as PMs; CYP2C9 enzyme allelic distribution: 44 patients (81.48%) with∗1/∗1 genotype were NMs; 10 patients (18.52%) with ∗1/∗2;∗1/∗3 genotypes were IMs.The results of our study indicate that deviations from the normal enzymatic activity is common amongst Lithuanian people and combinatory genotyping of CYP2D6, CYP2C9, and CYP2C19 has to be promoted as an advanced method because of most commonly prescribed medicines like analgesics, antihypertensive, antidepressants are metabolized by multiple pathways involving enzymes in the CYP450 family.     

细胞色素P450基因多态性对他克莫司临床应用的影响

肝移植是终末期肝病患者最有效的治疗手段,而免疫抑制剂的应用是影响患者移植术后长期存活的关键。本文介绍了最常用的免疫抑制剂——他克莫司的作用机制,以及细胞色素P450基因多态性对他克莫司应用影响的最新研究进展。为临床上合理使用他克莫司,减少相关并发症的发生,提高肝移植患者的长期生存率提供参考。     

细胞色素P450 2C19基因多态性与原发性肝细胞癌的相关性研究

细胞色素P450（CYP）2C19代谢美芬妥英的酶活性在人群中呈快代谢型和慢代谢型二态分布。突变型等位基因是CYP2C19基因多态性的分子生物学基础。目的：对原发性肝细胞癌（HCC）患者的CYP2C19等位基因进行基因分型．探讨CYP2C19基因多态性与原发性HCC的关系。方法：纳入48例原发性HCC患者和88名健康对照者。设计相应引物，以聚合酶链反应．限制性片段长度多态性（PCR-RFLP）方法检测CYP2C19ml和CYP2C19m2突变型等位基因．对两组基因多态性进行分析比较。结果：HCC组CYP2C19慢代谢型（ml／m1和ml／m2）发生率为25．0％（12例）．与健康对照组的11．4％（10例）相比差异有统计学意义（P〈0．05，OR=3116，95％CI：1140—7113）。结论：CYP2C19慢代谢型与原发性HCC之间存在相关性，可能增加人群对HCC的易感性。     

细胞色素P4502C19基因多态性对介入术后服用氯吡格雷冠心病患者临床预后的影响

目的 探讨细胞色素P450(CYP)2C19 681G>A基因多态性对经皮冠状动脉介入治疗(PCI)后服用氯吡格雷冠心病患者临床预后的影响.方法 入选2009年1月1日至8月31日拟行PCI,并在术后服用氯吡格雷12个月的冠心病患者267例.采用MassARRAY时间飞行质谱检测入选患者CYP2C19 681G>A位点.按基因型不同,将患者分为CYP2C19*1/*1组 (n=130)和CYP2C19*2携带组(n=137).观察两组患者术后1年心绞痛复发、紧急血运重建术、急性心肌梗死、支架内血栓形成和死亡的发生情况.结果 两组患者的临床基本资料差异无统计学意义(P>0.05).PCI术后1年,CYP2C19*2携带组紧急血运重建术和联合终点事件的发生率均高于CYP2C19*1/*1组 (分别为7.3%比1.5%和8.0%比2.3%,P均<0.05).两组患者心绞痛复发、急性心肌梗死、支架内血栓形成和死亡的发生率差异均无统计学意义(P均>0.05).CYP2C19*2携带组随访1年的累积联合终点事件发生风险是CYP2C19*1/*1组的3.59倍(HR=3.59,95%CI:1.02～12.87,P<0.05).结论 CYP2C19 681G>A基因多态性可能是影响PCI术后服用氯吡格雷冠心病患者临床预后的因素.

Abstract：

Objective To investigate the impact of cytochrome P450 (CYP) 2C19 681G>A polymorphism on long-term prognosis of clopidogrel-treated Chinese patients after percutaneous coronary intervention (PCI).Methods Between January 1, 2009 and August 31,2009, 267 patients with coronary heart disease who received PCI and treated with clopidogrel for 12 months were enrolled. CYP2C19*2 was detected by MALDI-TOF MS and patients were grouped into CYP2C19*1/*1(n=130) and CYP2C19*2 carriers group (n=137). Follow-up was 12 months. The primary endpoint was angina recurrence, urgent coronary revascularization, acute myocardial infarction, stent thrombosis, death and the combined end points. Results Baseline data were similar between two groups (P>0.05).Urgent coronary revascularization and the combined end points occurred more frequently in CYP2C19*2 carriers than in CYP2C19*1/*1 patients (7.3% vs. 1.5% and 8.0% vs. 2.3% respectively,all P<0.05). But incidence of angina recurrence, acute myocardial infarction, stent thrombosis and death was similar between two groups (all P>0.05).Hazard risk of 1 year cumulative survival of CYP2C19*2 carriers group was significantly higher than CYP2C19*1/*1 group after PCI (HR=3.59, 95%CI: 1.02-12.87, P<0.05). Conclusion CYP2C19 681G>A polymorphism is a determinant of prognosis in coronary heart disease patients receiving chronic clopidogrel treatment after PCI.