CYP450基因多态性对抗肿瘤药物影响的研究进展

药物代谢酶的差异是药物个体疗效和副作用差异的决定因素之一。作为I相药物代谢酶,细胞色素P450酶及其编码基因在不同种群、不同个体之间均存在着差异和突变,这种基因的多态性导致了肿瘤患者对抗肿瘤药物的敏感性及预后的不同,本文就CYP家族的基因多态性对抗肿瘤药物的药动学、药效学及不良反应的影响进行综述,以期为抗肿瘤药物的个体化给药提供参考。     

基因组学相关基因遗传多态性对他汀类药物代谢、转运及药效的影响

他汀类药物为羟甲戊二酰铺酶A(HMG-CoA)还原酶抑制剂,可降低心血管疾病患者的发病率及死亡率,然而此类药物有发生肌病等不良反应的风险,因此,研究导致该类药物个体差异大的原因具有重大意义。通过研究CYP450酶、药物转运体(OATP1B1、ABCG2)、药效基因(APOE、HMG-CoA还原酶)的基因多态性对他汀类药物代谢、转运及药效的影响,以期为指导他汀类的临床用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

CYP2C19基因多态性对药物代谢的影响及其个体化用药

CYP2C19是一种重要的药物代谢酶,参与多种药物的体内代谢。该酶的活性在不同个体和种族之间存在着显著的差异。本文综述了CYP2C19酶的基因多态性对药物代谢的影响,以期为指导临床合理用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正的实现个体化用药。     

CYP3A4基因多态性对药物代谢及其个体化给药的影响

CYP3A4是一种重要的药物代谢酶,参与多种药物的体内代谢,该酶的活性在不同的体内,种族和联用药物之间存在着明显的差异。本文综述了CYP3A4酶的基因多态性对药物代谢的影响,以期为指导临床合理用药打下理论基础,确保临床合理用药的安全性和有效性。     

药物基因多态性与个体化用药的研究进展

［摘要］药物的安全性、有效性和可控性是评价药物是否为好药的评判标准.但是,传统的药物使用模式是一种基于某一种族、某一地区的统计学意义上的判断.随着新理论、新技术的出现,使人们认识到了需要有更新颖的模式来评判药物.该文讨论了传统模式缺陷机制,分析了目前的研究现状,并且探讨了新的基因为导向的个体化临床用药模式,以及就此模式所产生的临床意义.     

CYP450氧化还原酶基因多态性的临床研究进展

CYP450氧化还原酶（POR）是所有肝微粒体的细胞色素P450氧化酶（CYP450）的唯一电子供体,负责甾醇激素、胆固醇、胆酸、维生素以及临床上超过80％药物的氧化代谢。POR本身具有高度的多态性,国内外报道显示POR基因的突变可使其本身活性或它与CYP450酶之间的相互作用发生改变,致使它与临床某些疾病的发生及某些药物体内代谢活性的改变密切相关。而POR基因多态性与CYP介导的药物代谢之间存在着CYP酶种类及底物的特异性,且国内相关研究相对较少。因此,我们通过对近年来POR基因多态性的临床研究进展进行综述,为今后相关研究及临床药物的个体化治疗提供参考。     

不同基因多态性对他汀类药物影响的研究进展

他汀类药物是目前临床应用最广泛的降脂药物,为心血管疾病的一级、二级预防的基石。他汀类药物为羟基-甲基戊二酰辅酶A还原酶抑制剂,可以显著降低血清总胆固醇、低密度脂蛋白胆固醇、三酰甘油水平,同时可轻度升高高密度脂蛋白胆固醇水平。目前研究的参与他汀类药物代谢的酶、转运蛋白、受体等基因多态性对他汀类药物安全性、不良反应有重要影响。阐述遗传因素载脂蛋白E、SLCO1B1、ATP结合盒转运蛋白B1、ABCG2、CYP、3-羟基-3-甲基戊二酰辅酶A还原酶基因等相关基因多态性对他汀类药物疗效和安全性的影响,为他汀类药物的个体化用药提供参考依据。     

基于基因多态性不同位点的检测结果对阿片类药物给药剂量的评价

大部分基因多态性对于阿片类镇痛药物使用剂量有一定程度的影响,从药物基因组学角度分析影响阿片类药物的镇痛作用,主要包括阿片样物质肽受体、效应分子、代谢酶和转运蛋白等影响因素的基因多态性,以及这些基因多态性带来的关于药物给药剂量以及不良反应发生的差异.系统性地研究影响阿片类镇痛药物使用剂量的各种基因的多态性,并进行合理分析...     

基因多态性对他莫昔芬治疗乳腺癌的影响与个体化用药进展

他莫昔芬(Tamoxifen)为人工合成的非胆固醇类抗雌激素药物,被广泛用于临床的雌激素受体(estrogen receptor,ER)阳性乳腺癌患者防治,有显著的个体差异。他莫昔芬经肝药酶CYP2D6、CYP3A4/5和SULT1A1等调节,这些基因的多态性现象是,导致临床治疗个体化差异的重要原因。该文就近年来药物基因多态性对他莫昔芬在乳腺癌治疗的作用与个体化用药进展情况综述。     

细胞色素P450(CYP450)遗传多态性研究进展

近年来对CYP450基因型和表型相关性的研究越来越受到重视,从临床合理用药方面来说,人们希望利用基因型分析来了解个体中药物代谢酶的活性,期望既能提高药物治疗水平同时又降低不良反应的发生;从新药研发角度来说,研究药物的代谢酶CYP450的功能能够指导新药的设计、筛选及优化。该文通过查阅国内外相关文献综述了近年来关于CYP450遗传多态性研究的进展,分别介绍了CYP2C19、CYP2C9、CYP3A4、CYP2D6、CYP1A2和CYP2E1这6种主要的药物代谢酶。研究CYP450对新药设计、筛选、评价及优化有重要意义。     

细胞色素P450酶基因多态性的研究进展及临床意义

细胞色素P450（cytochrome P450,CYP）是重要的药物代谢酶,参与催化多种内源和外源化合物,特别是多种临床药物的生物转化。CYP存在广泛的基因多态性和表型多态性,体现在个体对于各种化合物的代谢存在明显差异。本文综述了CYP的基因多态性、与药物代谢相关的CYP各亚型的特点和临床意义,主要目的是合理解释和预测临床上药物间相互作用和药物不良反应等,为实现临床个体化给药提供科学依据。     

细胞色素P450基因多态性与药物代谢研究进展

细胞色素P450酶(cytochrome P450,CYP450)是参与人类药物代谢过程的重要酶,在肝细胞和小肠上皮细胞的光滑内质网中含量丰富,其主要功能是氧化还原各种内源性物质和外源性物质。CYP450酶参与80%目前应用药物的I相代谢,参与各种激素合成,影响与激素相关的肿瘤疾病发展。CYP450基因和表型存在高度多态性,体现在个体对于各种物质的代谢存在明显差异。本文综述了CYP450的基因多态性、与药物代谢相关的CYP450各亚型特点和临床意义,对发展以指导个体化用药为基础的精准医学具有重要意义。     

细胞色素P450氧化酶基因多态性对药物代谢影响的研究进展

细胞色素P450氧化酶是人体内的一种重要代谢酶,它能代谢和/或活化许多种药物、前致癌物、前毒物和致变剂。细胞色素P450氧化酶的基因具有遗传多态性,在人类存在等位基因的突变体。本文从基因结构、底物和影响其活性的因素、遗传多态性的分子机制等方面综述细胞色素P450氧化酶的研究进展。     

Lipid-lowering response to statins is affected by CYP3A5 polymorphism

Individuals expressing the polymorphic CYP3A5 enzyme might show a more than average efficiency in the metabolism of lovastatin, simvastatin and atorvastatin. We studied whether the expression of CYP3A5 is associated with an impaired lipid-lowering response to statins in 69 Caucasian patients. Lovastatin, simvastatin and atorvastatin were significantly less effective in CYP3A5 expressors than in non-expressors. The mean serum total cholesterol concentration at 1 year was 23% higher (P = 0.0014) and the mean serum low-density lipoprotein cholesterol concentration was 24% higher (P = 0.036) in subjects possessing the CYP3A5*1 allele (CYP3A5 expressors, n = 7) than in subjects homozygous for the CYP3A5*3 allele (non-expressors, n = 39). The mean percentage reduction in serum total cholesterol from baseline was significantly smaller in CYP3A5 expressors than in non-expressors (17% versus 31%, P = 0.026). No association between hypolipidemic efficacy and CYP3A5 polymorphism was observed among 23 subjects taking statins that are not dependent on CYP3A5 (fluvastatin, pravastatin). These findings suggest that CYP3A5 may be a genetic determinant of interindividual differences in response to certain statins.     

The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.

The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2 and CYP2C9*3, differing from the wild-type CYP2C9*1 by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect of CYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9 genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutant CYP2C9 allele (n = 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day; P < 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9 allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.     

细胞色素氧化酶P450及其遗传多态性

细胞色素氧化酶P45 0是药物代谢中的一个重要的酶系。近年来 ,对细胞色素P45 0氧化酶与药物氧化代谢多态性的关系进行了研究。CYP2C19与CYP2D6等在表型和基因型水平上均发现存在氧化代谢多态性 ,并对其分子机制有了深入的了解 ,而CYP2C9,CYP1A1等其他酶可能存在多态性 ,但其分子机制尚不清楚。本文综述了这些P45 0酶的底物 ,种族差异 ,遗传多态性 ,以及其对药物代谢和疾病易感性的影响     

影响他汀类药物降脂治疗的相关基因的多态性及其与高脂血症的关系

目的观察他汀类药物降脂治疗相关的基因多态性位点CYP3A4*1G、CYP3A 5*3、MDRl C3435T、SLC21A6 A388G、SLC21A6 T521C、CYP7Al A-204C及ABCG8 T400K在河南地区的分布及其与高脂血症的关系。方法采用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)和等位基因特异性-聚合酶链式反应(AS-PCR)技术对400名高脂血症病人和320名正常对照者进行基因分型。结果等位基因SLC21A6 A388G、SLC21A6 T521C、CYP3A4*1G、CYP3A5*3、MDR1 C3435T、CYP7A1 A-204C及ABCG8 400K的分布频率在高脂血症病人中分别为72.1%、16.2%、27.9%、73.7%、39.9%、34.7%和12.8%,在正常对照组中分别为71.5%、16.1%、27.4%、74.5%、39.4%、33.3%和7.4%;ABCG8 400K等位基因携带者患高脂血症的风险显著增加(OR=1.870,CI:1.259-2.777,P=0.002)。结论CYP3A5*3、MDR1 C3435T、SLC21A6 A388G、SLC21A6 T521C和ABCG8 T400K基因多态性分布可能存在地区或种族差异,ABCG8 400K等位基因是高脂血症的高风险因素。     

The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement

Clozapine is an atypical antipsychotic drug that is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Smoking is a potent inducer of CYP1A2 enzyme activity, resulting in significant lower clozapine serum concentrations in smokers compared with non-smokers, upon a given dose. Recently, a single nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was reported to affect the inducibility of the enzyme. Because this polymorphism in relation to smoking behaviour may be relevant in treatment with clozapine, we studied the effect of CYP1A2 genotype on clozapine clearance and dose requirement in a group of 80 smoking and non-smoking schizophrenic patients on long-term clozapine therapy. Clozapine serum concentration and CYP1A2 genotype had been determined routinely by high-performance liquid chromatography and polymerase chain reaction analyses, respectively. In smokers, the clozapine serum concentration corrected for dose (C/D ratio) was on average 2.5 times lower compared with non-smokers, indicating an enhanced clearance. The mean required maintenance doses of clozapine for smokers and non-smokers were 382 mg/day and 197 mg/day, respectively (P < 0.01). Neither among smokers, nor among non-smokers mean C/D ratios and daily doses did vary significantly between patients with the different CYP1A2 genotypes. The results show that clozapine clearance and daily dose requirement are strongly associated with smoking behaviour, while the CYP1A2 genetic polymorphism seems to have no significant clinical effect. Dosage adjustment based on smoking behaviour would be of value in order to lower the incidence of non-therapeutic serum drug levels and, consequently, intoxication or inadequate antipsychotic response.