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1.
细胞色素氧化酶CYP2C9的研究进展   总被引:14,自引:0,他引:14  
CYP2C9是人类肝脏中含量丰富的一种CYP450酶,它能代谢和/或活化许多种药物、前致癌物、前毒物和致突变剂。CYP2C9基因具有遗传多态性,在人类存在几种等位基因的突变体。本文从基因结构、底物和探针药、影响其活性的因素、遗传多态性的分子机制等方面综述CYP2C9的研究进展。  相似文献   

2.
Objective Several reports of CYP2C genetic polymorphism demonstrate its potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy. We estimated the distribution of CYP2C9 and CYP2C19 common variants in the Bolivian population (a South American population), and compared these data with those from Asian, African, Caucasian and Oceanian populations.Methods Genomic DNA was obtained from 778 unrelated healthy volunteers from Bolivia. The genotypic status of CYP2C9 and CYP2C19 was determined by means of polymerase chain reaction–restriction fragment length polymorphism.Results Allelic and genotypic frequencies of CYP2C9 and CYP2C19 were determined for the Bolivian population, and comparison of the data with other ethnic groups revealed a lower CYP2C9*2 frequency (4.8%) than in Caucasians, but a higher frequency than in Asians; frequencies of CYP2C9*3 (3.0%) and CYP2C9 (0.4%) poor metabolizers (PMs) were similar to those seen in Asian populations. Frequencies of CYP2C19*2 (7.8%), CYP2C19*3 (0.1%), and CYP2C19 PMs (1.0%) in the Bolivian population were for the most part lower than in Caucasian, Asian, Oceanian and African populations.Conclusion This is the first study to investigate a South American population for genetic polymorphism in the CYP2C subfamily. The Bolivian population differs from most other ethnic groups in the incidence of CYP2C9 and CYP2C19 common variants that might be influenced by its admixture characteristics.  相似文献   

3.
目的:探讨中国汉族人群相关基因多态性以及患者临床因素对华法林剂量的影响。方法:采用限制性片段长度多态性技术和碱基淬灭探针技术,检测197名心脏机械瓣膜置换术后患者的VKORC1rs9923231、CYP2C9rs1057910以及CYP4F2rs2108622单核苷酸多态性,结合患者临床特征,分析对华法林剂量的影响。结果:VKORC1rs9923231、CYP2C9rs1057910和CYP4F2rs2108622基因多态性及年龄、体质量对华法林剂量的影响在统计学上有显著性差异(P<0.05),并解释了45.2%的华法林剂量差异。结论:中国汉族人群VKORC1rs9923231、CYP2C9rs1057910和CYP4F2rs2108622以及体质量和年龄都是影响华法林剂量的因素。  相似文献   

4.
VKORC1、CYP2C9、CYP4F2、EPHX1基因多态性对华法林剂量的影响   总被引:1,自引:0,他引:1  
目的:探讨中国汉族人群VKORC1、CYP2C9、CYP4F2和EPHX1基因多态性对华法林剂量的影响。方法:采用限制性片段多态性技术和碱基淬灭探针技术检测197名心脏机械瓣膜置换术后患者的VKO RC1-1639G>A、CYP2C9 1075A>C、CYP4F2 rs2108622和EPHX1 rs2292566的基因多态性,结合患者的临床特征,分析各因素对华法林剂量的影响。结果:VKO RC1-1639G>A、CYP2C9 1075A>C、CYP4F2 rs2108622、EPHX1 rs2292566基因多态性以及体重和年龄分别解释了30.2%、7.0%、2.8%、3.6%、1.9%和1.7%的华法林个体剂量差异,多因素联合可解释46.7%的华法林个体剂量差异。结论:VKORC1-1639G>A和CYP2C9 1075A>C基因多态性是影响华法林稳定剂量重要的遗传因素;CYP4F2 rs2108622和EPHX1 rs2292566基因多态性以及年龄、体重对华法林的稳定剂量有影响,但较小。  相似文献   

5.
AIM: Rabeprazole is metabolized to some extent by CYP2C19. The purpose of this study was to elucidate the pharmacokinetics of each rabeprazole enantiomer in three different CYP2C19 genotype groups. METHODS: Twenty-four healthy subjects, of whom each each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs) and poor metabolizers (PMs) for CYP2C19, participated in our study. After a single oral dose of 20 mg of racemic rabeprazole, the plasma concentrations of the rabeprazole enantiomers were measured over the course of 24 h. RESULTS: The area under the plasma concentration-time curves (AUC) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.8-, 2.2- and 2.4-fold, respectively, greater than those of (S)-rabeprazole; the relative AUC ratios of (R)- and (S)-rabeprazole in homEMs, hetEMs and PMs were 1:1.1:2.1 and 1:0.9:1.5, respectively. The mean maximum plasma concentrations (Cmax) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.7-, 1.9- and 1.8-fold higher, respectively, than those of the corresponding (S)-enantiomer (P<0.05). There was no difference between homEMs and PMs in the elimination half-life of (S)-rabeprazole, whereas the elimination half-life of (R)-rabeprazole was significantly longer in PMs than in homEMs [1.7 h (1.4, 2.0) (mean (95% confidence interval)]vs. 0.8 h (0.6, 1.0), respectively, P<0.0001). CONCLUSIONS: (R)-Rabeprazole disposition was influenced to a greater degree by CYP2C19 genetic polymorphisms than was that of (S)-rabeprazole. The effect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole was less than those of lansoprazole and omeprazole.  相似文献   

6.
癫痫患者CYP2C19基因多态性分析   总被引:1,自引:0,他引:1  
目的研究癫痫患者CYP2C19基因多态性。方法运用PCR-RFLP方法对67例应用丙戊酸的癫痫患者的CYP2C19*2和CYP2C19*3位点进行基因型分析。结果两个位点共有5种基因型组合:681GG-636GG、681GA-636GG、681GG-636GA、681AA-636GG、681GA-636GA。快代谢者(EMs)包括681GG-636GG、681GA-636GG、681GG-636GA基因型,分布频率为86.57%;慢代谢者(PMs)包括681AA-636GG、681GA-636GA基因型,分布频率为13.43%。结论PMs发生率与国内报道相近,CYP2C19基因多态性分析有助于丙戊酸的临床合理应用。。  相似文献   

7.
CYP2C19 is a clinically important enzyme responsible for the metabolism of a number of therapeutic drugs, such as mephenytoin, omeprazole, diazepam, proguanil, propranolol and certain antidepressants. Genetic polymorphisms in this enzyme result in poor metabolizers of these drugs. There are racial differences in the incidence of the poor metabolizer trait, which represents 13-23% of Asians but only 3-5% of Caucasians. In this study, single nucleotide polymorphisms (SNPs) in CYP2C19 were identified by direct sequencing of genomic DNA from 92 individuals from three different racial groups of varied ethnic background, including Caucasians, Asians and blacks. Several new alleles were identified containing the coding changes Arg114 His (CYP2C19*9), Pro227 Leu (CYP2C19*10), Arg150 His (CYP2C19*11), stop491 Cys (CYP2C19*12), Arg410 Cys (CYP2C19*13), Leu17 Pro (CYP2C19*14) and Ile19 Leu (CYP2C19*15). When expressed in a bacterial cDNA expression system, CYP2C19*9 exhibited a modest decrease in the V(max) for 4'-hydroxylation of -mephenytoin, and no alteration in its affinity for reductase. CYP2C19*10 exhibited a dramatically higher K(m) and lower V(max) for mephenytoin. CYP2C19*12was unstable and expressed poorly in a bacterial cDNA expression system. Clinical studies will be required to confirm whether this allele is defective in vivo. CYP2C19*9, CYP2C19*10 and CYP2C19*12 all occurred in African-Americans, or individuals of African descent, and represent new potentially defective alleles of CYP2C19 which are predicted to alter risk of these populations to clinically important drugs.  相似文献   

8.
Many administered drugs are first activated by phase I drug-metabolizing enzymes, such as cytochrome P450 (CYP), and then conjugated with ligands such as UDPGA, PAPS, and glutathione by phase II drug-metabolizing enzymes, and finally excreted by transporters. There are some defective activity mutants due to CYP polymorphisms. In these cases, drugs are not metabolized [poor metabolizer (PM)], the high drug levels in blood are maintained, and toxic effects appear in the patients. To clarify the ratio of PMs, in the general population, it is necessary to estimate the drug level to not only prevent toxic reactions, but also to provide more efficient drug therapies, according to their polymorphic information about CYPs. In Caucasians and Asians, PM and allele frequency levels of CYPs (CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) are summarized from previous findings. In Caucasians, high PM ratios (7%) of CYP2D6 deriving from the high frequency of CYP2D6*4 and CYP2D6*5, and 2% CYP2C19 from CYP2C19*2, were found. Meanwhile, in Asians, high PM ratios (19%) of CYP2C19 from high frequencies of CYP2C19*2 and CYP2C19*3, and 2% to 4% CYP2A6 from CYP2A6*4, were found. In both populations, the PM frequencies of the CYP3A4 of major drug-metabolizing CYP and CYP2C9 were low.  相似文献   

9.
Effects of smoking and cytochrome P450 2C19 (CYP2C19) status on the single dose kinetics of zotepine and pharmacokinetic interaction between zotopine and diazepam were investigated. In 14 healthy volunteers, the pharmacokinetics of zotepine after a single oral 25 mg dose were compared between eight smokers and six non-smokers, or between seven extensive metabolizers (EMs) and seven poor metabolizers (PMs) ofS-mephenytoin. There was no significant difference in any pharmacokinetic parameters between smokers and non-smokers, or between the EM and PM groups. In 17 patients treated with zotepine 80–340 mg/day, intra-individual changes in plasma concentrations of zotepine caused by coadministration of diazepam 10 mg/day for 2 weeks were examined. Plasma concentrations of zotepine were significantly increased after coadministration of diazepam (P<0.05). Consequently, it is suggested that neither smoking nor CYP2C19 status affects the metabolism of zotepine. The elevation in plasma concentrations of zotepine after coadministration of diazepam may be a result of competitive inhibition of zotepine metabolism by diazepam via other isoenzyme than CYP2C19, e.g., CYP3A4.  相似文献   

10.
The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.  相似文献   

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