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Sample records for 2d6 substrate activity

  1. QSAR Models for P-450 (2D6) Substrate Activity

    Ringsted, Tine; Nikolov, Nikolai Georgiev; Jensen, Gunde Egeskov;

    2009-01-01

    activity relationship (QSAR) modelling systems. They cross validated (leave-groups-out) with concordances of 71%, 81% and 82%, respectively. Discrete organic European Inventory of Existing Commercial Chemical Substances (EINECS) chemicals were screened to predict an approximate percentage of CYP 2D6...... substrates. These chemicals are potentially present in the environment. The biological importance of the CYP 2D6 and the use of the software mentioned above were discussed....

  2. CYP2D6*1,CYP2D6*10 co-expressed with CYPOR in Bac-to-Bac expression system and activity determination%与CYPOR共表达CYP2D6*1和CYP2D6*10及其代谢活性比较

    钱鸣蓉; 陈静; 刘瑶; 余露山; 陈枢青; 曾苏

    2011-01-01

    FastBac-CYPOR were constructed and transformed into DH10Bac cell to obtain the recombinant Bacmid-CYPOR, Bacmid-CYP2D6 *1 and Bacmid-CYP2D6*10. And then the recombinant CYP2D6 *1 and CYP2D6 *10 virus were obtained by transfecting Sf9. Then homogenate protein activity was determined witb dextromethorphan as substrate. The multiple of infection (MOI) and its ratio of recombinant CYP2D6 virus to CYPOR virus were adjusted by detecting the activity of the homogenate protein. The Km and Vmax are 26.67±2.71 μmol·L-1 (n=3) and 666.7±56.78 pmol·nmol-1(CYP2D6)·min-1 (n=3) for CYP2D6*1 to catalyze dextromethaphan. The Km and Vmax are 111.36±10.89 μmol·L-1 (n=3) and 222.2±20.12 pmol·nmol-1(CYP2D6)·min-1 (n=3) for CYP2D6*10 to catalyze dextromethorphan. There is significant difference between CYP2D6*1 and CYP2D6*10 for Vmax and Km (P<0.01). The clearance ratio of CYP2D6*1 is 25.0 and the clearance ratio of CYP2D6*10 is 2.0. The expressed CYP2D6*1 and CYP2D6*10 are useful tools to screen the metabolism profile of many xenobiotics and endobiotics in vitro, which are benefit to understand individual metabolism difference.

  3. Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis

    Jónsdóttir, Svava Ósk; Ringsted, Tine; Nikolov, Nikolai G.;

    2012-01-01

    This paper presents four new QSAR models for CYP2C9 and CYP2D6 substrate recognition and inhibitor identification based on human clinical data. The models were used to screen a large data set of environmental chemicals for CYP activity, and to analyze the frequency of CYP activity among these...... compounds. A large fraction of these chemicals were found to be CYP active, and thus potentially capable of affecting human physiology. 20% of the compounds within applicability domain of the models were predicted to be CYP2C9 substrates, and 17% to be inhibitors. The corresponding numbers for CYP2D6 were 9......% and 21%. Where the majority of CYP2C9 active compounds were predicted to be both a substrate and an inhibitor at the same time, the CYP2D6 active compounds were primarily predicted to be only inhibitors. It was demonstrated that the models could identify compound classes with a high occurrence of...

  4. The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.

    Bedada, Worku; de Andrés, Fernando; Engidawork, Ephrem; Pohanka, Anton; Beck, Olof; Bertilsson, Leif; Llerena, Adrián; Aklillu, Eleni

    2015-12-01

    The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans. PMID:26444948

  5. The antitussive effect of dextromethorphan in relation to CYP2D6 activity

    Abdul Manap, R; Wright, C E; Gregory, A; Rostami-Hodjegan, A; Meller, S T; Kelm, G R; Lennard, M S; Tucker, G T; Morice, A H

    1999-01-01

    Aims To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P < 0.001). The mean (±s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P < 0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P < 0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 (P = 0.071, −7, +241; P = 0.254, −37, +211; P = 0.187, −29, +219, respectively). Conclusions A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition. PMID

  6. CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers : indications for oral contraceptive-related gender differences

    Tamminga, WJ; Wemer, J; Oosterhuis, B; Wieling, J; Wilffert, B; de Leij, LFMH; de Zeeuw, RA; Jonkman, JHG

    1999-01-01

    Objective: We examined a large database containing results on CYP2D6 and CYP2C19 activity of 4301 Dutch volunteers phenotyped in the context of various clinical pharmacology studies. Methods: The subjects were given 22 mg dextromethorphan, 100 mg mephenytoin and 200 mg caffeine. For CYP2D6, the dext

  7. New aQTL SNPs for the CYP2D6 Identified by a Novel Mediation Analysis of Genome-Wide SNP Arrays, Gene Expression Arrays, and CYP2D6 Activity

    Guanglong Jiang

    2013-01-01

    Full Text Available Background. The genome-wide association studies (GWAS have been successful during the last few years. A key challenge is that the interpretation of the results is not straightforward, especially for transacting SNPs. Integration of transcriptome data into GWAS may provide clues elucidating the mechanisms by which a genetic variant leads to a disease. Methods. Here, we developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTL driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. Results. 389,573 and 1,214,416 SNP-transcript-CYP2D6 activity trios are found strongly associated (P<10-5, FDR=16.6% and 11.7% for two different genotype platforms, namely, Affymetrix and Illumina, respectively. The majority of eQTLs are trans-SNPs. A single polymorphism leads to widespread downstream changes in the expression of distant genes by affecting major regulators or transcription factors (TFs, which would be visible as an eQTL hotspot and can lead to large and consistent biological effects. Overlapped eQTL hotspots with the mediators lead to the discovery of 64 TFs. Conclusions. Our mediation analysis is a powerful approach in identifying the trans-QTL-phenotype associations. It improves our understanding of the functional genetic variations for the liver metabolism mechanisms.

  8. Molecular dynamics of CYP2D6 polymorphisms in the absence and presence of a mechanism-based inactivator reveals changes in local flexibility and dominant substrate access channels.

    Parker W de Waal

    Full Text Available Cytochrome P450 enzymes (CYPs represent an important enzyme superfamily involved in metabolism of many endogenous and exogenous small molecules. CYP2D6 is responsible for ∼ 15% of CYP-mediated drug metabolism and exhibits large phenotypic diversity within CYPs with over 100 different allelic variants. Many of these variants lead to functional changes in enzyme activity and substrate selectivity. Herein, a molecular dynamics comparative analysis of four different variants of CYP2D6 was performed. The comparative analysis included simulations with and without SCH 66712, a ligand that is also a mechanism-based inactivator, in order to investigate the possible structural basis of CYP2D6 inactivation. Analysis of protein stability highlighted significantly altered flexibility in both proximal and distal residues from the variant residues. In the absence of SCH 66712, *34, *17-2, and *17-3 displayed more flexibility than *1, and *53 displayed more rigidity. SCH 66712 binding reversed flexibility in *17-2 and *17-3, through *53 remained largely rigid. Throughout simulations with docked SCH 66712, ligand orientation within the heme-binding pocket was consistent with previously identified sites of metabolism and measured binding energies. Subsequent tunnel analysis of substrate access, egress, and solvent channels displayed varied bottle-neck radii. Taken together, our results indicate that SCH 66712 should inactivate these allelic variants, although varied flexibility and substrate binding-pocket accessibility may alter its interaction abilities.

  9. The effect of TongXuan LiFei pill on the activity of CYP2D6%通宣理肺丸对CYP2D6酶活性的影响

    徐娟; 赵钢涛; 邸晓辉; 张梅; 郑绯

    2013-01-01

    目的 研究通宣理肺丸对CYP2D6酶活性的影响,探讨通宣理肺丸的代谢途径,为临床指导合理用药提供依据.方法 筛选30名健康志愿者作为受试者.以右美沙芬作为CYP2D6的探针药,研究服用通宣理肺丸对人体内代谢酶CYP2D6活性的影响.采用高效液相色谱法-质谱(HPLC-MS/MS)法测定探针药及其代谢产物的血药浓度.连续服用14 d通宣理肺丸.以曲线下面积(AUC0~12)为指标,评价CYP2D6代谢酶的活性.结果 受试者用药前CYP2D6代谢酶活性为6.1±1.5,服用通宣理肺丸后代谢酶活性为6.5±1.7,差异无统计学意义.结论 服用通宣理肺丸对CYP2D6代谢酶活性没有明显影响.

  10. Cyp2D6 catalyzes 5-hydroxylation of 1-(2-pyrimidinyl)-piperazine, an active metabolite of several psychoactive drugs, in human liver microsomes.

    Raghavan, Nirmala; Zhang, Donglu; Zhu, Mingshe; Zeng, Jianing; Christopher, Lisa

    2005-02-01

    1-(2-Pyrimidinyl)-piperazine (1-PP) is an active metabolite of several psychoactive drugs including buspirone. 1-PP is also the major metabolite in the human circulation and in rat brains following oral administration of buspirone. This study was conducted to identify the enzyme responsible for the metabolic conversion of 1-PP to 5-hydroxy-1-(2-pyrimidinyl)-piperazine (HO-1-PP) in human liver microsomes (HLMs). The product HO-1-PP was quantified by a validated liquid chromatography-tandem mass spectrometry method. In the presence of NADPH, 1-PP (100 microM) was incubated separately with human cDNA-expressed cytochrome P450 isozymes (including CYP2D6, 3A4, 1A2, 2A6, 2C9, 2C19, 2E1, and 2B6) at 37 degrees C. CYP2D6 catalyzed the formation of HO-1-PP from 1-PP. This catalytic activity was >95% inhibited by quinidine, a CYP2D6 inhibitor. HO-1-PP formation rates correlated well with the bufuralol 1-hydroxylase (CYP2D6) activities of individual HLMs. The formation of HO-1-PP followed a Michaelis-Menten kinetics with a K(m) of 171 microM and V(max) of 313 pmol/min x mg protein in HLMs. Collectively, these results indicate that polymorphic CYP2D6 is responsible for the conversion of 1-PP to HO-1-PP. PMID:15507542

  11. 以普罗帕酮为探针测定人肝微粒体中CYP2D6的活性%Determination of CYP2D6 activity in human liver microsomes using propafenone as a probe

    张顺国; 唐跃年; 卜书红

    2004-01-01

    目的:测定普罗帕酮(PPF)和5-羟基普罗帕酮(5-OHP)的比值以表达人肝微粒体中CYP2D6的活性.方法:以1g·L-1微粒体蛋白浓度37℃孵育PPF 1 h,以HPLC测定PPF和5-OHP的含量.结果:PPF和5-OHP的线性方程分别为Y=0.452 0 C+0.003 0,r=0.999 7;Y=0.749 4 C-0.020 5,r=0.997 5.结论:人肝微粒体CYP2D6酶的活性可以通过测定5-OHP与PPF的比值进行预测.

  12. Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers.

    Glue, Paul; Winter, Helen; Garbe, Kira; Jakobi, Hannah; Lyudin, Alexander; Lenagh-Glue, Zoe; Hung, C Tak

    2015-06-01

    Conversion of ibogaine to its active metabolite noribogaine appears to be mediated primarily by CYP2D6. We compared 168 hours pharmacokinetic profiles of both analytes after a single oral 20 mg dose of ibogaine in 21 healthy subjects who had been pretreated for 6 days with placebo or the CYP2D6 inhibitor paroxetine. In placebo-pretreated subjects, ibogaine was rapidly converted to noribogaine. Median peak noribogaine concentrations occurred at 4 hours. Compared with placebo-pretreated subjects, paroxetine-pretreated subjects had rapid (Tmax  = 1.5 hours) and substantial absorption of ibogaine, with detectable levels out to 72 hours, and an elimination half-life of 10.2 hours. In this group, ibogaine was also rapidly converted to noribogaine with a median Tmax of 3 hours. Extent of noribogaine exposure was similar in both groups. CYP2D6 phenotype was robustly correlated with ibogaine AUC0-t (r = 0.82) and Cmax (r = 0.77). Active moiety (ibogaine plus noribogaine) exposure was ∼2-fold higher in paroxetine-pretreated subjects. Single 20 mg ibogaine doses were safe and well tolerated in all subjects. The doubling of exposure to active moiety in subjects with reduced CYP2D6 activity suggests it may be prudent to genotype patients awaiting ibogaine treatment, and to at least halve the intended dose of ibogaine in CYP2D6 poor metabolizers. PMID:25651476

  13. Meta-analysis of correlation between CYP2 D6 polymorphisms and tamoxifen concentrations and its activity in Chinese breast cancer patients%中国人群CYP2D6的基因多态性与乳腺癌患者他莫昔芬及其代谢物血药浓度关系的Meta分析

    熊萱; 张思超; 朱昶宇

    2015-01-01

    目的:系统评价 CYP2 D6基因型与乳腺癌患者他莫昔芬及其活性代谢物血药浓度的关系。方法计算机检索Cochrane图书馆、PubMed、EMBase、CNKI、CBM、Weipu Data、Wanfang Data等数据库,并手工检索相关文献,查找关于CYP2D6基因型与他莫昔芬及其活性代谢物血药浓度的文献。检索时间1995年1月~2014年10月。采用RevMan5.3软件进行meta分析。结果共纳入4篇文献,包含438例研究对象。 Meta分析结果显示,携带CYP2D6*10/*10基因型患者的他莫昔芬活性代谢物( HTAM、endoxifen)血药浓度明显低于携带其他基因型患者(P<0.0001);携带CYP2D6*10/*10基因型患者的他莫昔芬血药浓度低于携带CYP2D6Wt/Wt基因型患者(P<0.05)。而CYP2D6Wt/Wt及CYP2D6Wt/*10基因型携带患者间,TAM及其活性代谢物血药浓度比较,差异无统计学意义。结论中国人群CYP2D6的基因多态型对乳腺癌患者体内他莫西芬及其代谢物的浓度有影响。%Objective To systematically review the correlation between polymorphisms of CYP2D6 genotypes and concentrations of tamoxifen and its activity in Chinese breast cancer patients.Methods Such databases as Cochrane Library, PubMed, EMBase, CNKI, CBM, WeipuData and WanfangDate,from January 1995 to October 2014 were searched on line for the studies about the correlation between polymorphisms of CYP2D6 genotypes concentrations of tamoxifen and its activity in Chinese breast cancer patients.And references about it were checked.The meta-analysis was performed with RevMan 5.3 software.Results A total of 4 articles involving 438 patients were included.The results of meta-analysis showed that,the concentrations of HTAM and endoxifen in patients who had CYP2D6*10/*10 genotypes were lower than the other genotypes ( P<0.0001 ) .The concentration of tamoxifen in patients who had CYP2D6*10/*10 genotypes was lower than CYP2D6Wt/Wt ( P<0.05 ) .There was no significant

  14. Modeling chemical interaction profiles: I. Spectral data-activity relationship and structure-activity relationship models for inhibitors and non-inhibitors of cytochrome P450 CYP3A4 and CYP2D6 isozymes.

    McPhail, Brooks; Tie, Yunfeng; Hong, Huixiao; Pearce, Bruce A; Schnackenberg, Laura K; Ge, Weigong; Valerio, Luis G; Fuscoe, James C; Tong, Weida; Buzatu, Dan A; Wilkes, Jon G; Fowler, Bruce A; Demchuk, Eugene; Beger, Richard D

    2012-01-01

    techniques, providing an independent estimator that can increase confidence in a structure-activity assessment. When modeling was applied to hazardous environmental chemicals, it was found that up to 20% of them may be substrates and up to 10% of them may be inhibitors of the CYP3A4 and CYP2D6 isoforms. The developed models provide a rare opportunity for the environmental health branch of the public health service to extrapolate to hazardous chemicals directly from human clinical data. Therefore, the pharmacological and environmental health branches are both expected to benefit from these reported models. PMID:22421792

  15. Modeling Chemical Interaction Profiles: I. Spectral Data-Activity Relationship and Structure-Activity Relationship Models for Inhibitors and Non-inhibitors of Cytochrome P450 CYP3A4 and CYP2D6 Isozymes

    Richard D. Beger

    2012-03-01

    techniques, providing an independent estimator that can increase confidence in a structure-activity assessment. When modeling was applied to hazardous environmental chemicals, it was found that up to 20% of them may be substrates and up to 10% of them may be inhibitors of the CYP3A4 and CYP2D6 isoforms. The developed models provide a rare opportunity for the environmental health branch of the public health service to extrapolate to hazardous chemicals directly from human clinical data. Therefore, the pharmacological and environmental health branches are both expected to benefit from these reported models.

  16. Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro

    Wang Z

    2016-06-01

    Full Text Available Zhe Wang,1,* Li Wang,2,3,* Ren-ai Xu,4 Yun-yun Zhan,2 Cheng-ke Huang,1 Da-peng Dai,5 Jian-ping Cai,5 Guo-xin Hu2 1Department of Pharmacy, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, 2Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 3Department of Pharmacy, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 4Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 5The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Cytochrome P450 2D6 (CYP2D6 is a highly polymorphic enzyme that catalyzes the metabolism of a great number of therapeutic drugs. Up to now, >100 allelic variants of CYP2D6 have been reported. Recently, we identified 22 novel variants in the Chinese population in these variants. The purpose of this study was to examine the enzymatic activity of the variants toward the CYP2D6 substrate carvedilol in vitro. The CYP2D6 proteins, including CYP2D6.1 (wild type, CYP2D6.2, CYP2D6.10, and 22 other novel CYP2D6 variants, were expressed from insect microsomes and incubated with carvedilol ranging from 1.0 µM to 50 µM at 37°C for 30 minutes. After termination, the carvedilol metabolites were extracted and detected using ultra-performance liquid chromatography tandem mass-spectrometry. Among the 24 CYP2D6 variants, CYP2D6.92 and CYP2D6.96 were catalytically inactive and the remaining 22 variants exhibited significantly decreased intrinsic clearance values (ranging from ~25% to 95% compared with CYP2D6.1. The present data in vitro suggest that the newly found variants significantly reduced catalytic activities compared with CYP2D6.1. Given that CYP2D6 protein activities could affect carvedilol plasma levels, these findings are greatly relevant to

  17. High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish Population.

    Pietarinen, Paavo; Tornio, Aleksi; Niemi, Mikko

    2016-09-01

    CYP2D6 participates in the biotransformation of many commonly used drugs. Large genetic variability in CYP2D6 results in a wide interindividual variability in the response to CYP2D6 substrate drugs. Previous studies have assessed the phenotype and genotype distributions of CYP2D6 in relatively small Finnish population samples. The aim of our study was to investigate the frequencies of CYP2D6 genotypes in a larger Finnish population cohort of 857 healthy volunteers. The volunteers were genotyped for 10 CYP2D6 genetic variants (*2, *3, *4, *5, *6, *9, *10, *17, *39, *41) and copy number variation performed with TaqMan genotyping assays and copy number assay targeting exon 9. CYP2D6 phenotypes were inferred from the genotype data with the classical and activity score methods. According to the classical method, a large majority of the study cases were extensive metabolizers (EM; 87.3%; 95% confidence interval 84.9-89.3) and the second largest group was ultrarapid metabolizers (UM; 7.2%; 5.7-9.2%). Intermediate (IM) and poor metabolizers (PM) were in clear minority (3.0%; 2.1-4.4% and 2.3%; 1.5-3.6%, respectively). The activity score method yielded similar phenotype predictions. These results show that the frequency of UM genotype is higher and that of PM and IM genotype is lower in the Finnish population than in other North European populations. Accordingly, CYP2D6 genetic profile of the Finnish population differs from its geographically close neighbours, which has implications for the effective and safe use of drugs metabolized by CYP2D6. PMID:27038154

  18. Effects of Flos carthami on CYP2D6 and on the Pharmacokinetics of Metoprolol in Rats

    Gaofeng Liu

    2011-01-01

    Full Text Available Flos carthami is a traditional Chinese herbal medicine. Clinically, the Flos carthami Injection has been used concomitantly with other Western drugs and may be used concomitantly with β-blockers, such as metoprolol, to treat cerebrovascular and coronary heart diseases, in China. Metoprolol is a CYP2D6 substrate and is predominantly metabolized by this isozyme. However, we do not know whether there is an effect of Flos carthami on CYP2D6 and the consequences of such an effect. Concern is raised regarding the possible herb-drug interaction. In this report, the effects of Flos carthami on the activity of CYP2D6 in vivo and in vitro and on the pharmacokinetics of metoprolol, in rats, are investigated. To assess the inhibitory potency of Flos carthami, the concentration associated with 50% inhibition (IC50 of dextromethorphan metabolism was determined based on the concentration-inhibition curves. The inhibitory effect of Flos carthami on CYP2D6 was also compared with cimetidine in vitro. Flos carthami could significantly inhibit CYP2D6 in rats both in vitro and in vivo (P<.05 and could slow down the metabolic rate of metoprolol as suggested by prolonged t1/2 (67.45%, by increased Cmax (74.51% and AUC0−∞ (76.89%. These results suggest that CYP2D6 is a risk factor when Flos carthami is administered concomitantly with metoprolol or other CYP2D6 substrates.

  19. The Impact of CYP2D6 Genotyping on Tamoxifen Treatment

    Ferraldeschi, Roberta; William G Newman

    2010-01-01

    Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxifen metabolites. Several studies suggest that germline genetic variants in CYP2D6 influence the clini...

  20. CYP2D6 genotype and phenotype relationship in South Indians

    Naveen A

    2006-01-01

    Full Text Available Background : Genotypes of the drug-metabolizing enzyme CYP2D6 influence plasma levels of 25% of commonlyprescribed drugs. This is the first study in India to investigate the genotype-phenotype relationship of CYP2D6. Aim : To study the influence of some CYP2D6 genotypes on the metabolism of its substrate dextromethorphanin healthy South Indian volunteers and to assess the contribution of the CYP2D6FNx0110 and CYP2D6FNx014 alleles. Materials and Methods : Twenty-six subjects from a previous CYP2D6 genotyping study of healthy volunteerswere included for phenotyping in this study. Selected volunteers belonged to any one of three genotype groups:Group I - two normal activity alleles, Group II - one reduced activity allele and one normal activity allele andGroup III - one loss of function allele along with either a wild type or reduced activity allele. Volunteers werephenotyped for the CYP2D6 enzyme using dextromethorphan as probe drug. Concentrations of the parent drugand metabolite dextrorphan were estimated using high performance liquid chromatography. Metabolic ratioswere calculated as the ratio of parent drug to metabolite in 0-8h urine samples. Statistical Analysis : Metabolic ratios from each genotype group were compared using the Mann-Whitney testat 5% significance, to observe their difference between genotype groups. Results : The mean metabolic ratios±SD in Groups I, II and III were 0.0039±0.0031, 0.0032±0.0017 and0.0391±0.0331 respectively. The mean metabolic ratio of Group III was significantly higher when comparedwith Groups I or II. In heterozygous individuals, the FNx011 or FNx012 alleles compensated for the reduced enzymeactivity due to the FNx0110 allele. However, if a heterozygous individual had a FNx014 allele, the reduced enzyme activitycould not be compensated by the FNx011 or FNx012 alleles. Conclusions : The CYP2D6 enzyme activity was found to be decreased in individuals carrying FNx014 or FNx015 alleles.The FNx011 or FNx

  1. CYP2D6 genotype determination in the Danish population

    Brøsen, K; Nielsen, P N; Brusgaard, K;

    1994-01-01

    CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for.......11-9.10). The median difference was 0.09 (95% confidence interval: 0.02-0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM...... and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring. Udgivelsesdato: 1994-null...

  2. The Impact of CYP2D6 Genotyping on Tamoxifen Treatment

    Roberta Ferraldeschi

    2010-04-01

    Full Text Available Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6 isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxifen metabolites. Several studies suggest that germline genetic variants in CYP2D6 influence the clinical outcomes of patients treated with adjuvant tamoxifen. Here, we review the existing data relating CYP2D6 genotypes to tamoxifen efficacy.

  3. Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants

    S. Kwadijk-De Gijsel (Sonja); M.J. Bijl (Monique); L.E. Visser (Loes); R.H.N. van Schaik (Ron); A. Hofman (Albert); A.G. Vulto (Arnold); T. van Gelder (Teun); B.H.Ch. Stricker (Bruno)

    2009-01-01

    textabstractWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). • The variant allele CYP2D6*4 is the main polymorphism resulting in decreased enzyme activity in Caucasians. • Decreased CYP2D6 enzyme activity poten

  4. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer

    Regan, Meredith M; Leyland-Jones, Brian; Bouzyk, Mark;

    2012-01-01

    Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the...... clinical relevance of CYP2D6 polymorphisms....

  5. The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

    L.A. Lammers (Laureen); R.H.J. Matthijsen (Ron); T. van Gelder (Teun); M.J. Bijl (Monique); A.J.M. de Graan (Anne-Joy); C.M. Seynaeve (Caroline); M.A. van Fessem (Marianne); P.M.J.J. Berns (Els); A.G. Vulto (Arnold); R.H.N. van Schaik (Ron)

    2010-01-01

    textabstractAbstract BACKGROUND: Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant

  6. Duplication of CYP2D6 predicts high clearance of desipramine but high clearance does not predict duplication of CYP2D6

    Bergmann, T K; Bathum, L; Brøsen, Kim

    2001-01-01

    OBJECTIVE: Duplication of CYP2D6 causes very rapid metabolism of CYP2D6 substrates such as desipramine. However, we have previously shown that in the Danish population, only about 15% of very rapid metabolisers, defined as subjects with a metabolic ratio of sparteine of 0.15 or less, carried a...... duplicated allele. The question is whether gene duplication is a relatively rare cause (perhaps predictor) of very rapid metabolism or whether a low metabolic ratio is a poor predictor of this. METHODS: After measuring metabolic ratios anew, we selected six volunteers with duplication of CYP2D6 and metabolic...... duplication of CYP2D6 is poor; there must be other causes (or predictors) of very rapid metabolism and with much higher frequency than duplication of CYP2D6....

  7. Clinical Utility and Economic Impact of CYP2D6 Genotyping.

    Reynolds, Kristen K; McNally, Beth A; Linder, Mark W

    2016-09-01

    Pharmacogenetics examines an individual's genetic makeup to help predict the safety and efficacy of medications. Practical application optimizes treatment selection to decrease the failure rate of medications and improve clinical outcomes. Lack of efficacy is costly due to adverse drug reactions and increased hospital stays. Cytochrome P450 2D6 (CYP2D6) metabolizes roughly 25% of all drugs. Detecting variants that cause altered CYP2D6 enzymatic activity identifies patients at risk of adverse drug reactions or therapeutic failure with standard dosages of medications metabolized by CYP2D6. This article discusses the clinical application of pharmacogenetics to improve care and decrease costs. PMID:27514466

  8. The Effects of H2S on the Activities of CYP2B6, CYP2D6, CYP3A4, CYP2C19 and CYP2C9 in Vivo in Rat

    Xianqin Wang

    2013-12-01

    Full Text Available Hydrogen sulfide (H2S is a colorless, flammable, extremely hazardous gas with a “rotten egg” smell. The human body produces small amounts of H2S and uses it as a signaling molecule. The cocktail method was used to evaluate the influence of H2S on the activities of CYP450 in rats, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: bupropion, metroprolol, midazolam, omeprazole and tolbutamide, respectively. The rats were randomly divided into two groups, control group and H2S group. The H2S group rats were given 5 mg/kg NaHS by oral administration once a day for seven days. The mixture of five probes was given to rats through oral administration and the blood samples were obtained at a series of time-points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by LC-MS. In comparing the H2S group with the control group, there was a statistically pharmacokinetics difference for midazolam and tolbutamide; the area under the plasma concentration-time curve (AUC was decreased for midazolam (p < 0.05 and increased for tolbutamide (p < 0.05; while there was no statistical pharmacokinetics difference for bupropion, metroprolol and omeprazole. H2S could not influence the activities of CYP2B6, CYP2D6 and CYP2C19 in rats, while H2S could induce the activity of CYP3A4 and inhibit the activity of CYP2C9 in rats.

  9. Multiplex Phenotyping for Systems Medicine: A One-Point Optimized Practical Sampling Strategy for Simultaneous Estimation of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 Activities Using a Cocktail Approach.

    de Andrés, Fernando; Terán, Santiago; Bovera, Marcela; Fariñas, Humberto; Terán, Enrique; LLerena, Adrián

    2016-02-01

    Phenotyping of the CYP450 enzyme activities contributes to personalized medicine, but the past phenotyping approaches have followed a piecemeal strategy measuring single enzyme activities in vivo. A barrier to phenotyping of populations in rural and remote areas is the limited time and resources for sample collection. The CEIBA cocktail approach allows metabolic capacity estimation of multiple CYP450 enzymes in a single sample analysis, but the attendant sample collection schemes for applications in diverse global settings are yet to be optimized. The present study aimed to select an optimal matrix to simultaneously analyze CYP450 enzyme activities so as to simplify the sampling schemes in the phenotyping protocol to enhance its throughput and feasibility in native populations or in remote and underserviced geographies and social contexts. We evaluated 13 Ecuadorian healthy volunteers for CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotypes and their metabolic phenotypes, including CYP3A4, in plasma and urine after administering one reduced dose of caffeine, losartan, omeprazole, and dextromethorphan. Pharmacokinetic analyses were performed, and the correlation between AUC parent/AUC metabolite and the ratio between concentrations of probe drugs and their corresponding metabolites at timepoints ranging from 0 to 12 hours post-dose were analyzed. A single sampling timepoint, 4 hours post-dose in plasma, was identified as optimal to reflect the metabolic activity of the attendant CYP450 enzymes. This study optimizes the CEIBA multiplexed phenotyping approach and offers new ways forward for integrated drug metabolism analyses, in the pursuit of global personalized medicine applications in resource-limited regions, be they in developed or developing countries. PMID:26600202

  10. The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism

    Zwisler, Stine T; Enggaard, Thomas P; Noehr-Jensen, Lene;

    2009-01-01

    Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity...

  11. MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

    Rafael eDe La Torre

    2012-11-01

    Full Text Available In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.

  12. Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner.

    Pan, Xian; Lee, Yoon-Kwang; Jeong, Hyunyoung

    2015-07-01

    Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6-humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(-/-);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064. PMID:25926433

  13. Effects of 22 novel CYP2D6 variants found in Chinese population on the metabolism of dapoxetine

    Xu RA

    2016-02-01

    Full Text Available Ren-ai Xu,1,* Er-min Gu,2,* Quan Zhou,2 Lingjing Yuan,2 Xiaoxia Hu,2 Jianping Cai,3 Guoxin Hu1,2 1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, 2Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, 3The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, People’s Republic of China *These authors contributed equally to this work Background: CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. Methods and results: The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96,*97, *98, *R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km values of most variants were significantly altered when compared with the counterpart of CYP2D6*1, with most of these variants exhibiting either reduced Vmax and/or increased Km values. For dapoxetine demethylation pathway (which produces desmethyldapoxetine, 2D6*89 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide, the relative clearance values of three variants, 2D6*90, *94, and

  14. CYP2D6基因多态性及对药物代谢的影响%Polymorphism of CYP2D6 and the influence to the drug metabolism

    韩璐; 刘洁

    2011-01-01

    CYP2D6代谢酶是细胞色素P450家族中的成员之一,是参与I相代谢和众多内源性物质和不同药物消除的酶.虽然它在肝脏中的含量大约只占肝脏总量的200,但在临床上却参与了25%以上的常用药物的代谢活动.在所有参与药物代谢的细胞色素P450基因家族中,CYP2D6 是唯一不能被诱导的酶,这种酶具有广泛的多态性,这种多态性对酶的药物代谢功能具有重要影响,CYP2D6的这种多态性和药物代谢功能所表现的对个体活性的差异,在遗传药理学上具有重要意义.本文从CYP2 D6基因多态性和它对药物代谢的影响这两方面进行了阐述.%CYP2D6 is a member of cytochrome P450 gene family - a group of enzymes that is responsible for phase Ⅰ metabolism and elimination of numerous endogenous substrates and a diverse array of drugs.It is now thought to be involved in the metabolism of up to 25 % of the drugs that are in common use in the clinic,despite its low hepatic content (about 2 %).Among the drug-metabolizing cytochrome P450s,CYP2D6 is the only non-inducible enzyme and is highly polymorphic, which results in a large contribution of genetic variation to its inter-individual variation in enzyme activity and is an enzyme of great historical importance for pharmacogenetics.Here we summarize the polymorphism of CYP2D6 gene and their influence to drug metabolism.

  15. Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences

    Sachse, C.; Brockmoeller, J.; Bauer, S.; Roots, I. [Humboldt Univ., Berlin (Germany)

    1997-02-01

    Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles. Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine. For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed. The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was .364. The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of .324, .018, and .015, respectively. By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of.005 (*1 x 2), .013 (* 2 x 2), and .001 (*4 x 2). Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were .207 (*4), .020 (*3 and *5), .009 (*6), and .001 (*7, *15, and *16). The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found. All 41 PMs (7.0%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity. Three novel variants of known CYP2D6 alleles were discovered: *1C (T{sub 1957}C), *2B (additional C{sub 2558}T), and *4E (additional C{sub 2938}T). Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EN/PM (mean MR = .006) and IM/PM (mean MR = .014) alleles and between carriers of one (mean MR = .009) and two (mean MR = .003) functional alleles. The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment. 35 refs., 4 figs., 5 tabs.

  16. Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia

    Zwisler, S T; Enggaard, T P; Mikkelsen, S;

    2009-01-01

    Background: Oxycodone is a semi-synthetic opioid with a mu-receptor agonist-mediated effect in several pain conditions, including post-operative pain. Oxycodone is metabolized to its active metabolite oxymorphone by O-demethylation via the polymorphic CYP2D6. The aim of this study was to...... investigate whether CYP2D6 poor metabolizers (PMs) yield the same analgesia post-operatively from intravenous oxycodone as extensive metabolizers (EMs). Methods: Two hundred and seventy patients undergoing primarily thyroid surgery or hysterectomy were included and followed for 24 h post-operatively. The CYP2...... for the first time in patients that the oxymorphone formation depends on CYP2D6, but we found no difference in the post-operative analgesic effect of intravenous oxycodone between the two CYP2D6 genotypes....

  17. Nomenclature for human CYP2D6 alleles.

    Daly, A K; Brockmöller, J; Broly, F; Eichelbaum, M; Evans, W E; Gonzalez, F J; Huang, J D; Idle, J R; Ingelman-Sundberg, M; Ishizaki, T; Jacqz-Aigrain, E; Meyer, U A; Nebert, D W; Steen, V M; Wolf, C R; Zanger, U M

    1996-06-01

    To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented. PMID:8807658

  18. CYP2D6 genotype dependent oxycodone metabolism in postoperative patients.

    Ulrike M Stamer

    Full Text Available BACKGROUND: The impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption. METHODS: Patients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele, HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity, EM (extensive metabolizers, normal CYP2D6 activity and UM (ultrarapid metabolizers, increased CYP2D6 activity. Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide. RESULTS: Metabolism differed between CYP2D6 genotypes. Mean (95%-CI oxymophone/oxycodone ratios were 0.10 (0.02/0.19, 0.13 (0.11/0.16, 0.18 (0.16/0.20 and 0.28 (0.07/0.49 in PM, HZ/IM, EM and UM, respectively (p = 0.005. Oxycodone consumption up to the 12(th hour was highest in PM (p = 0.005, resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8; EM and UM 2.2 (2.1/2.3; p<0.001. Pain scores did not differ between genotypes. CONCLUSIONS: In this postoperative setting, the number of

  19. CYP2D6 polymorphism and mental and personality disorders in suicide attempters.

    Blasco-Fontecilla, Hilario; Peñas-Lledó, Eva; Vaquero-Lorenzo, Concepción; Dorado, Pedro; Saiz-Ruiz, Jerónimo; Llerena, Adrián; Baca-García, Enrique

    2014-12-01

    Prior studies on the association between the CYP2D6 polymorphism and suicide did not explore whether mental and personality disorders mediate this association. The main objective of the present study was to test an association between CYP2D6 polymorphism and mental and personality disorders among suicide attempters. The MINI and the DSM-IV version of the International Personality Disorder Examination Screening Questionnaire were used to diagnose mental and personality disorders, respectively, in 342 suicide attempters. Suicide attempters were divided into four groups according to their number of CYP2D6 active genes (zero, one, and two or more). Differences in mental and personality disorders across the four groups were measured using linear-by-linear association, chi square-test, and 95% confidence intervals. Suicide attempters carrying two or more active CYP2D6 genes were more likely to be diagnosed with at least one personality disorder than those with one or zero CYP2D6 active genes. PMID:25437930

  20. CYP2D6基因与药物代谢%CYP2D6 gene and drug metabolism

    施安国

    2003-01-01

    细胞色素P-450(CYP)中的CYP2D6酶在抗抑郁药、安定药及某些抗心律失常药的代谢中起重要作用,CYP2D6基因位于22号常染色体上为隐性遗传,CYP2D6基因呈多态性约有70余种等位基因变异型,也存在特异人群差别,因而导致所编码的酶活性不同,这些数据有助于理解药物代谢的个体差异、有助于预测药物之间的相互作用.

  1. Identification of novel CYP2D7-2D6 hybrids: non-functional and functional variants

    Andrea Gaedigk

    2010-10-01

    Full Text Available Polymorphic expression of CYP2D6 contributes to the wide range of activity observed for this clinically important drug metabolizing enzyme. In this report we describe novel CYP2D7/2D6 hybrid genes encoding non-functional and functional CYP2D6 protein and a CYP2D7 variant that mimics a CYP2D7/2D6 hybrid gene. Five kb long PCR products encompassing the novel genes were entirely sequenced. A quantitative assay probing in different gene regions was employed to determine CYP2D6 and 2D7 copy number variations and the relative position of the hybrid genes within the locus was assessed by long-range PCR. In addition to the previously known CYP2D6*13 and *66 hybrids, we describe three novel non-functional CYP2D7-2D6 hybrids with gene switching in exon 2 (CYP2D6*79, intron 2 (CYP2D6*80 and intron 5 (CYP2D6*67. A CYP2D7-specific T-ins in exon 1 causes a detrimental frame shift. One subject revealed a CYP2D7 conversion in the 5’-flanking region of a CYP2D6*35 allele, was otherwise unaffected (designated CYP2D6*35B. Finally, three DNAs revealed a CYP2D7 gene with a CYP2D6-like region downstream of exon 9 (designated CYP2D7[REP6]. Quantitative copy number determination, sequence analyses and long-range PCR mapping were in agreement and excluded the presence of additional gene units. Undetected hybrid genes may cause over-estimation of CYP2D6 activity (CYP2D6*1/*1 vs *1/hybrid, etc, but may also cause results that may interfere with the genotype determination. Detection of hybrid events, ‘single’ and tandem, will contribute to more accurate phenotype prediction from genotype data.

  2. National Prociency Testing Result of CYP2D6*10 Genotyping for Adjuvant Tamoxifen Therapy in China.

    Lin, Guigao; Zhang, Kuo; Yi, Lang; Han, Yanxi; Xie, Jiehong; Li, Jinming

    2016-01-01

    Tamoxifen has been successfully used for treating breast cancer and preventing cancer recurrence. Cytochrome P450 2D6 (CYP2D6) plays a key role in the process of metabolizing tamoxifen to its active moiety, endoxifen. Patients with variants of the CYP2D6 gene may not receive the full benefit of tamoxifen treatment. The CYP2D6*10 variant (the most common variant in Asians) was analyzed to optimize the prescription of tamoxifen in China. To ensure referring clinicians have accurate information for genotype-guided tamoxifen treatment, the Chinese National Center for Clinical Laboratories (NCCL) organized a national proficiency testing (PT) to evaluate the performance of laboratories providing CYP2D6*10 genotyping. Ten genomic DNA samples with CYP2D6 wild-type or CYP2D6*10 variants were validated by PCR-sequencing and sent to 28 participant laboratories. The genotyping results and pharmacogenomic test reports were submitted and evaluated by NCCL experts. Additional information regarding the number of samples tested, the accreditation/certification status, and detecting technology was also requested. Thirty-one data sets were received, with a corresponding analytical sensitivity of 98.2% (548/558 challenges; 95% confidence interval: 96.7-99.1%) and an analytic specificity of 96.5% (675/682; 95% confidence interval: 97.9-99.5%). Overall, 25/28 participants correctly identified CYP2D6*10 status in 10 samples; however, two laboratories made serious genotyping errors. Most of the essential information was included in the 20 submitted CYP2D6*10 test reports. The majority of Chinese laboratories are reliable for detecting the CYP2D6*10 variant; however, several issues revealed in this study underline the importance of PT schemes in continued external assessment and provision of guidelines. PMID:27603206

  3. Cytochrome P450-2D6 Screening Among Elderly Using Antidepressants (CYSCE)

    2015-12-09

    Depression; Depressive Disorder; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Intermediate Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant

  4. Progress on research for genetic polymorphism of drug metabolic enzyme cytochrome P450 2D6%药物代谢酶细胞色素P450 2D6的遗传多态性研究进展

    徐田雪; 杨信怡; 赵昆; 张喜川; 游雪甫

    2009-01-01

    CYP2D6是肝脏中重要的药物代谢酶,其代谢的药物占临床应用药物的20%~25%.其遗传多态性对依赖CYP2D6代谢的药物具有重要的影响.本文综述了CYP2D6在遗传多态性方面的研究进展及其临床意义.%Cytochrome P450 2D6 (CYP2D6) is an important microsome enzyme in liver which metabolizes about 20%~25% of drugs used in clinic. And these substrates of CYP2D6 are affected intensively by its genetic polymorphism. In the present article, genetic polymorphism of CYP2D6 and its clinical implications were reviewed.

  5. CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics-guided clinical trials.

    Peñas-Lledó, Eva M; Llerena, Adrián

    2014-04-01

    Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under- or over-representation of certain CYP2D6 metabolic groups. PMID:24033670

  6. Establishment and Optimization of Incubation System of Bactrian Camel Studying CYP2D6 Enzyme in Vitro%双峰驼 CYP2D6酶体外孵育体系的建立与优化

    王艳; 高飞; 哈斯苏荣

    2016-01-01

    为了研究双峰驼 CYP2D6酶体外活性,建立双峰驼肝微粒体孵育体系并对孵育体系中探针底物浓度、肝微粒体蛋白浓度和孵育时间等进行优化研究。首先采用改良差速离心法制备双峰驼肝微粒体、BCA 法测定双峰驼肝微粒体蛋白浓度、CO 还原差示光谱法检测 CYP 总酶含量,然后采用 HPLC 法跟踪检测孵育体系中 CYP2D6酶特异性底物的主要代谢产物去甲右美沙芬含量进而优化孵育条件。结果表明,双峰驼肝微粒体蛋白浓度为5.5650 mg/mL±0.5197 mg/mL,CYP 总酶含量为0.1777 nmol/mg±0.0503 nmol/mg;肝微粒体孵育体系的最适底物浓度为250μg/mL,肝微粒体蛋白浓度为5.5650 mg/mL,最适孵育时间为40 min 。所制备的双峰驼肝微粒体各项指标和优化后的肝微粒体孵育条件均能满足后续对双峰驼 CYP2D6酶体外活性研究的基本要求。%In order to study the in vitro activities of Bactrian Camel CYP2D6 enzyme,the liver microsome in-cubation system was established and optimized by studying the concentration of probe substrate,protein content of liver microsome and incubation time,etc.Firstly,liver microsomes of bactrian camel was pre-pared by modified differential centrifugation method,the protein content of bactrian camel liver microsomes was detected by using BCA method and the total content of CYP enzyme was determined by using CO re-duction method.Secondly,the incubation system was optimized by detecting and tracking the concentration of dextrophan,an active essential metabolite of dextromethorphan,in incubation system by using HPLC method.The results showed that the liver microsomal protein content of bactrian camel was 5.565 0 mg/mL±0.519 7 mg/mL,total CYP enzyme content was 0.177 7 nmol/mg±0.050 3 nmol/mg and the optimum substrate concentration in the liver microsome incubation system was 250 μg/mL,the op-timum concentration of protein in liver microsomes was 5

  7. Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug Response

    Goetz, MP; Kamal, A; Ames, MM

    2007-01-01

    Tamoxifen continues to be a standard endocrine therapy for the prevention and treatment of estrogen receptor (ER)-positive breast cancer. Tamoxifen can be considered a classic “pro-drug,” requiring metabolic activation to elicit pharmacological activity. CYP2D6 is the rate-limiting enzyme catalyzing the conversion of tamoxifen into metabolites with significantly greater affinity for the ER and greater ability to inhibit cell proliferation. Both genetic and environmental (drug-induced) factors...

  8. Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism.

    Ahmed, Nermin S; Elghazawy, Nehal H; ElHady, Ahmed K; Engel, Matthias; Hartmann, Rolf W; Abadi, Ashraf H

    2016-04-13

    Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-α and ER-β receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI50) that was 1000 times more potent than that of TAM (GI50 < 0.005 μM vs 1.58 μM, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers. PMID:26896706

  9. Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art.

    Marcsisin, Sean R; Reichard, Gregory; Pybus, Brandon S

    2016-05-01

    Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria. PMID:27016470

  10. In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4.

    Li, Jinghu; Gödecke, Tanja; Chen, Shao-Nong; Imai, Ayano; Lankin, David C; Farnsworth, Norman R; Pauli, Guido F; van Breemen, Richard B; Nikolić, Dejan

    2011-08-01

    Women who experience hot flashes as a side effect of tamoxifen (TAM) therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since pharmacological activity of TAM is dependent on the metabolic conversion into active metabolites by the action of cytochromes P450 2D6 (CYP2D6) and 3A4, the objective of this study was to evaluate whether black cohosh extracts can inhibit formation of active TAM metabolites and possibly reduce its clinical efficacy. At 50 μg/mL, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy- TAM by 66.3%, N-desmethyl TAM by 74.6% and α-hydroxy TAM by 80.3%. In addition, using midazolam and dextromethorphan as probe substrates, this extract inhibited CYP3A4 and CYP2D6 with IC(50) values of 16.5 and 50.1 μg/mL, respectively. Eight triterpene glycosides were identified as competitive CYP3A4 inhibitors with IC(50) values ranging from 2.3-5.1 µM, while the alkaloids protopine and allocryptopine were identified as competitive CYP2D6 inhibitors with K(i) values of 78 and 122 nM, respectively. The results of this study suggests that co-administration of black cohosh with TAM might interfere with the clinical efficacy of this drug. However, additional clinical studies are needed to determine the clinical significance of these in vitro results. PMID:21827327

  11. Impact of CYP2D6 Genetic Variation on the Response of the Cardiovascular Patient to Carvedilol and Metoprolol.

    Lymperopoulos, Anastasios; McCrink, Katie A; Brill, Ava

    2015-01-01

    Carvedilol and metoprolol are two of the most commonly prescribed β-blockers in cardiovascular medicine and primarily used in the treatment of hypertension and heart failure. Cytochrome P450 2D6 (CYP2D6) is the predominant metabolizing enzyme of these two drugs. Since the first description of a CYP2D6 sparteinedebrisoquine polymorphism in the mid-seventies, substantial genetic heterogeneity has been reported in the human CYP2D6 gene, with ~100 different polymorphisms identified to date. Some of these polymorphisms render the enzyme completely inactive while others do not modify its activity. Based on all the identified variants, four metabolizer phenotypes are nowadays used to characterize drug metabolism via CYP2D6 in humans: ultra-rapid metabolizer (UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes. As a consequence of these CYP2D6 metabolizer phenotypes, pharmacokinetics and bioavailability of carvedilol and metoprolol can range from therapeutically ineffective levels (in the UM patients) to excessive (overdose) and potentially toxic concentrations (in PM patients). This, in turn, can result in elevated risks for either treatment failure (in terms of blood pressure reduction of hypertensive patients and of improving survival and cardiovascular function of heart failure patients) or for adverse effects (e.g. hypotension and bradycardia). The present review will discuss the impact of these CYP2D6 genetic polymorphisms on the therapeutic responses of cardiovascular patients treated with either of these two β-blockers. In addition, the potential advantages and disadvantages of implementing CYP2D6 genetic testing in the clinic to guide/personalize therapy with these two drugs will be discussed. PMID:26537419

  12. Comparison of Paeoniflorin and Albiflorin on Human CYP3A4 and CYP2D6

    Li-Na Gao

    2015-01-01

    Full Text Available Peony (Paeonia lactiflora Pall- is a plant medicine and a functional food ingredient with wide application for more than 2000 years. It can be coadministrated with many other drugs, composed of traditional Chinese medicine compound such as shaoyao-gancao decoction. In order to explore the efficacy and safety of peony, effects of paeoniflorin and albiflorin (the principal components of peony on cytochrome P450 (CYP 3A4 and CYP2D6 were analyzed in human hepatoma HepG2 cells and evaluated from the level of recombinant CYP enzymes in vitro. The findings indicated that albiflorin possessed stronger regulation on the mRNA expression of CYP3A4 and CYP2D6 than paeoniflorin. For the protein level of CYP3A4, albiflorin showed significant induction or inhibition with the concentration increasing from 10−7 M to 10−5 M, but no remarkable variation was observed in paeoniflorin-treated group. Enzyme activity assay implied that both paeoniflorin and albiflorin could regulate CYP3A4 and CYP2D6 with varying degrees. The results showed that albiflorin should be given more attention because it may play a vital role on the overall efficacy of peony. The whole behavior of both paeoniflorin and albiflorin should be focused on ensuring the rationality and effectiveness of clinical application.

  13. Stable expression of human cytochrome P450 2D6*10 in HepG2 cells

    Jian Zhuge; Ying-Nian Yu; Xiao-Dan Wu

    2004-01-01

    AIM: Over 90% of drugs are metabolized by the cytochrome P-450 (CYP) family of liver isoenzymes. The most important enzymes are CYP1A2, 3A4, 2C9/19, 2D6 and 2E1. Although CYP2D6 accounts for <2% of the total CYP liver enzyme content, it mediates metabolism in almost 25% of drugs. In order to study its enzymatic activity for drug metabolism, its cDNA was cloned and a HepG2 cell line stably expressing CYP2D6 was established.METHODS: Human CYP2D6 cDNA was amplified with reverse transcription-polymerase chain reaction (RT-PCR)from total RNA extracted from human liver tissue and cloned into pGEM-T vector, cDNA segment was identified by DNA sequencing and subcloned into a mammalian expression vector pREP9. A cell line was established by transfecting the recombinant plasmid of pREP9-CYP2D6 to hepatoma HepG2 cells. Expression of mRNA was validated by RT-PCR.Enzyme activity of catalyzing dextromethorphan O-demethylation in postmitochondrial supernant (S9) fraction of the cells was determined by high performance liquid chromatography (HPLC).RESULTS: The cloned cDNA had 4 base differences, e.g.100 C→T, 336 T→C, 408 C→G and 1 457 G→C, which resulted in P34S, and S486T amino acid substitutions, and two samesense mutations were 112 F and 136 V compared with that reported by Kimura et al(GenBank accession number: M33388). P34S and S486T amino acid substitutions were the characteristics of CYP2D6*10 allele. The relative activity of S9 fraction of HepG2-CYP2D6*10 metabolized detromethorphan O-demethylation was found to be 2.31±0.19 nmol.min-1.mg-1 S9 protein (n=3), but was undetectable in parental HepG2 cells.CONCLUSION: cDNA of human CYP2D6*10can be successfully doned. A cell line, HepG2-CYP2D6*10, expressing CYP2D6*10 mRNA and having metabolic activity, has been established.

  14. Effects of cytochrome P450 2D6 and 3A5 genotypes and possible coadministered medicines on the metabolic clearance of antidepressant mirtazapine in Japanese patients.

    Okubo, Maho; Murayama, Norie; Miura, Jun; Chiba, Yasuji; Yamazaki, Hiroshi

    2015-01-01

    A personalized treatment approach should be considered with the second-generation psychiatric drug mirtazapine because of high frequencies of side effects, including characteristic drowsiness. Plasma concentrations of mirtazapine in patients are influenced by many factors, including polymorphic cytochrome P450 enzymes contributing to its transformation to 8-hydroxymirtazapine and N-demethylmirtazapine. The aim of this study was to investigate the determinant factors for individual variations of metabolic clearance of mirtazapine using in vitro and in vivo methods. In vitro analyses using liver microsomes from individual humans in correlation assays and recombinantly expressed P450 enzymes revealed that CYP2D6 was the major contributor to mirtazapine 8-hydroxylation with high affinity, and that CYP3A5 catalyzed N-demethylation in a similar high-capacity manner to that of CYP3A4. CYP1A2 was a minor contributor to mirtazapine 8-hydroxylation. Metabolic clearance of mirtazapine determined in substrate depletion assays and mirtazapine 8-hydroxylation activities in individual liver microsomes were significantly lower in CYP2D6 intermediate metabolizers (IM) and poor metabolizers (PM) than in extensive metabolizers (EM) (pCYP3A5 poor-expressors group than in the expressors group (pinhibitor), ketoconazole (a CYP3A inhibitor), and in combination with risperidone and duloxetine, possible coadministered medicines. These results suggested that mirtazapine metabolic clearance could be variously influenced by the CYP2D6 and CYP3A5 genotypes and coadministered drugs in clinical patients. PMID:25475885

  15. Untersuchung des Konzeptes der semiquantitativen CYP2D6-Gendosis bei Ultraschnellmetabolisierern im Vergleich zu Schnellmetabolisierern anhand der Pharmakokinetik von S- und R-Metoprolol

    Seeringer, Angela

    2010-01-01

    The background of this thesis was a clinical study on metoprolol as a CYP2D6 probe drug studying the influence of the CYP2D6 gene-duplication on pharmacokinetics of metoprolol in healthy volunteers. The aim of our study was to generate a more precise classification of the activitiy of CYP2D6 taking the contribution of alleles with decreased or increased activity into account. For this reason we further genotyped the study participants for CYP2D6, and established a concept of semiquantitative ...

  16. Detection of Cytochrome P450 2D6 Allele CYP2D6*6 by Using Allele-specific Amplification%ASA法测定细胞色素P450 2D6等位基因CYP2D6*6

    陈枢青; Wedl.,PJ

    1999-01-01

    细胞色素P450 2D6(CYP2D6)基因2064G→A突变,造成表达产物212位上谷氨酸变成甘氨酸,从而引起酶分子失活,被称为CYP2D6*6.利用等位基因特异扩增法,建立了ASA-PCR测定CYP2D6*6的方法.经396例测定,说明本法快捷、准确.测定结果显示CYP2D6*6与CYP2D6T共存,如果只为准确预测CYP2D6酶活性,对CYP2D6*6进行测定并无意义.

  17. CYP2D6*2 Polymorphism as a Predictor of Failed Outpatient Tramadol Therapy in Postherpetic Neuralgia Patients.

    Nasare, Namita Vilas; Banerjee, Basu Dev; Suryakantrao Deshmukh, Pravin; Mediratta, Pramod Kumari; Saxena, Ashok Kumar; Ahmed, Rafat Sultana; Bhattacharya, Sambit Nath

    2016-01-01

    Human cytochrome P4502D6 (CYP2D6) gene is highly polymorphic, leading to wide interindividual ethnic differences in CYP2D6-mediated drug metabolism. Its activity ranges from complete deficiency to excessive activity, potentially causing toxicity of the medication or therapeutic failure with recommended drug dosages. The aim of the study was to find the association of CYP2D6*2 polymorphisms with demographic characters (age, sex, and weight), pain intensity scales [numerical rating scale (NRS) sleep, global perceived effect (GPE)], and adverse drug effects in postherpetic neuralgia (PHN) patients receiving tramadol. The study comprised 246 patients [including 123 nonresponders (NRs) and 123 responders (Rs)] with PHN undergoing analgesic treatment at the pain clinic, Out Patient Department, University College of Medical Sciences, Guru Teg Bahadur Hospital, Delhi, India. Patients with any history of diabetes mellitus, human immunodeficiency virus, malignancy, hematological or liver disease, psychiatric illness, alcohol abuse, and tramadol sensitivity were excluded from the study. The NRSs of (resting and movement), NRS-sleep, and GPE were evaluated by the treating physician. Adverse drug effects during the time of the study were recorded. All samples were analyzed for CYP2D6*2 polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. The genotype distribution did not vary significantly among genders [NR (P = 0.723); R (P = 0.947)] and different age groups in NRs (P = 0.763) and Rs (P = 0.268). Clinically, statistically significant (P 0.05). In addition, CYP2D6*2 genotype was not related to the adverse effects of analgesic therapy. The overall results suggested that CYP2D6*2 polymorphism plays no role in the PHN patients receiving tramadol treatment. The CYP2D6*2 polymorphism may not be a predictor of treatment outcome of patients with respect to PHN-receiving tramadol. PMID:23567787

  18. A novel simple method for determining CYP2D6 gene copy number and identifying allele(s with duplication/multiplication.

    Taimour Langaee

    Full Text Available Cytochrome P450 2D6 (CYP2D6 gene duplication and multiplication can result in ultrarapid drug metabolism and therapeutic failure or excessive response in patients. Long range polymerase chain reaction (PCR, restriction fragment length polymorphism (RFLP and sequencing are usually used for genotyping CYP2D6 duplication/multiplications and identification, but are labor intensive, time consuming, and costly.We developed a simple allele quantification-based Pyrosequencing genotyping method that facilitates CYP2D6 copy number variation (CNV genotyping while also identifying allele-specific CYP2D6 CNV in heterozygous samples. Most routine assays do not identify the allele containing a CNV. A total of 237 clinical and Coriell DNA samples with different known CYP2D6 gene copy numbers were genotyped for CYP2D6 *2, *3, *4, *6, *10, *17, *41 polymorphisms and CNV determination.The CYP2D6 gene allele quantification/identification were determined simultaneously with CYP2D6*2, *3, *4, *6, *10, *17, *41 genotyping. We determined the exact CYP2D6 gene copy number, identified which allele had the duplication or multiplication, and assigned the correct phenotype and activity score for all samples.Our method can efficiently identify the duplicated CYP2D6 allele in heterozygous samples, determine its copy number in a fraction of time compared to conventional methods and prevent incorrect ultrarapid phenotype calls. It also greatly reduces the cost, effort and time associated with CYP2D6 CNV genotyping.

  19. Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders

    Saruwatari J

    2014-04-01

    Full Text Available Junji Saruwatari,1 Hiroo Nakashima,1 Shoko Tsuchimine,2 Miki Nishimura,1 Naoki Ogusu,1 Norio Yasui-Furukori21Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, JapanAbstract: It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis–Menten constant (Km and maximum velocity (Vmax, in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females who were treated with paroxetine. The CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 polymorphisms were evaluated. A total of 56 blood samples were collected from the patients. The Km and Vmax values of paroxetine were estimated for each patient. The allele frequencies of CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 were 6.7%, 0%, 10.0%, 56.7%, 0%, 26.7%, and 0%, respectively. The mean values of Km and Vmax were 50.5±68.4 ng/mL and 50.6±18.8 mg/day, respectively. Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2±18.3 ng/mL versus 122.5±106.3 ng/mL, P=0.008; 44.2±16.1 mg/day versus 68.3±15.0 mg/day, P=0.022, respectively. This is the first study to demonstrate that the CYP2D6*10 polymorphism could affect the nonlinear pharmacokinetic parameter estimates of

  20. Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.

    Shen, Hong-Wu; Wu, Chao; Jiang, Xi-Ling; Yu, Ai-Ming

    2010-07-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency (V(max)/K(m)), respectively, in producing bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R(2)=0.98; P<0.0001) and CYP2D6 contents (R(2)=0.77; P=0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6. PMID:20206139

  1. Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

    Ana Fernández-Santander

    Full Text Available Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001. No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively, as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.

  2. META-ANALYSIS OF CYP2D6 METABOLIZER PHENOTYPE AND METOPROLOL PHARMACOKINETICS

    Blake, CM; Kharasch, ED; Schwab, M.; Nagele, P.

    2013-01-01

    Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate release metoprolol was performed. ...

  3. Active Matter on Asymmetric Substrates

    Reichhardt, C. J. Olson; Drocco, J.; Mai, T.; Wan, M. B.; Reichhardt, C.

    2011-01-01

    For collections of particles in a thermal bath interacting with an asymmetric substrate, it is possible for a ratchet effect to occur where the particles undergo a net dc motion in response to an ac forcing. Ratchet effects have been demonstrated in a variety of systems including colloids as well as magnetic vortices in type-II superconductors. Here we examine the case of active matter or self-driven particles interacting with asymmetric substrates. Active matter systems include self-motile c...

  4. Prolactin release in children treated with risperidone: impact and role of CYP2D6 metabolism.

    Troost, P.W.; Lahuis, B.E.; Hermans, M.H.; Buitelaar, J.K.; Engeland, H. van; Scahill, L.; Minderaa, R.B.; Hoekstra, P.J.

    2007-01-01

    OBJECTIVE: Little is known about the role of CYP2D6 polymorphism in risperidone-induced prolactin release in children. METHOD: Twenty-five children (aged 5-15 years) with pervasive developmental disorders were genotyped for CYP2D6 polymorphisms. Serum prolactin, risperidone, and 9-hydroxyrisperidone

  5. ASA法测定细胞色素P450 2D6酶缺陷等位基因CYP2D6E%Analysis of cytochrome P450 2D6 enzyme defect allele CYP2D6E by allele-specific amplification

    陈枢青; Wedl.,PJ

    1999-01-01

    目的:建立细胞色素P450 2D6(CYP2D6)第3023位A→C突变造成CYP2D6酶活性缺陷的等位基因CYP2D6E的测定方法.方法:利用等位基因特异扩增法(ASA)为基本原理,设计两对引物分别扩增野生型等位基因和突变型等位基因.结果:经396例测定,发现2例CYP2D6E与CYP2D6B的异突变型纯合子,其表现型均为慢代谢者.阳性对照说明本法重复性好,阴性对照显示本法无污染问题.结论:本法比PCR-RFLP法更为快捷、更少污染.对CYP2D6E的测定有助于准确预测CYP2D6表现型.

  6. Novel +90G>A Intronic Polymorphism of CYP2D6

    Monir Modaresi-nejad

    2015-04-01

    Full Text Available Objective: CYP2D6, an enzyme, metabolizes a large number of commonly prescribed drugs. Variations in CYP2D6 gene encoding this enzyme have been associated with individual differences in drug metabolism rates. The purpose of our study was to identify some allelic variants of CYP2D6 gene and to detect defective CYP2D6 alleles, as part of a pharmacogenetic screening program. Materials and Methods: A prospective study was done on 120 participants referred to Royan Institute in 2013. Allele and genotype frequencies for polymorphism of CYP2D6 gene in exons 1 and 4 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP analysis and sequencing on PCR products, respectively. Results: We identified a novel variant of the gene encoding cytochrome P450 2D6 (CYP2D6 at position +90 of intron 4 by sequencing method. This novel polymorphism of CYP2D6 has been deposited in GeneBank® under the accession number KF225465 in Jun 2013. Conclusion: In the current study, we identified novel polymorphism in intron 4. This single nucleotide polymorphism (SNP is known as +90G>A in the fourth intron.

  7. Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants.

    Subehan; Usia, Tepy; Iwata, Hiroshi; Kadota, Shigetoshi; Tezuka, Yasuhiro

    2006-05-24

    Thirty samples of Indonesian medicinal plants were tested for their mechanism-based inhibition on cytochrome P450 3A4 (CYP3A4) and CYP2D6 via erythromycin N-demethylation and dextromethorphan O-demethylation activities in human liver microsomes. From screening with 0 and 20min preincubation at 0.5mg/ml of methanol extracts, five plants (Cinnamomum burmani bark, Foeniculum vulgare seed, Strychnos ligustrina wood, Tinospora crispa stem, and Zingiber cassumunar rhizome) showed more than 30% increase of CYP3A4 inhibition, while three (Alpinia galanga rhizome, Melaleuca leucadendron leaf, and Piper nigrum fruit) showed more than 30% increase of CYP2D6 inhibition. In these eight plants, Foeniculum vulgare seed, Cinnamomum burmani bark, and Strychnos ligustrina wood showed time-dependent inhibition on CYP3A4 and Piper nigrum fruit and Melaleuca leucadendron leaf on CYP2D6. Among these, four plants other than Melaleuca leucadendron revealed NADPH-dependent inhibition. Thus, Foeniculum vulgare, Cinnamomum burmani, and Strychnos ligustrina should contain mechanism-based inhibitors on CYP3A4 and Piper nigrum contain that on CYP2D6. PMID:16414224

  8. Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-Methoxy-N,N-dimethyltryptamine Metabolism and Pharmacokinetics

    Shen, Hong-Wu; Wu, Chao; Jiang, Xi-Ling; Yu, Ai-Ming

    2010-01-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibi...

  9. A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine

    Jornil, J; Nielsen, T S; Rosendal, I;

    2013-01-01

    pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity...... combined with genotyping were considered very useful in this fatal drug poisoning case. Keywords CYP2D6; CYP2C19; Venlafaxine; Poor metabolizer; Drug poisoning; Mechanistic pharmacokinetic simulation --------------------------------------------------------------------------------...

  10. Distribution of CYP2D6 alleles and phenotypes in the Brazilian population.

    Deise C Friedrich

    Full Text Available The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The CYP2D6 gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of CYP2D6 alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and CYP2D6 duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen CYP2D6 alleles were identified in the Brazilian population. The CYP2D6*1 and CYP2D6*2 alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of CYPD6 alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil to 10.2% (Northern Brazil. The analysis of molecular variance showed that CYP2D6 is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%. Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique CYP2D6 testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions.

  11. Meta-Analysis of Cytochrome P2D6 Gene Polymorphisms and Susceptibility to Acute Leukemia

    Ma Limin; Ruan Linhai

    2013-01-01

    Objective:To provide a more robust assessment to the effect of cytochrome P2D6 (CYP2D6) polymorphisms on the risk of acute leukemia (AL), and to evaluate the association between the two most commonly studied CYP2D6 polymorphisms (CYP2D6*3 and CYP2D6*4) and AL risk by meta-analysis. Methods:All case-control studies investigating an association between the CYP2D6*3 or CYP2D6*4 polymorphisms and AL risk were included. Either fixed-effects or random-effects models were applied to combine odds ratios (ORs) and 95%conifdence intervals (CIs) by RevMan 5.1. Q-statistic was used to evaluate the heterogeneity, and both Egger’s test and funnel plots were used to assess publication bias. Results:Six studies were included in the meta-analysis. The results we acquired were that the OR value and 95%CI of CYP2D6*4 wild type, heterozygous mutant and homozygous mutant were 0.94 (0.66-1.35), 1.04(0.74-1.45) and 1.63 (0.95-2.81), respectively with Z=0.33, 0.23 and 1.76 (P>0.05), indicating that there was no signiifcant association between CYP2D6*4 polymorphism and the risk of AL. We also performed subgroup analysis by the AL immunophenotype for those groups with heterogeneity. The results of the combined analysis of CYP2D6*4 wild type, heterozygous mutant and acute lymphoblastic leukemia (ALL) were Z=0.08, 0.08 (P>0.05), for acute myeloblastic leukemia (AML) were Z=0.17, 0.26 (P>0.05), indicating that there was no signiifcant association between CYP2D6*4 polymorphism and the development of both ALL and AML. Conclusion:CYP2D6 polymorphisms are not associated with AL risk.

  12. Lack of association between schizophrenia and the CYP2D6 gene polymorphisms

    Pirmohamed, M.; Wild, M.J.; Kitteringham, N.R. [Univ. of Liverpool (United Kingdom)] [and others

    1996-04-09

    Approximately 5-10% of the Caucasian population lack the P450 isoform, CYP2D6. This polymorphism may be of importance in determining individual susceptibility to Parkinson`s disease. In this journal, Daniels et al. recently reported a negative association between the CYP2D6 gene locus and schizophrenia, a disease characterized by dopamine overactivity. It is important to exclude such an association because CYP2D6 is expressed in the brain and it is involved in dopamine catabolism. Between 1992 and 1993, we also performed a study similar to that, and reached the same conclusion. 7 refs., 1 tab.

  13. Three new alternative splicing variants of human cytochrome P450 2D6 mRNA in human extratumoral liver tissue

    Jian Zhuge; Ying-Nian Yu

    2004-01-01

    AIM: To identify the new alternative splicing variants of human CYP2D6 in human extratumoral liver tissue with RT-PCR and sequencing.METHODS: Full length of human CYP2D6 cDNAs was amplificated by reverse transcription-polymerase chain reaction (RT-PCR) from a human extratumoral liver tissue and cloned into pGEM-T vector. The cDNA was sequenced.Exons from 1 to 4 of human CYP2D6 cDNAs were also amplificated by RT-PCR from extratumoral liver tissues of17 human hepatocellular carcinomas. Some RT-PCR products were sequenced. Exons 1 to 4 of CYP2D6 gene were amplified by PCR from extratumoral liver tissue DNA.Two PCR products from extratumoral liver tissues expressing skipped mRNA were partially sequenced.RESULTS: One of the CYP2D6cDNAs had 470 nucleotides from 79 to 548 (3' portion of exons 1 to 5' portion of exon 4),and was skipped. Exons 1 to 4 of CYP2D6 cDNA were assayed with RT-PCR in 17 extratumoral liver tissues. Both wild type and skipped mRNAs were expressed in 4 samples,only wild type mRNA was expressed in 5 samples, and only skipped mRNA was expressed in 8 samples. Two more variants were identified by sequencing the RT-PCR products of exons 1 to 4 of CYP2D6cDNA. The second variant skipped 411 nucleotides from 175 to 585. This variant was identified in 4 different liver tissues by sequencing the RT-PCR products. We sequenced partially 2 of the PCR products amplified of CYP2D6 exon 1 to exon 4 from extratumoral liver tissue genomic DNA that only expressed skipped mRNA by RT-PCR. No point mutations around exon 1, intron 1, and exon 4, and no deletion in CYP2D6gene were detected. The third variant was the skipped exon 3, and 153 bp was lost.CONCLUSION: Three new alternative splicing variants of CYP2D6 mRNA have been identified. They may not be caused by gene mutation and may lose CYP2D6 activity and act as a down-regulator of CYP2D6.

  14. CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients

    Sirachainan E

    2012-10-01

    Full Text Available Ekaphop Sirachainan,1 Sureerat Jaruhathai,1 Narumol Trachu,2 Ravat Panvichian,1 Thitiya Sirisinha,1 Touch Ativitavas,1 Vorachai Ratanatharathorn,1 Montri Chamnanphon,3 Chonlaphat Sukasem31Division of Medical Oncology, Department of Medicine, 2Research Center, Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAim: We evaluated single nucleotide polymorphisms (SNPs of CYP2D6 to identify those that influence the efficiency of tamoxifen in adjuvant treatment of breast cancer through a matched case–control study.Methods: Peripheral blood DNA was collected from 20 patients with disease recurrence during adjuvant tamoxifen treatment and from 19 patients who had completed 5 years of tamoxifen therapy without recurrence of breast cancer. CYP2D6*4 (1846G > A; rs3892097, CYP2D6*10 (100C > T, rs1065852, and CYP2D6*5 (deletion were genotyped. The correlation between disease-free survival (DFS and genotype and clinical outcome were assessed using Kaplan–Meier analysis and a log-rank test.Results: We found the allelic frequency of CYP2D6*10 during this study. Patients with the CYP2D6*10 homozygous variant T/T genotype had a significantly shorter median of DFS than those with C/T (P = 0.036, but DFS was not significantly different from that of patients with the C/C genotype (P = 0.316. One patient who was a carrier both of CYP2D6 G/A (1846G > A and T/T (100C > T had DFS of 22.7 months.Conclusions: This study demonstrated that CYP2D6*10/*10 was significantly associated with shorter DFS in Thai breast cancer patients receiving tamoxifen. This was a pilot study investigating the correlation of CYP2D6 polymorphisms and their influence on clinical outcomes in Thai estrogen receptor

  15. Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

    Kristin eDickschen

    2012-05-01

    Full Text Available Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+ mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6. It is widely accepted that CYP2D6 poor metabolizers (PM exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers (EM. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved.In this context, physiologically-based pharmacokinetic (PBPK-modeling provides a useful tool to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy.It has long been thought that only a minor percentage of endoxifen is formed via 4-hydroxytamoxifen. However, the current investigation supports very recently published data that postulates a contribution of 4-hydroxytamoxifen above 20 % to total endoxifen formation. The developed PBPK-model describes tamoxifen PK in rats and humans. Moreover, tamoxifen metabolism in dependence of CYP2D6 phenotype in populations of European female individuals is well described, thus providing a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity or co-treatment with CYP2D6 inhibitors.

  16. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine

    Jeppesen, U; Gram, L F; Vistisen, K;

    1996-01-01

    OBJECTIVE: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. METHODS: The study was...... by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given...... fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady...

  17. Impact of Tetrahydropalmatine on the Pharmacokinetics of Probe Drugs for CYP1A2, 2D6 and 3A Isoenzymes in Beagle Dogs.

    Zhao, Yong; Liang, Aihua; Zhang, Yushi; Li, Chunying; Yi, Yan; Nilsen, Odd Georg

    2016-06-01

    Tetrahydropalmatine (Tet) exhibit multiple pharmacological activities and is used frequently by clinical practitioners. In this study, we evaluate the in vivo effects of single and repeated oral Tet administrations on CYP1A2, 2D6 and 3A activities in six beagle dogs in a randomized, controlled, open-label, crossover study. A cocktail approach, with dosages of the probe drugs caffeine (3.0 mg/kg), metoprolol (2.33 mg/kg) and midazolam (0.45 mg/kg), was used to measure cytochrome P450 (CYP) metabolic activities. The cocktail was administered orally as a single dose (12 mg/kg) 1 day prior to and 4 days after repeated oral Tet administrations (12 mg/kg three times daily). The probe drugs and their metabolites in plasma were quantified simultaneously by a validated HPLC technique, and non-compartmental parameters were used to evaluate metabolic variables for assessment of CYP inhibition or induction. Tet had no or minor impact on the pharmacokinetics and metabolism of the probe drugs caffeine and metoprolol, CYP1A2 and CYP2D6 substrates, respectively. However, Tet increased AUC0-24 h and decreased AUCratio(0-24 h) (1-hydroxymidazolam/midazolam ratio) for midazolam statistically significant, both in single or multiple dosing of Tet, with up to 39 or 57% increase for AUC0-24 h and 29% or 22 decrease for AUCratio(0-24 h), respectively, in line with previous in vitro findings for its CYP3A4 inhibition. The extensive use of Tet and herbal medicines containing Tet makes Tet a candidate for further evaluation of CYP3A-mediated herb-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26990021

  18. Active matter on asymmetric substrates

    Olson Reichhardt, C. J.; Drocco, J.; Mai, T.; Wan, M. B.; Reichhardt, C.

    2011-10-01

    For collections of particles in a thermal bath interacting with an asymmetric substrate, it is possible for a ratchet effect to occur where the particles undergo a net dc motion in response to an ac forcing. Ratchet effects have been demonstrated in a variety of systems including colloids as well as magnetic vortices in type-II superconductors. Here we examine the case of active matter or self-driven particles interacting with asymmetric substrates. Active matter systems include self-motile colloidal particles undergoing catalysis, swimming bacteria, artificial swimmers, crawling cells, and motor proteins. We show that a ratchet effect can arise in this type of system even in the absence of ac forcing. The directed motion occurs for certain particle-substrate interaction rules and its magnitude depends on the amount of time the particles spend swimming in one direction before turning and swimming in a new direction. For strictly Brownian particles there is no ratchet effect. If the particles reflect off the barriers or scatter from the barriers according to Snell's law there is no ratchet effect; however, if the particles can align with the barriers or move along the barriers, directed motion arises. We also find that under certain motion rules, particles accumulate along the walls of the container in agreement with experiment. We also examine pattern formation for synchronized particle motion. We discuss possible applications of this system for self-assembly, extracting work, and sorting as well as future directions such as considering collective interactions and flocking models.

  19. CARACTERIZACIÓN DE VARIANTES ALÉLICAS DE CITOCROMO CYP2D6 EN LA POBLACIÓN DE LA REGIÓN CENTROCCIDENTAL DE VENEZUELA

    GRIMÁN PEDRO

    2009-04-01

    Full Text Available

    RESUMEN

    El gen CYP2D6 codifica para una monooxigenasa perteneciente al citocromo P450, la cual está involucrada en la biotransformación de un gran número de drogas comúnmente prescritas, como antidepresivos, antineoplásicos y antihipertensivos. Algunos efectos adversos, así como falla terapéutica pueden ser relacionados con la actividad anormal de CYP2D6 producto de polimorfismos en el gen de dicha enzima. Con el fin de predecir la frecuencia de algunos fenotipos metabolizadores pobres de CYP2D6 en la población de la región centroccidental de Venezuela se determinaron las frecuencias alélicas y genotípicas de las variantes alélicas CYP2D6*3, *4 y *6. Se extrajo ADN genómico a partir de sangre periférica de 100 individuos voluntarios aparentemente sanos, y se procedió a la genotipificación por PCR tetra-primer alelo-específica y análisis por electroforesis en geles de agarosa. Se compararon las frecuencias obtenidas con poblaciones de otros países. El alelo más frecuente fue CYP2D6*4 con 16,5%, mostrando una diferencia significativa con la reportada con poblaciones asiáticas. Este trabajo constituye un estudio preliminar en la caracterización de un grupo más amplio de alelos de CYP2D6 con el fin de asistir al desarrollo de una farmacoterapia individualizada en nuestro país.

    Palabras clave: Citocromo P450, CYP2D6, Farmacogenética.


    ABSTRACT

    The CYP2D6 gene encodes for a monooxygenase belonging to the cytochrome P450, which is involved in the biotransformation of a large number of commonly prescribed drugs such as antidepressants, antihypertensive and antineoplastic. Some side effects, as well as therapeutic failure may be related to abnormal activity of CYP2D6 product of polymorphisms in the CYP2D6 gene. In order to predict the frequency of some poor metabolisers phenotypes of CYP2D6 in the population of the

  20. CYP2D6基因多态性及其临床意义

    徐艳娇; 龚森; 纪洪艳; 刘东

    2012-01-01

    CYP2D6是CYP酶系中重要的一种氧化代谢酶,参与多种药物的代谢.CYP2D6具有基因多态性,使药物代谢在不同种族之间,甚至在同种族不同人群中产生较大的差异,从而影响药物的疗效.因此,深入了解CYP2D6基因的多态性以及对药物代谢的影响,对指导临床合理用药和调整用药方案具有重大意义.

  1. Allelic distributions of CYP2D6 gene copy number variation in the Eastern Han Chinese population

    Hai-hui SHENG; Yun-lan DU; Jian SUN; Hua-sheng XIAO; Ai-ping ZENG; Wen-xiang ZHU; Ren-fang ZHU; Hong-mei LI; Zhi-dong ZHU; Ying QIN; Wei JIN; Yan LIU

    2007-01-01

    Aim: The human cytochrome P450 2D6 (CYP2D6) gene copy number variation, involving CYP2D6 gene deletion (CYP2D6*5) and duplication or multiduplication (CYP2D6*×N), can result in reduced or increased metabolism of many clinically used drugs. The identification of CYP2D6*5 and CYP2D6*×N and the investigation of their allelic distributions in ethnic populations can be important in deter-mining the right drug and dosage for each patient. Methods: The CYP2D6*5 andCYP2D6 genes, and CYP2D6 gene duplication were identified by 2 modified long PCR, respectively. To determine duplicated alleles, a novel long PCR was developed to amplify the entire duplicated CYP2D6 gene which was used as template for subsequent PCR amplification. A total of 363 unrelated Eastern Han Chinese individuals were analyzed for CYP2D6 gene copy number variation. Results: The frequency of CYP2D6*5 and CYP2D6*×N were 4.82% (n=35) and 0.69% (n=5) in the Eastern Han Chinese population, respectively. Of the 5 duplicated alleles, 3were CYP2D6*1×N and 2 were CYP2D6*10×N. One individual was a carrier of both CYP2D6*5 and CYP2D6*1×N. Taken together, the CYP2D6 gene rear-rangements were present in 10.74% of subjects. Conclusion: Allelic distributions of the CYP2D6 gene copy number variation differ among Chinese from different regions, indicating ethnic variety in Chinese. Long PCR are convenient, cost effective, specific and semiquantitative for the detection of the CYP2D6 gene copy number variation, and amplification of the entire duplicated CYP2D6 gene is necessary for the accurate identification of duplicated alleles.

  2. Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans.

    Céspedes-Garro, Carolina; Jiménez-Arce, Gerardo; Naranjo, María-Eugenia G; Barrantes, Ramiro; Llerena, Adrián

    2014-12-01

    CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with Ibero-American populations published data. Finally, we also aimed to describe allele frequencies among different Costa Rican ethnic groups. This research has been undertaken within the framework of the RIBEF CEIBA Consortium studies on Latin American populations. A total of 385 individuals were included in the study: 139 mestizos, 197 Amerindians, and 49 Afro-Caribbeans. CYP2D6 genotypes were determined by XL-PCR and Real-Time PCR. The CYP2D6 variant alleles *2, *3, *4, *5, *6, *10, "17, *29, *35 and *41 were also determined. For the entire Costa Rican population, the frequency of PMs and UMs was 6% and 6.5%, respectively. The percentage of UMs in the mestizo population was higher than in the Amerindian population. CYP2D6 UMs vary from 3.6% to 10.1% and PMs from 1.4% to 10.2% among three Costa Rican groups. The highest frequencies of UMs (10.1%) and PMs (10.2%) were found in the mestizo and Amerindian populations, respectively. In conclusion, the frequencies of UMs and PMs for CYP2D6 varied widely across the mestizo, Amerindian and Afro-Caribbean Costa Rican populations. Future research in this population should be oriented to identify new CYP2D6 variants through sequencing methods, as well as

  3. Determination of Cytochrome P450 2D6 (CYP2D6 Gene Copy Number by Real-Time Quantitative PCR

    Laurent Bodin

    2005-01-01

    Full Text Available Gene dosage by real-time quantitative PCR has proved to be accurate for measuring gene copy number. The aim of this study was to apply this approach to the CYP2D6 gene to allow for rapid identification of poor and ultrarapid metabolizers (0, 1, or more than 2 gene copy number. Using the 2−ΔΔCt calculation method and a duplex reaction, the number of CYP2D6 gene copies was determined. Quantitative PCR was performed on 43 samples previously analyzed by Southern blotting and long PCR including 20 samples with a heterozygous deletion, 11 with normal copy number (2 copies, and 12 samples with duplicated genes. The average ratio ranged from 1.02 to 1.28, 1.85 to 2.21, and 2.55 to 3.30, respectively, for the samples with 1 copy, 2 copies, and 3 copies. This study shows that this method is sensitive enough to detect either a heterozygous gene deletion or duplication.

  4. Does the Medication Pattern Reflect the CYP2D6 Genotype in Patients With Diagnoses Within the Schizophrenic Spectrum?

    Jürgens, Gesche; Rasmussen, Henrik B; Werge, Thomas;

    2012-01-01

    Cytochrome P450 2D6 enzyme (CYP2D6) is an important metabolic pathway for many antipsychotics. Its genetic polymorphism causes pharmacokinetic variability that might lead to adverse drug reactions or treatment failure unless countered by appropriate dose adjustments or shift to CYP2D6-independent...

  5. The influence of the CYP2D6*4 polymorphism on drug response and disease susceptibility

    M.J. Bijl (Monique)

    2009-01-01

    textabstractThis thesis is about the role of CYP2D6, a drug-metabolizing enzyme, in today’s pharmacotherapy. Cytochrome P450 2D6 (CYP2D6) is an important member of a large family of enzymes with the name cytochrome P450 which is abundantly present in most non-monocellular living organisms. Its histo

  6. An optimized methodology for combined phenotyping and genotyping on CYP2D6 and CYP2C19

    Tamminga, C.A; Wemer, J; Oosterhuis, B; Brakenhoff, J.P G; Gerrits, M.G F; de Zeeuw, R.A; de Leij, Lou; Jonkman, J.H.G.

    2001-01-01

    A method for simultaneous phenotyping and genotyping for CYP2D6 and CYP2C19 was tested. Six healthy volunteers were selected (three extensive and three poor metabolisers for CYP2D6). CYP2D6 was probed with dextromethorphan and metoprolol and CYP2C19 was probed with omeprazole. Blood samples were col

  7. Role of Pharmacogenetics in Improving the Safety of Psychiatric Care by Predicting the Potential Risks of Mania in CYP2D6 Poor Metabolizers Diagnosed With Bipolar Disorder.

    Sánchez-Iglesias, Santiago; García-Solaesa, Virginia; García-Berrocal, Belén; Sanchez-Martín, Almudena; Lorenzo-Romo, Carolina; Martín-Pinto, Tomás; Gaedigk, Andrea; González-Buitrago, José Manuel; Isidoro-García, María

    2016-02-01

    One of the main concerns in psychiatric care is safety related to drug management. Pharmacogenetics provides an important tool to assess causes that may have contributed the adverse events during psychiatric therapy. This study illustrates the potential of pharmacogenetics to identify those patients for which pharmacogenetic-guided therapy could be appropriate. It aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as a primary improvement for predicting side effects.A broad series of 224 psychiatric patients comprising psychotic disorders, depressive disturbances, bipolar disorders, and anxiety disorders was included. The patients were genotyped with the AmpliChip CYP450 Test to analyzing 33 allelic variants of the CYP2D6 gene.All bipolar patients with poor metabolizer status showed maniac switching when CYP2D6 substrates such as selective serotonin reuptake inhibitors were prescribed. No specific patterns were identified for adverse events for other disorders.We propose to utilize pharmacogenetic testing as an intervention to aid in the identification of patients who are at risk of developing affective switching in bipolar disorder treated with selective serotonin reuptake inhibitors, CYP2D6 substrates, and inhibitors. PMID:26871771

  8. Correlation between polymorphism of CYP2D6 gene with effect of tamoxifen in patients with breast cancer%CYP2D6多态性与乳腺癌患者他莫昔芬疗效的相关性

    田超; 杨义; 李卉

    2014-01-01

    目的 探讨CYP2D6基因多态性与乳腺癌患者他莫昔芬(TAM)及其活性代谢产物4-羟基他莫昔芬(4-OH-TAM)血清浓度的相关性,并探讨CYP2D6基因多态性与乳腺癌患者预后的相关性.方法 收集2008年1月至2010年10月期间200例服用TAM的乳腺癌患者的口腔黏膜及血清标本,采用Real-time RT-PCR法检测CYP2D6* 10基因多态性,并分析其与临床病理特征和预后的关系.采用液相色谱-质谱方法(LC-MS)测定患者体内TAM及其活性代谢物4-OH-TAM的血清浓度.结果 200例乳腺癌中检测到CYP2D6* 10/* 10纯合子94例(47%),CYP2D6 wt/wt野生型48例(24%),CYP2D6 wt/* 10杂合型58例(29%).CYP2D6 wt/wt野生型和wt/* 10杂合型两组4-OH-TAM的血清浓度都明显高于*10/*10纯合型(F=4.31,P=0.01).CYP2D6* 10基因多态性与患者各项临床病理因素均无关(均P >0.05).Log-rank检验分析显示CYP2D6突变组患者平均无病生存时间(47.2个月)明显短于CYP2D6正常组患者(51.2个月),P=0.018.Cox回归分析显示CYP2D6基因型与患者无病生存时间明显相关(HR=2.755,95%CI:1.230 ~6.173,P=0.014).结论 CYP2D6*10/*10基因型与乳腺癌他莫昔芬的疗效相关,检测CYP2D6基因型可能有助于临床上有效选择他莫昔芬.%Objective To investigate the correlation of CYP2D6 gene polymorphism and serum tamoxifen (TAM) and its active metabolites (4-hydroxy tamoxifen,4-OH-TAM) in terms of prognosis of breast cancer patients.Methods The oral mucosas and serum were obtained from 200 breast cancer patients receiving oral TAM from Jan 2008 to Oct 2010.Real-time RT-PCR was used to determine CYP2D6* 10 gene polymorphism.The relationship between CYP2D6* 10 gene polymorphism and clinicopathological features and prognosis was assessed by Chi-square test and Cox proportional model.Serum TAM and 4-OH-TAM concentration were determined by liquid chromatography-trap mass spectrometry (LC-MS).Results Of 200 breast cancer patients,CYP2D6 * 10/* 10

  9. Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

    Ramón Cacabelos

    2012-01-01

    Full Text Available Dementia is a major problem of health in developed societies. Alzheimer’s disease (AD, vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.

  10. CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals.

    Schmid, Yasmin; Vizeli, Patrick; Hysek, Cédric M; Prestin, Katharina; Meyer Zu Schwabedissen, Henriette E; Liechti, Matthias E

    2016-08-01

    The role of genetic polymorphisms in cytochrome (CYP) 2D6 involved in the metabolism of 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) is unclear. Effects of genetic variants in CYP2D6 on the pharmacokinetics and pharmacodynamic effects of MDMA were characterized in 139 healthy individuals (70 men, 69 women) in a pooled analysis of eight double-blind, placebo-controlled crossover studies. In CYP2D6 poor metabolizers, the maximum concentrations (Cmax) of MDMA and its active metabolite 3,4-methylene-dioxyamphetamine were +15 and +50% higher, respectively, compared with extensive metabolizers and the Cmax of the inactive metabolite 4-hydroxy-3-methoxymethamphetamine was 50-70% lower. Blood pressure and subjective drug effects increased more rapidly after MDMA administration in poor metabolizers than in extensive metabolizers. In conclusion, the disposition of MDMA and its effects in humans are altered by polymorphic CYP2D6 activity, but the effects are small because of the autoinhibition of CYP2D6. PMID:27253829

  11. Novel variant of CYP2D6*6 is undetected by a commonly used genotyping procedure

    Rasmussen, Henrik Berg; Werge, Thomas

    2011-01-01

    We report the identification of a novel and defective variant of the gene encoding cytochrome P450 2D6 (CYP2D6). This novel variant is a subtype of CYP2D6*6 that was undetected by a commercially available 5' exonuclease-based assay. Because the novel variant was found in only one of 609 individuals......, it represents a rare subtype of CYP2D6*6 that may be restricted to a single family or a subpopulation. A procedure for the identification of the novel CYP2D6*6 variant using restriction enzyme treatment of amplified fragments was developed....

  12. Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination.

    Laurent-Kenesi, M A; Funck-Brentano, C; Poirier, J M; Decolin, D; Jaillon, P

    1993-01-01

    1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-bl...

  13. Pharmacokinetic interactions between monoamine oxidase A inhibitor harmaline and 5-methoxy-N,N-dimethyltryptamine, and the impact of CYP2D6 status.

    Jiang, Xi-Ling; Shen, Hong-Wu; Mager, Donald E; Yu, Ai-Ming

    2013-05-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics. PMID:23393220

  14. Effects of CYP2D6 and UGT2B7 polymorphisms on pharmacokinetics of tamoxifen in Thai breast cancer patients

    Areepium N

    2013-08-01

    Full Text Available N Areepium,1 D Panomvana,1 P Rungwanonchai,1 S Sathaporn,2 N Voravud3 1Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 2Department of Surgery, Phramongkutklao Hospital, Bangkok, 3Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Purpose: The objective of this study was to evaluate the impact of CYP2D6 and UGT2B7 polymorphisms on tamoxifen (TAM pharmacokinetics in Thai breast cancer patients. Methods: Thai female breast cancer patients treated with TAM were included in the study. Patients were genotyped for CYP2D6 and UGT2B7 polymorphism, and plasma levels of TAM and its potent active metabolite endoxifen (END, at steady state, were identified. Results: Fifty-nine female breast cancer patients were included in the study. The average age was 50 ± 9.3 years old; 76% were premenopausal and 85% had estrogen receptor-positive breast cancer. The allele frequencies of CYP2D6*10 and UGT2B7*2 were 53% and 28%, respectively. Patients with CYP2D6*10/*10 had lower END concentrations compared with CYP2D26*1/*10 and CYP2D6*1/*1 (9.62 ng/mL versus 15.67 ng/mL and 21.55 ng/mL, respectively, P = 0.045. Polymorphisms of UGT2B7 alone did not have any impact on TAM metabolism. However, among 20 patients with CYP2D6*10/*10, one with UGT2B7*2/*2 had higher END concentrations compared against patients with UGT2B7*1/*1 and UGT2B7*1/*2 (31.36 ng/mL versus 7.86 ng/mL, respectively, P = 0.023. Conclusion: Results from this study confirmed the impacts of CYP2D6 polymorphisms on the pharmacokinetics of TAM, while UGT2B7 polymorphisms tended to have impact on TAM metabolism in patients with homozygous CYP2D6*10. Keywords: tamoxifen, pharmacogenomics, CYP2D6, UGT2B7, breast cancer

  15. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

    ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R

    2014-01-01

    AIMS: Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clin

  16. An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.

    Halliday, R C; Jones, B. C.; Smith, D. A.; N. R. Kitteringham; Park, B.K.

    1995-01-01

    1. We have assessed the interaction of the antimalarial halofantrine with cytochrome P450 (CYP) enzymes in vitro, with the use of microsomes from human liver and recombinant cell lines. 2. Rac-halofantrine was a potent inhibitor (IC50 = 1.06 microM, Ki = 4.3 microM) of the 1-hydroxylation of bufuralol, a marker for CYP2D6 activity. Of a group of structurally related antimalarials tested, only quinidine (IC50 = 0.04 microM) was more potent. 3. Microsomes prepared from recombinant CYP2D6 and CY...

  17. CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment.

    Almoguera, Berta; Riveiro-Alvarez, Rosa; Lopez-Castroman, Jorge; Dorado, Pedro; Vaquero-Lorenzo, Concepción; Fernandez-Piqueras, José; Llerena, Adrián; Abad-Santos, Francisco; Baca-García, Enrique; Dal-Ré, Rafael; Ayuso, Carmen

    2013-11-01

    The variability in the antipsychotic response is, to some extent, genetically determined. Several studies have attempted to establish a role for genetic variation in genes coding pharmacokinetic and pharmacodynamic targets, but to date, no definite genetic predictive marker has been identified. We aimed to explore the putative role of 19 genetic variants and risperidone clinical improvement in 76 White schizophrenic inpatients, measured as change in Positive and Negative Syndrome Scale (PANSS). CYP2D6 poor metabolism was significantly associated with greater clinical improvement in total PANSS and a trend was also found for MDR1 3435C>T to higher total PANSS scores in 3435T carriers. This study suggests the importance that genetic variability on pharmacokinetic factors may have in risperidone response and gives evidence for the need for further investigation in order to establish the actual predictive value and clinical utility that CYP2D6 genotyping might have in risperidone therapy management. PMID:24026091

  18. Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6.

    González-Vacarezza, N; Abad-Santos, F; Carcas-Sansuan, A; Dorado, P; Peñas-Lledó, E; Estévez-Carrizo, F; Llerena, A

    2013-10-01

    In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrollment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and ≥ 2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products. PMID:22733239

  19. Molecular Dynamics Simulations to Investigate the Influences of Amino Acid Mutations on Protein Three-Dimensional Structures of Cytochrome P450 2D6.1, 2, 10, 14A, 51, and 62.

    Shuichi Fukuyoshi

    Full Text Available Many natural mutants of the drug metabolizing enzyme cytochrome P450 (CYP 2D6 have been reported. Because the enzymatic activities of many mutants are different from that of the wild type, the genetic polymorphism of CYP2D6 plays an important role in drug metabolism. In this study, the molecular dynamics simulations of the wild type and mutants of CYP2D6, CYP2D6.1, 2, 10, 14A, 51, and 62 were performed, and the predictions of static and dynamic structures within them were conducted. In the mutant CYP2D6.10, 14A, and 61, dynamic properties of the F-G loop, which is one of the components of the active site access channel of CYP2D6, were different from that of the wild type. The F-G loop acted as the "hatch" of the channel, which was closed in those mutants. The structure of CYP2D6.51 was not converged by the simulation, which indicated that the three-dimensional structure of CYP2D6.51 was largely different from that of the wild type. In addition, the intramolecular interaction network of CYP2D6.10, 14A, and 61 was different from that of the wild type, and it is considered that these structural changes are the reason for the decrease or loss of enzymatic activities. On the other hand, the static and dynamic properties of CYP2D6.2, whose activity was normal, were not considerably different from those of the wild type.

  20. Genetic polymorphism of CYP2D6 and its influence on the personalized usage of antipsychotics%CYP2D6基因多态性与抗精神病药物的个体化应用

    陈冰; 蔡卫民; 杨婉花

    2012-01-01

    CYP2D6是一种重要的细胞色素P450酶,存在着显著的基因多态性.CYP2D6在抗精神病类药物的代谢中发挥着重要作用,与许多抗精神病药物药动学及药效学的个体间变异存在着密切联系,检测CYP2D6基因型有助于患者抗精神病药物治疗方案的选择和调整,提高用药的安全性和有效性.本文综述CYP2D6基因多态性对抗精神病药物的药动学、不良反应及药物相互作用的影响,探讨了CYP2D6基因型检测在抗精神病个体化治疗中的应用前景.%CYP2D6 is one of the most important cytochrome P450 enzymes. There is remarkable genetic polymorphism of CYP2D6. CYP2D6 play an important role in the metabolism of antipsychotics, and has significant correlation with the inter-individual difference ol pharmacokinetics and pharmacodynamics of antipsychotics. Determination of CYP2D6 genotypes is helpful in the selection and regulation of antip-sychotic therapy regimen for the elevation of ef-ficiency and safety. The influence of CYP2D6 genetic polymorphism on the pharmacokinetics, adverse effect and drug-drug interaction was reviewed and the usefulness of CYP2D6 genoty-ping in the personalized antipsychotic therapy was discussed

  1. Genetic polymorphisms of CYP2D6 in Chinese mainland%中国大陆人群CYP2D6基因多态性的检测

    纪玲; 潘世秀; 等

    2002-01-01

    目的检测中国人群CYP2D6序列的差异性.方法在223个中国大陆人中,使用四引物聚合酶链反应、等位基因特异性扩增聚合酶链反应和多重长聚合酶链反应方法检测CYP2D6等位基因*2、*3、*4、*5、*6、*8、*10和*14.结果在中国人群中,频率最高的弱代谢(PM)等位基因是CYP2D6*5(7.2%),其次是仅存在于东方人中的CYP2D6*14(2.0%),再次为CYP2D6*4(0.2%),未发现CYP2D6*3、*6和*8等位基因.与白种人相比,中国大陆人群中分布频率最高的等位基因是CYP2D6*10(51.6%).结论在中国大陆人群中,PM等位基因CYP2D6* 5和CYP2D6* 14的频率比其它东方人高,但CYP2D6*10的频率比其它东方人低.%Objective To observe the significant differences in the frequencies of the cytochrome P450 2D6 (CYP2D6) alleles in Chinese popoulations. Methods Tetra-primer polymerase chain reaction (PCR), allele specific amplification (ASA) PCR and multiplex long PCR were developed to detect the CYP2D6 alleles * 2, * 3, * 4, * 5, * 6, * 8, * 10 and * 14 in 223 subjects from Chinese mainland.Results The CYP2D6*5 allele was the most frequent poor metabolizer (PM) allele in Chinese (7.2%), followed by CYP2D6*14 (2.0%) which was only detected in orientals. There was only 0.2% CYP2D6*4, and no CYP2D6*3, * 6 and * 8 were detected. In contrast to the Caucasians, the most frequent allele in Chinese was the * 10 allele with a frequency of 51.6%. Conclusion The frequencies of PM alleles, CYP2D6*5 and CYP2D6* 14, were higher; but the frequency of CYP2D6*10 was lower in mainland Chinese population than that in other orientals.

  2. Polymorphism of CYP2D6 gene and the influence on the metabolism of metoprolol%CYP2D6基因多态性及对美托洛尔代谢的影响

    熊丹; 熊玉卿

    2011-01-01

    CYP2D6是一种重要的P450系氧化代谢酶,主要参与多种重要药物的代谢.CYP2D6基因多态性会引起药物代谢有显著的个体和种族差异.美托洛尔为选择性β1受体阻滞剂,临床应用上存在巨大个体差异,主要在肝脏经多条途径代谢,大约70%的代谢由CYP2D6介导,CPY2D6基因多态性对美托洛尔代谢有较大影响.本文从CYP2D6的基因多态性及它对美托洛尔代谢的影响这两方面作一综述.%As one of major cytochrome P450s, CYP2D6 is responsible for the metabolism of many important drugs. Genetic polymorphism of CYP2D6 is the basis of lager interindividual and racial variability in the metabolism of drug. Metoprolol is a selective β1-adrenoceptor antagonist, there is an obvious individual difference in clinic. It is metabolized in the liver, in vivo data indicate that approximately 70% of themetabolism of metoptolol depends upon CYP2D6. Genetic polymorphism of CYP2D6 have a great influence on the metabolism of metoprolol. Here we summarize the polymorphism of CYP2D6 gene and the influence on the metabolism of metoprolol.

  3. The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers

    Tamminga, W.J; Wemer, J; Oosterhuis, B; de Zeeuw, R.A; de Leij, Lou; Jonkman, J.H.G.

    2001-01-01

    Aim: This study was performed in a sample of the Dutch population to estimate the prevalence of noncoding mutations of CYP2D6 and CYP2C19 as obtained by genotyping. In addition, the predictability of the genotyping strategy was assessed. Methods: The CYP2D6 and CYP2C19 status of 765 unrelated health

  4. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin

    Mulder, A B; van Lijf, H J; Bon, M A; van den Bergh, F A; Touw, D J; Neef, C; Vermes, I

    2001-01-01

    OBJECTIVE: Because clinical data about the therapeutic consequences of polymorphic oxidation of simvastatin by CYP2D6 have not been well reported, we sought to investigate the possible link between polymorphism of CYP2D6 and the efficacy and tolerability of simvastatin treatment in a group of 88 pat

  5. Antipsychotic-induced extrapyramidal syndromes and cytochrome P-450 2D6 genotype : a case-control study

    Schillevoort, [No Value; de Boer, A; van der Weide, J; Steijns, LSW; Roos, RAC; Jansen, PAF; Leufkens, HGM

    2002-01-01

    To study the association between polymorphism of the cytochrome P-450 2D6 gene (CYP2D6) and the risk of antipsychotic-induced extrapyramidal syndromes, as measured by the use of anti parkinsonian medication. Data for this case-control study were obtained from a psychiatric hospital where newly admit

  6. CYP2D6基因多态性与他奠昔芬治疗

    杨汐

    2011-01-01

    CYP2D6是细胞色素P450酶系中的一种重要的药物代谢酶,CYP2D6基因的遗传变异可导致CYP2D6酶活性的不同,从而影响他莫昔芬的代谢,使携带不同基因型的乳腺癌病人对他莫昔芬的治疗反应不同.本文从CYP2D6基因多态性与他莫昔芬代谢、疗效及预后、副反应的关系,CYP2D6抑制剂对他莫昔芬代谢的影响等方面进行了简要综述.

  7. CARACTERIZACIÓN DE VARIANTES ALÉLICAS DE CITOCROMO CYP2D6 EN LA POBLACIÓN DE LA REGIÓN CENTROCCIDENTAL DE VENEZUELA Characterization Of Cytochrome Cyp2d6 Allele Variants In The Population Of The Central-Western Region Of Venezuela

    PEDRO GRIMÁN

    Full Text Available El gen CYP2D6 codifica para una monooxigenasa perteneciente al citocromo P450, la cual está involucrada en la biotransformación de un gran número de drogas comúnmente prescritas, como antidepresivos, antineoplásicos y antihipertensivos. Algunos efectos adversos, así como falla terapéutica pueden ser relacionados con la actividad anormal de CYP2D6 producto de polimorfismos en el gen de dicha enzima. Con el fin de predecir la frecuencia de algunos fenotipos metabolizadores pobres de CYP2D6 en la población de la región centroccidental de Venezuela se determinaron las frecuencias alélicas y genotípicas de las variantes alélicas CYP2D6*3, *4 y *6. Se extrajo ADN genómico a partir de sangre periférica de 100 individuos voluntarios aparentemente sanos, y se procedió a la genotipificación por PCR tetra-primer alelo-específica y análisis por electroforesis en geles de agarosa. Se compararon las frecuencias obtenidas con poblaciones de otros países. El alelo más frecuente fue CYP2D6*4 con 16,5%, mostrando una diferencia significativa con la reportada con poblaciones asiáticas. Este trabajo constituye un estudio preliminar en la caracterización de un grupo más amplio de alelos de CYP2D6 con el fin de asistir al desarrollo de una farmacoterapia individualizada en nuestro país.The CYP2D6 gene encodes for a monooxygenase belonging to the cytochrome P450, which is involved in the biotransformation of a large number of commonly prescribed drugs such as antidepressants, antihypertensive and antineoplastic. Some side effects, as well as therapeutic failure may be related to abnormal activity of CYP2D6 product of polymorphisms in the CYP2D6 gene. In order to predict the frequency of some poor metabolisers phenotypes of CYP2D6 in the population of the Central-Western region of Venezuela it was determined the allelic and genotypic frequencies of CYP2D6 *3, *4, *6 allelic variants. DNA was extracted from peripheral blood of 100 apparently

  8. A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women.

    Ke, Alice Ban; Nallani, Srikanth C; Zhao, Ping; Rostami-Hodjegan, Amin; Isoherranen, Nina; Unadkat, Jashvant D

    2013-04-01

    Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy. PMID:23355638

  9. CYP2D7 sequence variation interferes with TaqMan CYP2D6*15 and *35 genotyping

    Amanda K Riffel

    2016-01-01

    Full Text Available TaqMan™ genotyping assays are widely used to genotype CYP2D6, which encodes a major drug metabolizing enzyme. Assay design for CYP2D6 can be challenging owing to the presence of two pseudogenes, CYP2D7 and CYP2D8, structural and copy number variation and numerous single nucleotide polymorphisms (SNPs some of which reflect the wild-type sequence of the CYP2D7 pseudogene. The aim of this study was to identify the mechanism causing false positive CYP2D6*15 calls and remediate those by redesigning and validating alternative TaqMan genotype assays. Among 13,866 DNA samples genotyped by the CompanionDx® lab on the OpenArray platform, 70 samples were identified as heterozygotes for 137Tins, the key SNP of CYP2D6*15. However, only 15 samples were confirmed when tested with the Luminex xTAG CYP2D6 Kit and sequencing of CYP2D6-specific long range (XL-PCR products. Genotype and gene resequencing of CYP2D6 and CYP2D7-specific XL-PCR products revealed a CC>GT dinucleotide SNP in exon 1 of CYP2D7 that reverts the sequence to CYP2D6 and allows a TaqMan assay PCR primer to bind. Because CYP2D7 also carries a Tins, a false-positive mutation signal is generated. This CYP2D7 SNP was also responsible for generating false-positive signals for rs769258 (CYP2D6*35 which is also located in exon 1. Although alternative CYP2D6*15 and *35 assays resolved the issue, we discovered a novel CYP2D6*15 subvariant in one sample that carries additional SNPs preventing detection with the alternate assay. The frequency of CYP2D6*15 was 0.1% in this ethnically diverse U.S. population sample. In addition, we also discovered linkage between the CYP2D7 CC>GT dinucleotide SNP and the 77G>A (rs28371696 SNP of CYP2D6*43. The frequency of this tentatively functional allele was 0.2%. Taken together, these findings emphasize that regardless of how careful genotyping assays are designed and evaluated before being commercially marketed, rare or unknown SNPs underneath primer and/or probe

  10. Cytochrome 450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation. A Case of Syncope Following

    Harry W. Daniell, MD

    2014-02-01

    Full Text Available An 81-year-old marathon runner-internist developed syncope followed by myocardial stunning two hours after conversion to normal sinus rhythm and 4 hours after adding a single 150mg dose of propafenone to 650mg of quinidine gluconate which he had ingested 3 hours earlier. Cardiac isoenzyme, electrolyte, CBC, TSH and EKG were normal. Echocardiogram one week later revealed left ventricular hypertrophy with an enlarged left atrium typical of men with habitual endurance-associated atrial fibrillation. Over the previous 24 years he had successfully converted more than 100 episodes of PAF with PIP oral quinidine sulfate (200mg-600mg or quinidine gluconate (650-975mg without utilizing other cardiac, anti-arrhythmic, or anti-coagulation therapy. Several months after we published his adverse event (37 CYP2D6 analysis demonstrated alleles 4 and 41, identifying him as an IM/PM 2D6-deficient subject. Within the next year, he successfully converted episodes of PAF on 2 occasions with 100mg of oral flecainide, but both were accompanied by mildly symptomatic EKG-documented atrial flutter with 2/1 AV block and a ventricular rate of 120-140 beats per minute, resulting in a return to PIP quinidine and successful conversion of over 60 additional mildly symptomatic but increasingly frequent episodes of PAF over the next 3 years by utilizing 200-600mg of oral quinidine sulfate each resolving within 4-8 hours, during which he was able to continue his daily exercise and other daily activities without interruption.

  11. Analysis of CYP2D6 gene duplication of Chinese population in Hubei%湖北地区人群的CYP2D6二倍体多态性基因分析

    纪玲; 马江涛; 何林; Martin Hersberger

    2004-01-01

    使用长模板PCR方法检测223例湖北地区人群中CYP2D6二倍体.在被检人群中,CYP2D6二倍体的基因频率为2.7%.检测到6例CYP2D6二倍体,基因型分别为*1×2(3/6),*2×2(2/6);*10×2(1/6).表明湖北地区人群中CYP2D6二倍体的基因频率比其他地区中国人群稍高.

  12. Stimulus control by 5methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice

    Winter, J. C.; Amorosi, D.J.; Rice, Kenner C.; Cheng, Kejun; Yu, Ai-Ming

    2011-01-01

    In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The t...

  13. CYP2D6基因多态性与药物基因组学研究的进展%Research advance in CYP2D6 genetic polymorphism and pharmacogenomics

    董天崴; 王爽; 杨军; 张志国

    2014-01-01

    CYP2D6 genetic polymorphism results in individual difference of therapeutic effect and adverse reaction of related drugs this article made an overview for that.%CYP2D6基因多态性导致有关药物疗效及不良反应的个体差异,本文就此进行综述。

  14. Length of psychiatric hospitalization is correlated with CYP2D6 functional status in inpatients with major depressive disorder

    Ruaño, Gualberto; Szarek, Bonnie L; Villagra, David; Gorowski, Krystyna; Kocherla, Mohan; Seip, Richard L; Goethe, John W; Schwartz, Harold I

    2016-01-01

    Aim This study aimed to determine the effect of the CYP2D6 genotype on the length of hospitalization stay for patients treated for major depressive disorder. Methods A total of 149 inpatients with a diagnosis of major depressive disorder at the Institute of Living, Hartford Hospital (CT, USA), were genotyped to detect altered alleles in the CYP2D6 gene. Prospectively defined drug metabolism indices (metabolic reserve, metabolic alteration and allele alteration) were determined quantitatively and assessed for their relationship to length of hospitalization stay. Results Hospital stay was significantly longer in deficient CYP2D6 metabolizers (metabolic reserve <2) compared with functional or suprafunctional metabolizers (metabolic reserve ≥2; 7.8 vs 5.7 days, respectively; p = 0.002). Conclusion CYP2D6 enzymatic functional status significantly affected length of hospital stay, perhaps due to reduced efficacy or increased side effects of the medications metabolized by the CYP2D6 isoenzyme. Functional scoring of CYP2D6 alleles may have a substantial impact on the quality of care, patient satisfaction and the economics of psychiatric treatment. PMID:23734807

  15. Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone

    Coller, J K; Joergensen, C; Foster, D J R;

    2007-01-01

    OBJECTIVE: To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. METHODS: In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by...... stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. RESULTS: The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being......: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone...

  16. Machine Learning Energies of 2 M Elpasolite (ABC$_2$D$_6$) Crystals

    Faber, Felix; von Lilienfeld, O Anatole; Armiento, Rickard

    2015-01-01

    Elpasolite is the predominant quaternary crystal structure (AlNaK$_2$F$_6$ prototype) reported in the Inorganic Crystal Structure Database. We have developed a machine learning model to calculate density functional theory quality formation energies of all the 2 M pristine ABC$_2$D$_6$ elpasolite crystals which can be made up from main-group elements (up to bismuth). Our model's accuracy can be improved systematically, reaching 0.1 eV/atom for a training set consisting of 10 k crystals. Important bonding trends are revealed, fluoride is best suited to fit the coordination of the D site which lowers the formation energy whereas the opposite is found for carbon. The bonding contribution of elements A and B is very small on average. Low formation energies result from A and B being late elements from group (II), C being a late (I) element, and D being fluoride. Out of 2 M crystals, the three degenerate pairs CaSrCs$_2$F$_6$/SrCaCs$_2$F$_6$, CaSrRb$_2$F$_6$/SrCaRb$_2$F$_6$ and CaBaCs$_2$F$_6$/BaCaCs$_2$F$_6$ yield ...

  17. CYP2D6*10B基因型对中国人普罗帕酮对映体药动学的影响%Influence of CYP2D6*10B genotype on pharmacokinetics of propafenone enantiomers in Chinese subjects

    陈冰; 蔡卫民

    2003-01-01

    AIM: To study the relationship between genotype of CYP2D6*10B and pharmacokinetics of propafenone enantiomers. METHODS: Genotype of 17 healthy Chinese HAN subjects was determined by an allele specific amplification method. The blood samples (0-15 h) of the subjects were taken after oral administration of a single dose (400 mg) of propafenone hydrochloride. Concentrations of propafenone enantiomers in plasma were mea sured by a reverse-phase HPLC with precolumn derivatization. RESULTS: Seventeen subjects characterized for CYP2D6* 1 0B genotype included (* 1/* 1) (n = 4), (* 1/* 10) (n = 5) and (* 10/* 10) (n = 8). The metabolic ratios (lg MR) of the three genotypes were -2.68+0.23, -2.2+0.7, and -1.1 +0.5, respectively. The AUC of the three groups that of *1/*10 group or *1/*1 group, and the CL of both enantiomers in *10/*10 is only half of that of *1/*10 group or * 1/* 1 group (P<0.05). CONCLUSION: CYP2D6* 10B alleles induce the declined activity of CYP2D6 and impair the metabolism of propafenone.

  18. 人CYP2D6基因体外表达体系和功能研究方法的建立%Expressing in Vitro and Functional Study of Human CYP2D6 Gene

    吴振强; 秦胜营

    2013-01-01

    根据G eneBank数据库中人CYP2D6基因构建表达载体pMA91-CYP2D6,转化酵母细胞AH22在体外进行表达,抽提所表达的CYP2D6微粒体蛋白进行Western Blot验证表明表达成功.该微粒体蛋白与探针药物异喹胍反应,利用HPLC检测生成产物4-羟基异喹胍,通过分析其得到酶动力学参数Km=10.14±0.94 μmol/L,最终建立起完整的人CYP2D6表达体系和功能研究方法,为未来测定CYP2D6各等位基因对应酶的活性,实现临床个性化用药奠定基础.

  19. CYP2D6基因克隆及在自身免疫性肝炎中的应用%CLONING OF CYP2D6 AND ITS APPLICATION IN AUTOIMMUNE HEPATITIS

    王达; 仲人前; 于嘉屏; 孔宪涛

    2000-01-01

    采用基因克隆与表达技术制备重组人CYP2D6抗原,建立免疫印迹法,检测几组肝炎患者中的抗CYP2D6抗体.605例ALT升高的成人肝炎患者组内CYP2D6自身抗体阳性检出率为3.97%(24/605),50例ALT升高的小儿肝炎患者组内阳性检出率为12%(6/50). 两组比较, 经统计学处理差异有显著性意义(P<0.01).50名正常人及40例HCV RNA阳性的肝炎患者中无一例发现该自身抗体阳性.检出的30例CYP2D6自身抗体阳性患者,30%合并有HBV感染.结果提示:CYP2D6自身抗体检测可作为自身免疫性肝炎诊断的一项重要指标.

  20. Systematic functional study of cytochrome P450 2D6 promoter polymorphisms in the Chinese Han population.

    Xueli Gong

    Full Text Available The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(-2183G>A, -1775A>G, -1589G>C, -1431C>T, -1000G>A, -678A>G, Haplo8(-2065G>A, -2058T>G, -1775A>G, -1589G>C, -1235G>A, -678A>G and MU3(-498C>A was 0.7-, 0.7-, 1.2- times respectively compared with the wild type in human hepatoma cell lines(p<0.05. These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine.

  1. Variantes alélicas de CYP2D6: *4, *6 y *10 en una muestra de residentes del estado Aragua, Venezuela

    Carlos Flores-Angulo

    2015-12-01

    Full Text Available El objetivo del estudio fue determinar la frecuencia de las variantes del gen CYP2D6: *4, *6 y *10 y predecir el fenotipo metabolizador en una muestra de 145 individuos no consanguíneos, aparentemente sanos, residentes del estado Aragua, Venezuela. Los genotipos fueron determinados mediante ensayos de reacción en cadena de la polimerasa seguidos de digestión con endonucleasas de restricción. La predicción del fenotipo metabolizador se realizó con base al sistema Activity score. Las frecuencias de CYP2D6 *4, *6 y *10 fueron de 14,5%, 0,3% y 1%, respectivamente; un porcentaje significativo de individuos fueron categorizados como metabolizador rápido heterocigoto/metabolizador intermedio (23,5% y metabolizador lento (4,1%. Esta información tiene impacto clínico potencial, porque CYP2D6 interviene en el metabolismo de fármacos de prescripción frecuente como: carvedilol, captopril, cloroquina, codeína, fluoxetina, fluvastatina, haloperidol, idarrubicina, indinavir, imatinib, loperamida, nifedipina, ondansetrón y tamoxifeno

  2. Variantes alélicas de CYP2D6: *4, *6 y *10 en una muestra de residentes del estado Aragua, Venezuela

    Carlos Flores-Angulo

    2015-10-01

    Full Text Available El objetivo del estudio fue determinar la frecuencia de las variantes del gen CYP2D6: *4, *6 y *10 y predecir el fenotipo metabolizador en una muestra de 145 individuos no consanguíneos, aparentemente sanos, residentes del estado Aragua, Venezuela. Los genotipos fueron determinados mediante ensayos de reacción en cadena de la polimerasa seguidos de digestión con endonucleasas de restricción. La predicción del fenotipo metabolizador se realizó con base al sistema Activity score. Las frecuencias de CYP2D6 *4, *6 y *10 fueron de 14,5%, 0,3% y 1%, respectivamente; un porcentaje significativo de individuos fueron categorizados como metabolizador rápido heterocigoto/metabolizador intermedio (23,5% y metabolizador lento (4,1%. Esta información tiene impacto clínico potencial, porque CYP2D6 interviene en el metabolismo de fármacos de prescripción frecuente como: carvedilol, captopril, cloroquina, codeína, fluoxetina, fluvastatina, haloperidol, idarrubicina, indinavir, imatinib, loperamida, nifedipina, ondansetrón y tamoxifeno

  3. Advances in correlation between CYP2D6 and tamoxifen therapy%CYP2D6与他莫昔芬疗效相关性的研究进展

    雷蕾; 王晓稼

    2009-01-01

    CYP2D6是一种重要的P450系氧化代谢酶,是他莫昔芬在体内代谢成更强抗雌激素作用代谢产物endoxifen的重要代谢酶,因此,强代谢乳腺癌患者服用他莫昔芬后引起明显的潮热症状,而潮热症状的发生与他莫昔芬疗效正相关.除了CYP2D6基因多态性可能影响他莫昔芬体内的代谢外,帕罗西汀(paroxetine)可竞争性抑制CYP2D6对他莫昔芬的代谢,使乳腺癌患者对他莫昔芬疗效明显降低.

  4. CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study

    Kobylecki, Camilla J; Jakobsen, Klaus D; Hansen, Thomas;

    2009-01-01

    OBJECTIVE: The aim of the present retrospective pilot study was to examine the clinical impact of the cytochrome P450 (CYP) enzyme CYP2D6 poor metabolizer (PM) genotype in patients taking antipsychotic medication. The impaired metabolic capacity of the PM genotype results in higher steady......-state plasma concentrations at a given dose, thus increasing the risk of toxic effects from medication. METHODS: We identified 18 PM patients with a schizophrenia spectrum diagnosis from a clinical database covering all patients who have been analyzed in an ongoing standardized CYP2D6 screening program. Each...... significantly higher prevalence of noncompliance among the same PM patients. Importantly, this association was not due to differences in the use of CYP2D6-dependent or EPS/TD-causing medication across the 3 matched patient groups. CONCLUSIONS: This leads us to conclude that genetically encoded differences in...

  5. CYP2 D6的基因多态性与药物临床应用

    刘周杰

    2016-01-01

    CYP2D6是CYP酶系中重要的一种氧化代谢酶,参与多种药物的代谢。 CYP2D6具有基因多态性,这是构成药物代谢个体差异和种族差异的基础,它主要参与心血管类、抗精神病类、镇痛药、以及一些抗癌药物等的代谢。研究 CYP2D6基因多态性与药物代谢个体差异的相关性,有助于减轻药物不良反应,提高治疗效果,实施个体化给药。

  6. Stimulus control by 5methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice

    Winter, J. C.; Amorosi, D. J.; Rice, Kenner C.; Cheng, Kejun; Yu, Ai-Ming

    2011-01-01

    In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT. PMID:21624387

  7. Stimulus control by 5-methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice.

    Winter, J C; Amorosi, D J; Rice, Kenner C; Cheng, Kejun; Yu, Ai-Ming

    2011-09-01

    In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT. PMID:21624387

  8. 厚朴提取物对大鼠CYP2D6亚型酶的影响%Influence of magnolia bark extract on CYP2D6 subtype enzyme in rats

    于卫江; 张斌; 张文周

    2013-01-01

    目的 观察厚朴提取物对大鼠CYP2D6亚型酶的影响.方法 将16只成年雄性Wistar大鼠随机分为对照组和实验组,2组分别经口给予生理盐水和厚朴提取物1周,采用高效液相色谱法(HPLC)测定大鼠尿样及肝微粒体中CYP2D6的探针药物右美沙芬(DM)的代谢率,观察厚朴提取物对CYP2D6亚型酶活性的影响,并通过特异性抑制剂确定肝微粒体重组系统中厚朴提取物对CYP2D6亚型酶活性的影响.结果 实验组大鼠尿样及体外肝微粒体中DM代谢率均明显低于对照组,差异有统计学意义;厚朴提取物组肝微粒体中DM代谢率显著低于西咪替丁组和对照组,差异有统计学意义,而西咪替丁组和对照组比较,差异无统计学意义.结论 厚朴提取物可有效抑制CYP2D6亚型酶的活性,且抑制能力优于西咪替丁.

  9. CYP2D6和GST在白种人晚期肾病中的遗传变异%Genetic Variation of CYP2D6 and GST in Caucasian ESRD Patients

    严奉祥; WedlundPJ; 等

    2002-01-01

    目的:生物转化酶细胞色素P4502D6(CYP2D6)和谷胱苷肽转移酶-M1(GST-M1)、谷胱苷肽转移酶-T1(GST-T1)共同代谢内源性和外源性毒素,一部分人群由于相应基因变异导致这些酶缺乏表达,我们检测白种人群中晚期肾病(ESRD)病人这些酶的基因多态性是否比健康者有较高的频率.方法:从列克星顿及周围地区征募330名晚期肾病病人和303名健康者,均为白种人,给予他们进行CYP2D6和GST-M1和T1基因分型.结果:在ESRD病人中CYP2D6和GST-M1和GST-T1以及CYP2D6和GST-M1或GST-T1都缺乏分别为2.1%和4.2%;而在健康者中均为0.3%(P<0.01).结论:CYP2D6和GST-M1和/或GST-T1酶缺乏在ESRD病人中有较高的频率,提示这些酶缺乏可以预计慢性肾病进展的可能性.

  10. Risperidone-associated adverse drug reactions and CYP2D6 polymorphisms in a South African cohort

    Tyren M. Dodgen

    2015-06-01

    Conclusion: CYP2D6 variation appeared not to be a good pharmacogenetic marker for predicting risperidone-related ADRs in this naturalistic South African cohort. Evaluation of a larger cohort would be needed to confirm these observations, including an examination of the role of potential intermediaries between the hypothesised genetic and clinical phenotypes.

  11. 宁夏回族人群CYP2D6*10基因多态性及功能分析%Analysis on polymorphism function of CYP2D6 * 10 in Ningxia Hui

    李居怡; 王健; 高鹏; 杜娟; 李宗吉

    2010-01-01

    目的 探讨基因突变对人CYP2D6蛋白结构与功能的影响.方法 采用等位基因特异扩增(ASA-PCR)及DNA测序技术分析宁夏网族人群CYP2D6*10(C188T)基因多态性,以生物信息学方法对突变造成的肝药酶活性的下降做出合理的解释.结果 蛋白质基本性质分析工具(ProtParam)分析显示,在溶液中CYP2D6*10突变型蛋白的不稳定指数高于野生型,都高于阈值40;二级结构预测软件(DNAStar/Protean)分析显示,突变型蛋白的二级结构在第33位多了一个转角(Gamier-Robson Turn);功能佗点预测程序(Motif Scan)对蛋白功能位点进行预测,结果显示CYP2D6*10野生型蛋白有2个P450酶激活位点.而突变型没有;信号肽预测程序(Signal P)分析显示.神经网络模型(NN)C-score计算结果为突变型蛋白没有信号肽,而野牛型有.结论 基因突变可引起CYP2D6蛋白结构与功能的改变;应用生物信息学方法对CYP2D6基因突变致使的酶活性的下降做出一些可能的解释是可行的.

  12. CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics-guided clinical trials

    Peñas-LLedó, Eva M; LLerena, Adrián

    2014-01-01

    Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter loca...

  13. Effect of CYP2D6*10 genotype on propafenone pharmacodynamics in Chinese patients with ventricular arrhythmia%CYP2D6*10基因型对中国室性心律失常病人普罗帕酮药效学的影响

    蔡卫民; 徐军; 陈冰; 张馥敏; 黄元铸; 张银娣

    2002-01-01

    important role in plasma levelsand effects of propafenone. In 450 mg/d group, patients with homozygous mutant of CYP2D6* 10 not only had aCmax of propafenone two times as high as those of wild-type genotype, but also showed a two fold higher inhibitoryrate of VPC compared with those with homozygous CYP2D6* 1 (P<0.05). CONCLUSION: CYP2D6* 10 geno-type is relevant to decreased activity of CYP2D6 enzyme in Chinese patients. Elevated plasma concentration isconsistent with better efficacy of propafenone in patients with ventricular arrhythmia.

  14. 氧化苦参碱对大鼠CYP2D6酶的影响

    张斌; 于卫江

    2008-01-01

    目的 通过氧化苦参碱的大鼠体内、外实验,观察氧化苦参碱对大鼠CYP2D6 亚型酶的影响.方法 HPLC法测定大鼠尿液及肝微粒体中探针药物右美沙芬(DM)、代谢物去甲右美沙芬(DT)的含量.对照组和氧化苦参碱组大鼠分别经口给予生理盐水和氧化苦参碱两周,HPLC法测定大鼠尿样及肝微粒体中CYP2D6的探针药物右美沙芬的代谢率,观察氧化苦参碱对CYP2D6活性的影响.并且通过特异性抑制剂确定在肝微粒体重组系统中氧化苦参碱对CYP2D6亚型的影响.结果 实验组大鼠给予氧化苦参碱(100mg/kg),其尿样中右美沙芬的代谢率与对照组相比没有明显差别(P>0.05);实验组大鼠肝微粒体中加入右美沙芬(0.324mmol/L),其右美沙芬的代谢率与对照组相比没有明显差别(P>0.05);氧化苦参碱没有明显降低右美沙芬的代谢率(P>0.05),而CYP2D6特异性抑制剂西米替丁却明显降低右美沙芬的代谢率(P<0.01).结论 氧化苦参碱对CYP2D6酶无明显影响.

  15. 细胞色素氧化酶CYP2D6的研究进展

    张泓波; 李宝群; 王瑞婷; 梅爱敏

    2005-01-01

    细胞色素氧化酶CYP450是药物代谢中的一个重要酶系。近年来,对CYP450与药物代谢多态性的关系进行了诸多方面的研究。现已明确CYP2C9、CYP2C19、CYP2D6在表型和基因型水平上均存在遗传多态性,且对其分子机制有了较为深入的了解;而CYPlA2等其他酶可能存在多态性,但各人群研究结果不甚一致。本文着重综述CYP2D6的研究进展情况。

  16. Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans.

    Steuer, Andrea E; Schmidhauser, Corina; Tingelhoff, Eva H; Schmid, Yasmin; Rickli, Anna; Kraemer, Thomas; Liechti, Matthias E

    2016-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism. PMID:26967321

  17. Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA and Its Phase I and II Metabolites in Humans.

    Andrea E Steuer

    Full Text Available 3,4-methylenedioxymethamphetamine (MDMA; ecstasy metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA, followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs, intermediate metabolizers (IMs, and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax and area under the plasma concentration-time curve from 0 to 24 h (AUC24 of R-MDMA (9% and 25%, respectively and S-MDMA (16% and 38%, respectively. Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

  18. Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients

    Yan FU; Chang-he FAN; He-huang DENG; San-hong HU; De-peng LV; Li-hua LI; Jun-jie WANG; Xin-qiao LU

    2006-01-01

    Aim:To investigate the possible association of the CYP2D6 gene C100T polymorphism and the CYP1A2 gene C163A polymorphism with tardive dyskinesia (TD) in Chinese patients with schizophrenia.Methods:The recruited schizophrenic patients were assessed with the Abnormal Involuntary Movement Scale (AIMS),and divided into groups with TD(n=91)and without TD(n=91)according to the AIMS score.Polymorphisms of the CYP2D6 and CYP1A2 genes were determined by polymerase chain reaction(PER)-restriction fragment length polymorphism(RFLP).Results:No allele frequencies deviated from Hardy-Weinberg equilibrium.No significant differences in genotypes frequencies of the CYP2D C100T polymorphism were observed between patients with TD and without TD (x2=4.078,P>0.05),but patients with TD had a significant excess of the T allele compared with those without TD(x2=4.28,P<0.05).Moreover,the frequency of the CYP1A2 C allele in patients with TD was significantly higher than that in those without TD(x2=6.38,P<0.05).An association between TD and the CyP2D6 100T and CYP1A2 163C alleles was observed.Additionally,there were no differences in the mean AIMS scores among different genotypes in TD patients as a group or in smokers.The results of logistic regression anatysls demonstrated that mean age and duration of illness were risk factors for TD,but not sex,cumulative exposure to neuroleptic drugs in years,CYP2D6 or CYP1A2 genotype.Conclusion:The C100T polymorphism of the CYP2D6 gene and the C163A polymorphism of the CYP1A2 gene may be associated with neuroleptic drug-induced tardive dyskinesia in Chinese patients with schizophrenia.However,genetic factors have a weaker association with susceptibility to TD compared with mean age and duration of illness.

  19. Polymorphisms in the genes of citohrom oxidase P450 2D6 (CYP2D6, paraoxonase 1 (PON1 and apolipoproteine E (APOE as risk factors for Parkinson's disease

    Đurić Gordana

    2007-01-01

    Full Text Available Background/Aim. The presence of Parkinson's disease (PD among the members of a family is a clear indication of the significance of genetics in its development. In spite of that, the majority of patients with PD shows a sporadic form of the disease induced as a result of interaction of both environmental and genetic factors. The aim of this study was to examine the effects of polymorphisms in the genes of cytohrome P450 2D6(CYP2D6, paraoxonase 1 (PON 1 and apolipoprotein E (APOE, as risk factors for PD. Methods. We examined 106 patients with PD (65 men and 41 women and 75 ethnically matched control subjects. The mean age at onset of PD in the patients was 46.9±9.4 years (ranging from 30 to 70 years. Genotyping was performed using standard PCR amplification and restriction endonuclease digestion protocols described for known polymorphism in the candidate genes under study. Results. The genotype A/A polymorphisms 2D6* gene of CYP2D6 and genotype M/M polymorphisms L54M gene of PON1 were significantly more frequent in the patients with PD than in the control group. The patients with genotypes A/A and M/M had 3.4 and 3.2 higher risk of PD, respectively than the control group (p = 0.01. The relation between genotypes A/A gene of CYP2D6 and M/M gene of PON1 was modified by the age at onset. The genotypes were associated with early onset of PD (p = 0.001, p = 0.004. The carriers of the A and M alleles in homozygote had 2.4 and 4.2 years respectively earlier onset of PD than carriers of other genotypes with these polymorphisms. The frequency allele ε4 gene of APOE was higher in the PD patients with early onset (20% than in PD with later onset (7.4%, while the genotype ε3/ε3 was associated with PD late onset (p = 0.024. Combined genotype I (carriers of the two risk allels in homozygote and one alleles risk in heterozygote and combined genotype II (carriers of the three alleles risk in homozygote caused early PD. Combined genotype II was detected in 12

  20. Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevitY

    Bathum, L; Andersen-Ranberg, K; Boldsen, J;

    1998-01-01

    OBJECTIVE: To test whether some genotypes for CYP2D6 or CYP2C19 could contribute to longevity, we genotyped 241 Danish nonagenarians and centenarians for CYP2D6 and CYP2C19. METHODS: For CYP2D6 we identified the alleles CYP2D6*1, CYP2D6*3 and CYP2D6*4 with allele-specific polymerase chain reaction...... (PCR). The CYP2D6*5 alleles were identified with a long PCR method. For CYP2C19 we identified the alleles CYP2C19*1, CYP2C19*2 and CYP2C19*3 with an oligonucleotide ligation assay. RESULTS: The four alleles for CYP2D6 did not occur in Hardy-Weinberg proportions. The frequency of poor metabolism was...... slightly higher (10.2%) than expected [7.7%; odds ratio (OR) = 1.36 (0.75-2.40)]. The genotypes for CYP2C19 occur in Hardy-Weinberg proportions. The frequency of poor metabolism (3.8%) was not significantly different from a young control group [3.1%; OR = 1.21 (0.26-5.75)]. CONCLUSION: CYP2D6 could play a...

  1. Effects of β1-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy%β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的药代动力学和药效学影响

    刘洁; 刘昭前; 刘英姿; 谭志荣; 胡冬莉; 李智; 王丹; 张伟; 周宏灏

    2007-01-01

    BACKGROUND: Metoprolol is a selective β1-Blocker commonly used in essential hypertension. It is metabolized by CYP2D6. CYP2D6*10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population. β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol. It was still unknown that whether the CYP2D6 and β1-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essential hypertension patients were enrolled in this study. Patients were mono-therapied with metoprolol for 12 weeks. Blood pressure was monitored every 4 weeks. PCR-RFLP method was use to identify CYP2D6*10 and β1-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms. Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0) of metoprolol was associated with CYP2D6*10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6*1*1, *1*10 and CYP2D6*10*10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes. Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers. CONCLUSION: CYP2D6*10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β1-adrenergic receptor were associated with the pharmacodynamics of metopolol in antihypertension therapy.%背景: 美托洛尔是临床常用的抗高血压药物,它经由CYP2D6代谢.CYP2D6*10降低CYP2D6活性,是中国人群中最为常见的多态性.β1肾上腺素受体为美托洛尔的作用靶标,Ser49Gly与Gly389Arg多态性显著改变受体功能.CYP2D6与β1肾上腺素受体遗传多态

  2. Utility and adoption of CYP2D6 and CYP2C19 genotyping and its translation into psychiatric clinical practice

    Jürgens, G; Jacobsen, C B; Rasmussen, H B;

    2012-01-01

    To describe clinical utility and adoption of routinely offered CYP2D6 and CYP2C19 genotyping (CYP test) in daily clinical practice of a psychiatric centre.......To describe clinical utility and adoption of routinely offered CYP2D6 and CYP2C19 genotyping (CYP test) in daily clinical practice of a psychiatric centre....

  3. Association of MDR1, CYP2D6, and CYP2C19 gene polymorphisms with prophylactic migraine treatment response.

    Atasayar, Gulfer; Eryilmaz, Isil Ezgi; Karli, Necdet; Egeli, Unal; Zarifoglu, Mehmet; Cecener, Gulsah; Taskapilioglu, Ozlem; Tunca, Berrin; Yildirim, Oznur; Ak, Secil; Tezcan, Gulcin; Can, Fatma Ezgi

    2016-07-15

    Prophylactic therapy response varies in migraine patients. The present study investigated the relationship between the resistance to the drugs commonly used in prophylactic therapy and the possible polymorphic variants of proteins involved in the metabolism of these drugs. Migraine patients with the MDR1 3435TT genotype exhibited a better treatment response to topiramate than migraine patients with the CC and CT genotypes (p=0.020). The MDR1 C3435T polymorphism was also found to be a higher risk factor for topiramate treatment failure in a comparison of the number of days with migraine (β2=1.152, p=0.015). However, there was no significant relationship between the treatment response to topiramate and either the CYP2D6 or CYP2C19 polymorphism, and there were no significant correlations between the treatment responses to amitriptyline, propranolol, and valproic acid and the MDR1, CYP2D6 and CYP2C19 gene polymorphisms. This is the first study to investigate the effect of the polymorphic variants on prophylactic therapy response in migraine patients. PMID:27288795

  4. Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD.

    Brown, J T; Abdel-Rahman, S M; van Haandel, L; Gaedigk, A; Lin, Y S; Leeder, J S

    2016-06-01

    The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 μM*h in EM2s to 5.8 ± 1.7 μM*h, 16.3 ± 2.9 μM*h, and 50.2 ± 7.3 μM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication. PMID:26660002

  5. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides

    Singh, Satyender [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Kumar, Vivek [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Vashisht, Kapil; Singh, Priyanka [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Banerjee, Basu Dev, E-mail: banerjeebd@hotmail.com [Environmental Biochemistry and Molecular Biology laboratory, Department of Biochemistry, University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi-110095 (India); Rautela, Rajender Singh; Grover, Shyam Sunder; Rawat, Devendra Singh; Pasha, Syed Tazeen [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Jain, Sudhir Kumar [Centre for Epidemiology and Parasitic Diseases, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India); Rai, Arvind [Division of Biochemistry and Biotechnology, National Centre for Disease Control 22, Sham Nath Marg, Delhi-110054 (India)

    2011-11-15

    Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p < 0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37 {+-} 2.15 vs. 6.24 {+-} 1.37 tail% DNA, p < 0.001). Further, the workers with CYP2D6*3 PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p < 0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions. -- Highlights: Black-Right-Pointing-Pointer Role of CYP1A1, CYP3A5, CYP2C, CYP2D6 and PON1 genotypes on DNA damage. Black-Right-Pointing-Pointer Workers exposed to some OPs demonstrated increased DNA damage. Black-Right-Pointing-Pointer CYP2D6 *3 PM and PON1 (Q192R and L55M) genotypes are associated with DNA damage. Black-Right-Pointing-Pointer Concomitant presence of certain CYP2D6 and PON1 genotypes can increase DNA damage.

  6. Role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to organophosphate pesticides

    Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR–RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p < 0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37 ± 2.15 vs. 6.24 ± 1.37 tail% DNA, p < 0.001). Further, the workers with CYP2D6*3 PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes (p < 0.05). In addition, significant increase in DNA damage was also observed in workers with concomitant presence of certain CYP2D6 and PON1 (Q192R and L55M) genotypes which need further extensive studies. In conclusion, the results indicate that the PON1 and CYP2D6 genotypes can modulate DNA damage elicited by some OPs possibly through gene-environment interactions. -- Highlights: ► Role of CYP1A1, CYP3A5, CYP2C, CYP2D6 and PON1 genotypes on DNA damage. ► Workers exposed to some OPs demonstrated increased DNA damage. ► CYP2D6 *3 PM and PON1 (Q192R and L55M) genotypes are associated with DNA damage. ► Concomitant presence of certain CYP2D6 and PON1 genotypes can increase DNA damage.

  7. Mutation frequencies of the cytochrome CYP2D6 gene in Parkinson disease patients and in families

    Lucotte, G.; Turpin, J.C. [CHR, Reims (France); Gerard, N. [INSERM, Paris (France)] [and others

    1996-07-26

    The frequencies of five mutations of the debrisoquine 4-hydroxylase (CYP2D6) gene (mutations D6-A, B, C, D, and T), corresponding to poor metabolizer (PM) phenotypes, were determined by restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) in 47 patients with Parkinson disease, and compared with the findings in 47 healthy controls. These mutant alleles were about twice as frequent among patients as in controls, with an approximate relative risk ratio of 2.12 (95% confidence interval, 1.41-2.62). There seem to be no significant differences in frequencies of mutant genotypes in patients among gender and modalities of response with levodopa therapy; but frequency of the mutations was slightly enhanced after age-at-onset of 60 years. Mutations D6-B, D, and T were detected in 7 patients belonging to 10 Parkinson pedigrees. 25 refs., 1 fig., 2 tabs.

  8. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    Vangsted, A. J.; Soeby, K.; Klausen, T.W.;

    2010-01-01

    patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. Results: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment....... We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion......: There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome....

  9. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome

  10. 基于CYP2D6代谢性相互作用的儿童用药安全提示

    李娟; 李毅; 郭兴蕾

    2015-01-01

    CYP2D6是一种重要的药物代谢酶,研究基于CYP2D6的代谢性相互作用具有重要的临床意义.本文综述了关于儿科常用的各类有关于CYP2D6的药物可能产生的代谢性相互作用,旨在为临床医生合理用药提供参考.

  11. Correlation between CYP2D6 * 10 gene polymorphism and prognosis of breast cancer patients treated with tamoxifen%CYP2D6*10基因多态性与服用他莫昔芬乳腺癌患者预后的相关性

    田超; 杨义; 李卉

    2013-01-01

    目的 探讨CYP2D6 * 10基因多态性与服用他莫昔芬(TAM)乳腺癌患者预后的相关性.方法 收集四川省肿瘤医院2008年1月至2010年10月期间200例服用TAM的乳腺癌患者的口腔黏膜,采用实时RT-PCR法检测CYP2D6 * 10基因多态性,并分为CYP2D6突变组(CYP2D6 * 10/ * 10)和CYP2D6正常组(CYP2D6 wt/ * 10和CYP2D6 wt/wt).采用卡方检验及秩和检验分析CYP2D6 * 10基因多态性与临床病理特征的关系,采用Cox比例风险回归模型分析其与预后的关系.结果 在200例乳腺癌中,CYP2D6 * 10/ * 10纯合子94例(47%),CYP2D6 wt/wt野生型48例(24%),CYP2D6 wt/ * 10杂合型58例(29%).CYP2D6 * 10基因多态性与患者的组织学分级、TNM分期、HER-2表达、肿瘤类型无关(Z=-0.444,P=0.674;Z=-0.716,P=0.500;χ2=0.066,P=0.797;χ2=0.694,P=0.405).Log-rank检验分析显示CYP2D6 * 10突变组患者平均无瘤生存时间明显短于CYP2D6 * 10正常组患者(47.2个月比51.2个月,χ2=5.554,P=0.018).Cox比例风险回归模型显示,CYP2D6 * 10基因型与患者无瘤生存时间明显相关(HR=2.755,95%CI:1.230~6.173,P=0.014).结论 CYP2D6 * 10/ * 10基因型乳腺癌患者服用他莫昔芬预后较差.

  12. CYP2D6基因多态性对帕罗西汀在中国健康人药动学影响%Influence of CYP2D6 genetic polymorphism on pharmacokinetics of paroxetine in Chinese healthy people

    王蒙; 周文佳; 肖莉; 张全英

    2012-01-01

    AIM To investigate the influence of CYP2D6 genetic polymorphism on pharmacokinetics of paroxetine in Chinese healthy people. METHODS Twenty-three Chinese volunteers genotyped for CYP2D6 were separated into three groups by PCR-RFLP: CYP2D6*1/*1 group (rc = 5), CYP2D6*l/*10 group (n = 7), and CYP2D6*10/*10 group ( n - 11). After administration of a single oral dose of paroxetine hydrochloride tablet 20 mg, blood samples were collected at various time points until 96 h. The plasma concentrations of paroxetine were measured by LC-MS/MS method and the pharmacokinetics disposition of them was analyzed. RESULTS Compared with CYP2D6*1/*1 group, the tmax and t1/2l in CYP2D6*l/*10 group and tmax in CYP2D6*10/*10 group had no significant differences (P>0.05); ρmax, AUC0-96h, AUC0_∞ CL (F) and Vd of paroxetine in CYP2D6*l/*10 group and CYP2D6*10/*10 group, and t1/2 in CYP2D6*10/*10 group all had significant differences (P < 0.05 and P < 0.01). CONCLUSION The allelic gene mutations of CYP2D6*10 can cause the changes of metabolic phenotype and have effects on the metabolism of paroxetine in healthy human body.%目的 研究中国健康人CYP2D6基因多态性对帕罗西汀药动学的影响.方法 使用PCR-RFLP方法将23位志愿者分为3组:CYP2D6*1/*1组(n=5),CYP2D6* 1/* 10组(n=7),CY P2D6*10/*10组(n=11).给予帕罗西汀20 mg单剂量口服,收集给药后96 h内的一系列血样,用LC-MS/MS法测定帕罗西汀的血药浓度并做药动学分析.结果 与CYP2D6*1/*1组药动学参数相比,CYP2D6*1/*10组tmax、t1/2和CYP2D6* 10/* 10组tmax无显著差异(P>0.05);CYP2D6*1/*10、CY P2D6*1 0/*10组的ρmax、AUC0-96h、AUC0-x、CL (F)、Vd和CYP2D6*10/*10组t1/2均有显著差异(P<0.05或P<0.01).结论 CY P2D6*1D等位基因突变能引起代谢表型的改变,影响帕罗西汀在健康人的体内代谢.

  13. 中国人群细胞色素P4502D6基因多态性对曲马多药代动力学的影响%Influence of CYP2D6 genetic polymorphism on pharmacokinetics of tramadol in Chinese population

    李芹; 王睿; 郭雅; 裴斐

    2009-01-01

    目的 研究中国人群CYP2D6基因多态性对曲马多(镇痛药)药代动力学的影响.方法 不同基因型中国健康志愿者随机分为4组:第1组CYP2D6*2W*10W,第2组:CYP2D6*2M*10W,第3组:CYP2D6*2M*10H,第4组:CYP2D6*2M*10M.各组单次口服曲马多100 mg后,用高效液相色荧光检测法测定血和尿中曲马多及其M1代谢产物O-去甲基曲马多(M1)的浓度,研究不同基因型对曲马多药代动力学的影响.结果 第2组曲马多及其M1的主要药代动力学参数与第1组相比没有显著性差异;第3组与第1组、第4组与第1组、第4组与第3组比较,主要药代动力学参数均有显著性差异(P<0.05),且呈基因剂量效应.结论 CYP2D6*2对于曲马多的药代动力学过程没有影响;但CYP2D6*10可降低酶活性,且CYP2D6*10纯合子变异较杂合子变异对曲马多药代动力学的影响更大,呈基因剂量效应.%Objective To investigate on influence of CYP2D6 genetic polymorphism on pharmacokinetics of tramadol in Chinese volunteers.Methods Adult healthy Chinese volunteers with different CYP2D6 genotypes were categorized into the following four groups: group 1:CYP2D6 * 2W * 10W, group 2:CYP2D6 * 2M * 10W, group 3:CYP2D6 * 2M * 10H, group 4 : CYP2D6 * 2M * 10M. After oral ad-ministration of 100 mg tramadol, plasma and urine samples were col-lected from each subject at different time within 32 h. The plasma and urine concentrations of tramadol and its metabolite O - desmethyltramad-ol (M1) were determined by HPLC with fluorescence detection. Re-suits The main pharmacokinetic parameters of tramadol and M, in group 2 were not significantly different from those in group 1. There are significant difference for the main pharmacokinetic parameters of tram-adol and M1 between group 3 and group 1, group 4 and group 1, group 4 and group 3, respectively (P<0.05 ). Conclusion The present re-sults shown that CYP2D6 * 2 has no influence on the pharmacokinetics of tramadol, but CYP2D6 * 10 reduces CYP2

  14. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    Vangsted, A. J.; Soeby, K.; Klausen, T.W.;

    2010-01-01

    Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the....... We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion......: There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome....

  15. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

    Hicks, J K; Bishop, J R; Sangkuhl, K; Müller, D J; Ji, Y; Leckband, S G; Leeder, J S; Graham, R L; Chiulli, D L; LLerena, A; Skaar, T C; Scott, S A; Stingl, J C; Klein, T E; Caudle, K E; Gaedigk, A

    2015-08-01

    Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org). PMID:25974703

  16. Comparison of CYP2D6 genotyping by allele-specific PCR with DXT phe-notype and gene chip testing%CYP2D6 PCR基因型与DXT表型和基因芯片检测的比较

    2002-01-01

    目的:为了评价CYP2D6的基因型和表型的联系以及基因芯片在CYP2D6多基因分析中的应用.方法:242健康志愿者,口服dextromethorphan后收集尿液测定其代谢率,收集20ml血提取DNA,并通过基因特异性PCR和/(或)基因芯片分析CYP2D6*2--*11,*17和多拷贝CYP2D6基因,其中5个基因(*3、*4、*6、*7和*9)用PCR和CYD450基因芯片同时分析.结果:CYP2D6基因型比表型更富有信息和更能反映CYP2D6酶的表达.CYP2D6*3、*4、*6、*7和*9的基因检测在CYP450基因芯片和基因特异性PCR中显示高度的一致性.结论:基因芯片在检测基因多位点的多基因中是一个有发展前途和可靠的方法.%To evaluate association of genotype and phenotype of CYP2D6 and the application of oligonucleotide microarray hybridization genetic testing in CYP2D6 multiple alleles analyses. METHODS: Two hundred forty-two healthy volunteers were recruited, and a 60 mg oral dose of dextromethorphan (DXT) was administered to each for assessment of the DXT metabolic ratio [ MR]. A 20 ml blood sample was also collected for DNA isolation and testing. CYP2D6 alleles * 2-*11; * 17 and multiple CYP2D6 gene copies were tested by allele-specific PCR and/or the affymetrix CYP450 gene chip assay. Five of the CYP2D6 alleles ( * 3, * 4, *6, * 7, and * 9) were evaluated by both PCR and the CYP450 gene chip assay. RESULTS: The CYP2D6genotype was more informative and reflective in CYP2D6 enzyme expression than a phenotype. Genetic tests for the CYP2D6 * 3, * 4, * 6, * 7 and * 9 alleles showed a high degree of concordance between the CYP450 gene chip and AS-PCR methods. CONCLUSION: Oligonucleotide microarray hybridization is a promising and reliable approach for detecting multiple alleles at gene loci.

  17. Influence of the CYP2D6 isoenzyme in patients treated with venlafaxine for major depressive disorder: clinical and economic consequences.

    Antoni Sicras-Mainar

    Full Text Available Antidepressant drugs are the mainstay of drug therapy for sustained remission of symptoms. However, the clinical results are not encouraging. This lack of response could be due, among other causes, to factors that alter the metabolism of the antidepressant drug.to evaluate the impact of concomitant administration of CYP2D6 inhibitors or substrates on the efficacy, tolerability and costs of patients treated with venlafaxine for major depressive disorder in clinical practice.We designed an observational study using the medical records of outpatients. Subjects aged ≥ 18 years who started taking venlafaxine during 2008-2010 were included. Three study groups were considered: no combinations (reference, venlafaxine-substrate, and venlafaxine-inhibitor. The follow-up period was 12 months. The main variables were: demographic data, comorbidity, remission (Hamilton <7, response to treatment, adverse events and costs. The statistical analysis included logistic regression models and ANCOVA, with p values <0.05 considered significant.A total of 1,115 subjects were recruited. The mean age was 61.7 years and 75.1% were female. Approximately 33.3% (95% CI: 30.5 to 36.1 were receiving some kind of drug combination (venlafaxine-substrate: 23.0%, and venlafaxine-inhibitor: 10.3%. Compared with the venlafaxine-substrate and venlafaxine-inhibitor groups, patients not taking concomitant drugs had a better response to therapy (49.1% vs. 39.9% and 34.3%, p<0.01, greater remission of symptoms (59.9% vs. 50.2% and 43.8%, p<0.001, fewer adverse events (1.9% vs. 7.0% and 6.1%, p<0.05 and a lower mean adjusted cost (€2,881.7 vs. €4,963.3 and €7,389.1, p<0.001, respectively. All cost components showed these differences.The patients treated with venlafaxine alone showed a better response to anti-depressant treatment, greater remission of symptoms, a lower incidence of adverse events and lower healthcare costs.

  18. CYP2D6*10基因型与接受他莫昔芬治疗乳腺癌患者的生存率的相关性研究%Association between CYP2 D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment

    魏影; 徐喆

    2014-01-01

    Objective To explore the association between between CYP 2D6*10 genotype and survival of breast cancer patients receiv-ing tamoxifen(TAM) treatment.Methods Basic clinical feature,survival state and blood samples,paraffin sections were collected from 257 breast cancer patients receiving TAM treatment .CYP2D6*10 allele of breast cancer patients were checked by means of Polymerase Chain Reaction ( PCR) .We observed the association between CYP 2D6*10 genotype and survival of breast cancer patients receiving tamoxifen(TAM) treatment.Results Fifteen percent (38/257) of the patients carried the CYP2D6*10/*10 genotype,41%(105/257) the CYP2D6 wild-type (Wt)/*10 genotype and 44%(114/257) the CYP2D6 wt/wt genotype.There were no discernible cor-relations between clinicopathologic parameters and the CYP 2D6*10 genotype.We determined whether there was a correlation between the CYP2D6*10 genotype and survival and found out that the clinical outcome for patients carrying the CYP 2D6*10/*10 genotype was similar to those with other genotypes .Conclusions Our results suggest that the CYP 2D6*10 genotype is unlikely to have any clinical significance for prognosis of breast cancer patients receiving adjuvant TAM treatment .%目的:研究CYP2D6*10基因型对接受他莫昔芬(tamoxifen,TAM)治疗乳腺癌患者的生存率相关性的影响。方法选择该院乳腺外科2008-2003年收治的257名接受TAM治疗乳腺癌患者。调查TAM使用情况和生存状态等相关资料;采集患者外周静脉血5 mL或石蜡切片用于DNA提取;用PCR技术检测CYP2D6*10基因多态性;查明CYP2D6*10基因多态性与患者的生存率相关性的关系。结果该次研究中,携带CYP2D6*10/*10患者占15%(38/257),CYP2D6野生型(Wt)/*10患者占41%(105/257)和CYP2D6Wt/Wt占44%(114/257)。各CYP2D6*10基因型的临床病理参数之间没有相关性差异。在中国CYP2D6*10/*10基因型对接受TAM治疗乳

  19. Physical Properties and Microbial Activity in Forest Residual Substrate

    Many growers in the horticulture industry have expressed concern that switching from a pine bark-based substrate to one with a significant wood content will increase microbial activity, resulting in nitrogen (N) immobilization. This study evaluated four growth substrates (pine bark, peat moss and tw...

  20. Probing small-molecule binding to cytochrome P450 2D6 and 2C9: An in silico protocol for generating toxicity alerts.

    Rossato, Gianluca; Ernst, Beat; Smiesko, Martin; Spreafico, Morena; Vedani, Angelo

    2010-12-01

    Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 and CYP2C9 would be beneficial for identifying cytochrome-mediated adverse effects triggered by drugs or chemicals (e.g., toxic reactions, drug-drug, and food-drug interactions). By identifying the binding mode by using pharmacophore prealignment, automated flexible docking, and by quantifying the binding affinity by multidimensional QSAR (mQSAR), we validated a model family of 56 compounds (46 training, 10 test) and 85 compounds (68 training, 17 test) for CYP2D6 and CYP2C9, respectively. The correlation with the experimental data (cross-validated r²=0.811 for CYP2D6 and 0.687 for CYP2C9) suggests that our approach is suited for predicting the binding affinity of compounds towards CYP2D6 and CYP2C9. The models were challenged by Y-scrambling and by testing an external dataset of binding compounds (15 compounds for CYP2D6 and 40 for CYP2C9). To assess the probability of false-positive predictions, datasets of nonbinders (64 compounds for CYP2D6 and 56 for CYP2C9) were tested by using the same protocol. The two validated mQSAR models were subsequently added to the VirtualToxLab (VTL, http://www.virtualtoxlab.org). PMID:21038340

  1. No association between cytochrome P450 2D6 gene polymorphism and risk of acute leukemia: evidence based on a meta-analysis

    RUAN Xiao-lan; LI Sheng; ZENG Xian-tao; XIA Ling-hui; HU Yu

    2013-01-01

    Background Many studies indicated the human cytochrome P450 2D6 (CYP2D6) gene polymorphism was associated with acute leukemia (AL) susceptibility,however,the results were inconsistent.So we performed this meta-analysis to evaluate the relationship between CYP2D6*3 or CYP2D6*4 polymorphism and AL susceptibility.Methods We searched PubMed database up to February 20,2013,and finally yielded 9 case-control studies including 1343 cases and 1843 controls which tested the association between CYP2D6*3 or *4 polymorphism and AL.After data extraction,we conducted a meta-analysis using the Comprehensive Meta Analysis software.Results Overall,no significant association between CYP2D6*3 or *4 polymorphism and AL risk was found in this metaanalysis (+ vs.-:OR=1.13,95% CI=0.79-1.63; +/+ vs.-/-:OR=1.73,95% C/=0.99-3.02;-/+ vs.-/-:OR=1.03,95% C/=0.68-1.56; (-/+ and +/+) vs.-/-:OR=1.08,95% C/=0.72-1.63; +/+ vs.(-/+ and-/-):OR=1.76,95% C/=0.98-3.17).Similar results were also been found in stratified subgroup analysis.There was no publication bias.Conclusion CYP2D6*3 or *4 polymorphism might not be associated with AL susceptibility.However,the results need to be further confirmed by well-designed and high quality randomized controlled trials with larger sample sizes.

  2. No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

    Vogel Ulla

    2010-08-01

    Full Text Available Abstract Background The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Methods Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion, *6, and CYP2D6 gene duplication. Results In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

  3. Substrate utilization and VSS relations in activated sludge processes

    Droste, R.L.; Fernandes, L.; Sun, X. [Ottawa Univ., ON (Canada). Dept. of Civil Engineering

    1993-12-31

    A new empirical substrate removal model for activated sludge in continuous flow stirred tank reactor (CFSTR) and sequencing batch reactor (SBR) was developed in this study. This model includes an exponential function of volatile suspended solids to express the active biomass which is actually involved in substrate utilization. Results indicate that the proposed exponential models predict more accurately effluent COD in CFSTR and SBR systems than the first or zero order models. (author). 7 refs., 1 fig., 4 tabs.

  4. CYP2D6*10等位基因特性对临床用药安全性和有效性的影响

    谭蓉; 郑志昌; 杨继红; 孙为民

    2009-01-01

    目的:促进CYP2D6底物药物临床合理用药.方法:从CYP2D6*10等位基因对底物药物的代谢特性角度,阐述应重视该等位基因携带者用药安全有效问题.结果:CYP2D6*10等位基因表达酶蛋白的活性及稳定性的特性,可影响其对底物药物的代谢,进而影响临床用药的安全性和有效性.结论:鉴于中国人CYP2D6*10等位基因携带频率高,为了该基因携带者用药安全和有效,应重新审视CYP2D6底物药物的使用模式.

  5. The Effect of CYP2B6, CYP2D6, and CYP3A4 Alleles on Methadone Binding: A Molecular Docking Study

    Nik Nur Syazana Bt Nik Mohamed Kamal

    2013-01-01

    Full Text Available Current methadone maintenance therapy (MMT is yet to ensure 100% successful treatment as the optimum dosage has yet to be determined. Overdose leads to death while lower dose causes the opioid withdrawal effect. Single-nucleotide polymorphisms (SNP in cytochrome P450s (CYPs, the methadone metabolizers, have been showen to be the main factor for the interindividual variability of methadone clinical effects. In this study, we investigated the effect of SNPs in three major methadone metabolizers (CYP2B6, CYP2D6, and CYP3A4 on methadone binding affinity. Results showed that CYP2B6*11, CYP2B6*12, CYP2B6*18, and CYP3A4*12 have significantly higher binding affinity to R-methadone compared to wild type. S-methadone has higher binding affinity in CYP3A4*3, CYP3A4*11, and CYP3A4*12 compared to wild type. R-methadone was shown to be the active form of methadone; thus individuals with CYP alleles that binds better to R-methadone will have higher methadone metabolism rate. Therefore, a higher dosage of methadone is necessary to obtain the opiate effect compared to a normal individual and vice versa. These results provide an initial prediction on methadone metabolism rate for individuals with mutant type CYP which enables prescription of optimum methadone dosage for individuals with CYP alleles.

  6. Lipid metabolizing enzyme activities modulated by phospholipid substrate lateral distribution.

    Salinas, Dino G; Reyes, Juan G; De la Fuente, Milton

    2011-09-01

    Biological membranes contain many domains enriched in phospholipid lipids and there is not yet clear explanation about how these domains can control the activity of phospholipid metabolizing enzymes. Here we used the surface dilution kinetic theory to derive general equations describing how complex substrate distributions affect the activity of enzymes following either the phospholipid binding kinetic model (which assumes that the enzyme molecules directly bind the phospholipid substrate molecules), or the surface-binding kinetic model (which assumes that the enzyme molecules bind to the membrane before binding the phospholipid substrate). Our results strongly suggest that, if the enzyme follows the phospholipid binding kinetic model, any substrate redistribution would increase the enzyme activity over than observed for a homogeneous distribution of substrate. Besides, enzymes following the surface-binding model would be independent of the substrate distribution. Given that the distribution of substrate in a population of micelles (each of them a lipid domain) should follow a Poisson law, we demonstrate that the general equations give an excellent fit to experimental data of lipases acting on micelles, providing reasonable values for kinetic parameters--without invoking special effects such as cooperative phenomena. Our theory will allow a better understanding of the cellular-metabolism control in membranes, as well as a more simple analysis of the mechanisms of membrane acting enzymes. PMID:21108012

  7. Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes.

    Miao Hao

    Full Text Available Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs. Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.

  8. Distribution of CYP2D6 gene copy number variation in chinese littoral han population of zhejiang%浙江沿海地区汉族人群CYP2D6基因拷贝数多态性研究

    周仁芳; 曾爱平

    2008-01-01

    目的 了解浙江沿海地区汉族人群中CYP2D6基因拷贝数多态性分布.方法 使用改良的长模板PCR技术对浙江沿海地区汉族人群中的285例健康人群,进行CYP2D6基因拷贝数多态性进行检测.结果 CYP2D6*5缺失型和CYP2D6*×N重复基因在总样本中的发生频率分别为5.09%(n=29)和0.70%(n=4),在4个重复等位的基因中,其中3个为CYP2D6*1×2,另外1个为CYP2D6*10×2.结论 实验表明本地区CYP2D6基因拷贝数多态性分布不同于其他地区,不同地区呈现出不同的特点,表现出中华民族的遗传多样性.

  9. The impact of CYP2D6 and CYP2C19 polymorphisms on suicidal behavior and substance abuse disorder among patients with schizophrenia: a retrospective study

    Kobylecki, Camilla J; Hansen, Thomas Folkmann; Timm, Sally;

    2008-01-01

    Suicidal behavior and substance abuse are frequent phenomena among patients with schizophrenia and may be attributable in part to antipsychotic treatment failure. Individuals who carry functional variants of the CYP2D6 and CYP2C19 genes, shown to cause altered drug metabolism of psychoactive drugs......, are at risk of toxic accumulation or rapid elimination of these drugs, leading to treatment failure. We tested whether substance abuse disorder and suicidal behavior were associated with the CYP2D6 and CYP2C19 genotypes among patients with schizophrenia. Three hundred sixty-two patients with schizophrenia...... spectrum disorders (International Classification of Diseases, 10th Revision) were genotyped for functional CYP2D6 and CYP2C19 polymorphisms. Based on available medical records and clinical interviews, their suicidal behavior and substance abuse disorder were evaluated. No significant associations between...

  10. Successful treatment of schizophrenia with melperone augmentation in a patient with phenotypic CYP2D6 ultrarapid metabolization: a case report

    Gahr Maximilian

    2012-02-01

    Full Text Available Abstract Introduction There are limited treatment options for people with schizophrenia with cytochrome P450 2D6 ultrarapid metabolizer status who do not respond to amisulpride. Furthermore, the literature does not provide evidence-based guidelines for this particular constellation. Case presentation We report the case of a 50-year-old Caucasian female patient with schizophrenia and cytochrome P450 2D6 ultrarapid metabolizer status who experienced an insufficient antipsychotic effect with amisulpride. She was successfully treated with melperone-augmented haloperidol. Conclusion This report yields melperone-augmented haloperidol as a possible pharmacological strategy in the described situation. In addition, our observations support the available evidence for the potential of melperone to act as an inhibitor of cytochrome P450 2D6.

  11. The impact of CYP2D6 and CYP2C19 polymorphisms on suicidal behavior and substance abuse disorder among patients with schizophrenia: a retrospective study

    Kobylecki, C.J.; Hansen, T.; Timm, S.;

    2008-01-01

    Suicidal behavior and substance abuse are frequent phenomena among patients with schizophrenia and may be attributable in part to antipsychotic treatment failure. Individuals who carry functional variants of the CYP2D6 and CYP2C19 genes, shown to cause altered drug metabolism of psychoactive drugs......, are at risk of toxic accumulation or rapid elimination of these drugs, leading to treatment failure. We tested whether substance abuse disorder and suicidal behavior were associated with the CYP2D6 and CYP2C19 genotypes among patients with schizophrenia. Three hundred sixty-two patients with...... schizophrenia spectrum disorders (International Classification of Diseases, 10th Revision) were genotyped for functional CYP2D6 and CYP2C19 polymorphisms. Based on available medical records and clinical interviews, their suicidal behavior and substance abuse disorder were evaluated. No significant associations...

  12. CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects.

    Ivanova, S A; Filipenko, M L; Vyalova, N M; Voronina, E N; Pozhidaev, I V; Osmanova, D Z; Ivanov, M V; Fedorenko, O Yu; Semke, A V; Bokhan, N A

    2016-03-01

    Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time. PMID:27021090

  13. Does Pharmacogenetic Testing for CYP450 2D6 and 2C19 among Patients with Diagnoses within the Schizophrenic Spectrum Reduce Treatment Costs?

    Herbild, Louise; Andersen, Stig Ejdrup; Werge, Thomas;

    2013-01-01

    The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate health care costs of treating patients with diagnoses within the schizophrenic spectrum for one year with or without pharmacogenetic...... testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive and...

  14. CYP2D6遗传多态性对临床个体化给药的影响

    杨勇; 王友群

    2006-01-01

    本文总结了经CYP2D6代谢的临床常用药物,并对此类药物实现临床个体化给药的方法进行了探讨.同时介绍了CYP2D6的各种表型及其在不同种族之间的分布情况,以及该分布对制定临床给药方案的影响.

  15. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol

    Laugesen, S; Enggaard, T P; Pedersen, R S;

    2005-01-01

    OBJECTIVE: Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a...... very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. METHODS: With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the...

  16. Development of a fluorescent substrate to measure hyaluronidase activity

    Zhang, Li-Shu; Mummert, Mark E.

    2008-01-01

    A novel fluorescent substrate (termed FRET-HA) to quantitatively assess hyaluronidase activity was developed. Hyaluronan (HA), the major substrate for hyaluronidase, was dual labeled with fluorescein amine and rhodamine B amine. The fluorescein amine fluorescence signal was significantly quenched while the rhodamine B amine signal was significantly enhanced due to fluorescence resonance energy transfer (FRET). In the presence of bovine testes hyaluronidase, cleavage of HA disrupted FRET resul...

  17. Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine : study protocol for a pragmatic randomized controlled trial (CYSCEtrial)

    Berm, Elizabeth J. J.; Hak, Eelko; Postma, Maarten; Boshuisen, Marjolein; Breuning, Laura; Brouwers, Jacobus R. B. J.; Dhondt, Ton; Jansen, Paul A. F.; Kok, Rob M.; Maring, Jan G.; van Marum, Rob; Mulder, Hans; Oude Voshaar, Richard; Risselada, Arne J.; Venema, Harry; Vleugel, Liesbeth; Wilffert, Bob

    2015-01-01

    Background: Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D

  18. Effect of the CYP2D6*10 allele on postoperative tramadol analgesia in patients after gastric cancer surgery%CYP2D6*10等位基因多态性对胃癌术后曲马多镇痛效果的影响

    汪国香; 黄丽霞; 张相彩; 陶凡

    2011-01-01

    目的:探讨中国人群CYP2D6*10等位基因对胃癌术后曲马多镇痛效果的影响.方法:70例胃癌根治术患者,手术结束前30 min静脉注入负荷剂量曲马多100 mg,随后采用持续背景剂量-PCA量的给药模式(曲马多10 mg/mL、甲氧氯普胺0.3 mg/mL)进行术后镇痛.全麻诱导后抽取血样,采用聚合酶链反应-限制性片断长度多态性方法分析患者CYP2D6*10基因多态性,根据不同CYP2D6基因型分为3组,比较不同基因组患者之间曲马多的用量.结果:CYP2D6*10等位基因频率为52.4%,不携带CYP2D6*10(I组)17例,CYP2D6*10杂合子(II组)26例,CYP2D6*10纯合子(III组)20例.48 h曲马多用量,III组明显高于I组和II组,I组和II组之间差异无统计学意义.结论:在中国人群中,CYP2D6*10等位基因对曲马多镇痛效果有显著影响.%Objective To investigate whether the CYP2D6*10 allele has an impact on the postoperative analgesia effect of tramadol in Chinese patients suffering from gastric cancer surgery. Methods Seventy gastric cancer patients suffering from gastrectomy were enrolled. After receiving a loading dose of 100 mg tramadol intravenously, patients could self-administer doses of 10 mg/mL tramadol plus 0.3 mg/mL metoclopramide via patient-controlled analgesia (PCA). Blood samples were collected after induction of anesthesia. The CYP2D6*10 polymorphism was analyzed by means of polymerase chain reaction-based restriction fragment length polymor-phism(PCR-RFLP). Demographic data among groups with different genotypes were analyzed using analysis of variance. The total consumption of tramadol between the three genotype groups for 48 h was compared. Results The allele frequency of CYP2D6*10 is 52.4%: Patients were categorized into three groups according to the CYP2D6 genotype: patients without CYP2D6*10 (group I,n=17), patients with heterozygote for CYP2D6*10 (group Ⅱ, n=26), and patients with homozygote for CYP2D6*10 (group Ⅲ, n=20). The demographic data among

  19. 细胞色素CYP2D6基因多态性与急性髓系白血病的关系研究

    里杨; 许俊锋; 王皓; 郭权; 曹楷翔

    2013-01-01

    目的:探讨细胞色素CYP2D6基因多态性与急性髓系白血病(AML)易感性的关系。方法:采用病例对照研究方法,应用聚合酶链反应-限制性片段长度多态性技术,对114例AML患者及180例健康对照者的CYP2D6(C188T)基因的多态分布进行分析。结果:AML 患者组CYP2D6各基因型频率分布与对照组之间无显著性差异;携带CYP2D6188T突变基因型的个体患AML的风险与野生型携带者相比无显著性差异。结论:CYP2D6基因多态性可能与AML遗传易感性不相关。

  20. A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances.

    Peñas-Lledó, E; Guillaume, S; Naranjo, M E G; Delgado, A; Jaussent, I; Blasco-Fontecilla, H; Courtet, P; LLerena, A

    2015-04-01

    This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05-1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19-2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both. PMID:25113522

  1. CYP2D6基因多态性与他莫昔芬及4-羟基他莫昔芬血清浓度的相关性研究%Clinical analysis of CYP2D6 gene polymorphism with serum concentration of tamoxifen and 4-Hydroxytamoxifen

    田超; 杨义; 李卉

    2014-01-01

    目的 探讨CYP2D6基因多态性与乳腺癌患者他莫昔芬(TAM)及其活性代谢产物4-羟基他莫昔芬(4-OH-TAM)血清浓度的相关性.方法 收集2008年1月~2010年10月期间200例服用TAM的乳腺癌患者的口腔粘膜及血清,采用Real-time RT-PC法检测CYP2D6*10基因多态性,采用液相色谱-质谱方法 (LC-MS)测定患者体内TAM及其活性代谢物4-OH-TAM的的血清浓度.结果 200例乳腺癌中检测到CYP2D6*10/*10纯合子94例(47%),CYP2D6 wt/wt野生型48例(24%),CYP2D6 wt/*10杂合型58例(29%).CYP2D6 wt/wt野生型和wt/*10杂合型两组4-OH-TAM的血清浓度都明显高于*10/*10纯合型(P0.05).结论 乳腺癌患者CYP2D6*10/*10基因型影响他莫昔芬的体内代谢过程,与疗效相关,服用TAM前均应推荐检测CYP2D6*10/*10基因型.

  2. Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy": the influence of gender and genetics (CYP2D6, COMT, 5-HTT.

    Ricardo Pardo-Lozano

    Full Text Available The synthetic psychostimulant MDMA (± 3,4-methylenedioxymethamphetamine, ecstasy acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6. It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT. This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6. A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75-100 mg which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles. Female subjects displayed more intense physiological (heart rate, and oral temperature and negative effects (dizziness, sedation, depression, and psychotic symptoms. Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/* determined greater cardiovascular effects, and with low functionality (met/* or s/s negative subjective effects (dizziness, anxiety, sedation. In conclusion, the contribution

  3. The Allele and Genotype Frequences of CYP2D6*10 in Ningxia Hui Population%宁夏回族人群CYP2D6*10等位基因及基因型分布频率

    李宗吉; 王健; 王惠成; 葛立军

    2009-01-01

    目的 了解宁夏回族人群CYP2D6*10等位基因及基因型分布频率,为临床使用CYP2D6底物药物提供依据.方法 采用等位基因特异扩增(ASA-PCR)技术,分析了180例回族体检者的CYP2D6基因型.结果 CYP2D6*10基因点突变结果中野生型纯合子频率为32.3%,杂合子频率为38.3%,突变型纯合子频率为29.4%,突变型等位基因频率为48.6%.结论 宁夏回族人群CYP2D6*10突变基因频率与国内外其他民族有一定差异,在临床应用经CYP2D6代谢的药物时应考虑个体间的代谢速率差异,确保用药安全有效.

  4. Determination of CYP2D6*10 and*14 genotypes by amplification refractory mutation methods in Chinese subjects%突变阻断扩增法检测中国人CYP2D6*10、*14等位基因

    陈冰; 马涛; 蔡卫民

    2009-01-01

    目的 根据突变阻断扩增原理,建立用于检测中国人CYP2D6*10及*14等位基因的方法.方法 采用单管四引物法检测CYP2D6*10等位基因,建立等位基因特异扩增法检测CYP2D6*14等位基因,检测295名健康中国汉族人CYP2D6*10等位基因.结果 CYP2D6*10及*14等位基因基因频率分别为55.8%和1.8%,295位受试者中包括1位*14/*14、6位*1/*14、3位*10/*14,基因型分布符合Hardy-Weinberg平衡(x2=2.15,df=5,P>0.82).结论 本室建立的CYP2D6*10、*14等位基因分析法具有方便快捷、结果准确可靠的特点.

  5. Unique Gold Nanoparticle Aggregates as a Highly Active SERS Substrate

    Schwartzberg, A M; Grant, C D; Wolcott, A; Talley, C E; Huser, T R; Bogomolni, R; Zhang, J Z

    2004-04-06

    A unique gold nanoparticle aggregate (GNA) system has been shown to be an excellent substrate for surface-enhanced Raman scattering (SERS) applications. Rhodamine 6G (R6G), a common molecule used for testing SERS activity on silver, but generally difficult to detect on gold substrates, has been found to readily bind to the GNA and exhibit strong SERS activity due to the unique surface chemistry afforded by sulfur species on the surface. This GNA system has yielded a large SERS enhancement of 10{sup 7}-10{sup 9} in bulk solution for R6G, on par with or greater than any previously reported gold SERS substrate. SERS activity has also been successfully demonstrated for several biological molecules including adenine, L-cysteine, L-lysine, and L-histidine for the first time on a gold SERS substrate, showing the potential of this GNA as a convenient and powerful SERS substrate for biomolecular detection. In addition, SERS spectrum of R6G on single aggregates has been measured. We have shown that the special surface properties of the GNA, in conjunction with strong near IR absorption, make it useful for SERS analysis of a wide variety of molecules.

  6. CYP2 D6基因多态性对帕罗西汀在河南汉族健康受试者体内药代动力学的影响%Influence of CYP2 D6 genetic polymorphism on pharmacokinetics of par-oxetine in Henan Han healthy subjects

    周霖; 薛文华; 张海朋; 刘克锋; 赵杰

    2014-01-01

    目的:研究CYP2D6基因多态性对帕罗西汀在河南汉族健康受试者体内药代动力学的影响。方法:河南汉族健康受试者48人,使用PCR-RFLP技术对其进行CYP2D6基因型检测。受试者单剂量(7.5 mg)口服甲磺酸帕罗西汀胶囊后,收集120 h内的系列血样,用建立的LC-MS/MS法测定血浆帕罗西汀浓度,绘制药-时曲线,进行药代动力学分析。结果:男性CYP2D6*1/*1型受试者9人,CYP2D6*1/*10型21人;女性CYP2D6*1/*1型受试者5人,CYP2D6*1/*10型13人;未检测到CYP2D6*10/*10型;男、女CYP2D6基因型分布差异无统计学意义(χ2=0.027,P>0.999)。与CYP2D6*1/*1型男性受试者比较,CYP2D6*1/*10型男性受试者tmax、t1/2无明显变化(Z=1.145,t=1.400,P>0.05),CL(F)、Vd 降低(Z=2.557,t=2.104,P<0.05),ρmax、AUC0-120和AUC0-∞增加(Z=2.421、2.512、2.557,P<0.05)。与CYP2D6*1/*1型女性受试者比较,CYP2D6*1/*10型女性受试者ρmax、tmax、t1/2及Vd 无明显变化(Z=1.992、1.921,t=2.117、1.905,P>0.05),但 CL(F)降低(Z=2.021,P<0.05), AUC0-120和AUC0-∞增加(Z=2.021、2.021,P<0.05)。结论:CYP2D6*10突变等位基因可影响甲磺酸帕罗西汀在河南汉族健康人群体内的代谢。%Aim:To investigate the influence of CYP2D6 genetic polymorphism on pharmacokinetics of paroxetine in Henan Han healthy people .Methods:A total of 48 Han healthy volunteers from Henan Province were subjected to detect genetic polymorphied by PCR R-FLP method .The volunteers were given a single oral dose of paroxetine mesylate capsule (7.5 mg), and blood samples were collected at different time points until 120 h.The concentrations of paroxetine in plas-ma were measured by LC-MS/MS method, and the pharmacokinetics was analyzed .Results: There were 9 males with CYP2D6*1/*1, 21 with CYP2D6

  7. Substrate independent ATPase activity may complicate high throughput screening.

    Tuntland, Micheal L; Fung, L W-M

    2016-10-01

    Inorganic phosphate release, [Pi], is often measured in an enzymatic reaction in a high throughput setting. Based on the published mechanism, we designed a protocol for our screening for inhibitors of SAICAR synthetase (PurC), and we found a gradual increase in [Pi] in positive control samples over the course of the day. Further investigation indicated that hydrolysis of ATP catalyzed by PurC, rather than substrate-related phosphate release, was responsible for a partial contribution to the signals in the control samples. Thus substrate-independent ATPase activity may complicate high throughput screening. PMID:27430931

  8. Comparison of Streptokinase Activity from Streptococcus mutans using Different Substrates

    Muhammad Anjum Zia*, Rana Faisal, Rao Zahid Abbas1, Gull-e-Faran, Muhammad Kashif Saleemi2 and Junaid Ali Khan3

    2013-01-01

    Streptokinase is a novel bacterial fibrinolytic enzyme that binds and activates plasminogen and is produced by several species of Streptococci. Streptococcus mutans was selected for optimum production of streptokinase using corn steep liquor, molasses, rice polishing and sugarcane bagass in liquid state fermentation. Substrates were applied in different concentrations ranging from 0.1-0.8%. Maximum fibrinolytic activity was observed by 0.3% corn steep liquor, 0.5% molasses and rice polishing ...

  9. Active substrate integrated terahertz waveguide using periodic graphene stack

    Yanfei Dong; Peiguo Liu; Dingwang Yu; Bo Yi; Gaosheng Li

    2015-01-01

    The transmission properties of a substrate integrated waveguide (SIW) based on periodic graphene stacks have been theoretically investigated in the terahertz (THz) region. The effects of the dielectric-graphene-dielectric structure of the stack on the propagation properties are shown to be significant and different from the conventional active SIW based on active components. By varying the graphene chemical potential, the cut-off frequency of the proposed waveguide can be dynamically tuned fr...

  10. 等位基因特异扩增法研究中国人CYP2D6中速代谢的相关基因%ALLELE SPECIFIC AMPLIFICATON FOR CYP2D6 GENE RELATED TO INTERMEDIATE METABOLIZER IN CHINESE SUBJECTS

    陈冰; 蔡卫民; 凌树森

    2001-01-01

    AIM To establish an allele specific PCR amplification (ASA-PCR) for determination of the genotype of CYP2D6*10B polymorphism in Chinese subjects. METHODS CYP2D6*10B alleles of 65 healthy Chinese subjects were analyzed by a two-step PCR assay and the correlation of genotype and phenotype was studied. RESULTS There were 20 CYP2D6*10B heterozygous genotypes subjects (wt/m) in 35 very extensive metabolizers (VEMs), which consisted the major part of VEM subjects (57%). Meanwhile, 20 subjects consisting 69% of 29 intermediate metabolizers were CYP2D6*10B homozygous mutant genotypes (m/m). The poor metabolizer was also m/m. The metabolic ratio of CYP2D6*10B m/m subjects were larger than wt/m and wild type, the values were -1.49±0.54, -2.20±0.49 and -2.47±0.61 (P<0.01). CONCLUSION PCR-ASA was shown to be a rapid and specific method. It can be used to study the genetic polymorphism, especially CYP2D6 intermediate metabolism.%目的 建立CYP2D6*10B的等位基因特异扩增法(ASA-PCR),以探讨中国人CYP2D6中速代谢的基因分型。方法 采用两步扩增法得到CYP2D6*10B等位基因特异片段,分析健康中国汉族人CYP2D6*10B等位基因,并探讨基因分型结果与右美沙芬表型分型结果的相关性。结果 35名表型为极快代谢受试者(VEMs)中,CYP2D6*10B以杂合子(wt/m)为主占57%;29名中速代谢受试者(IMs)以突变型纯合子(m/m)为主占69%;慢代谢受试者(PM)基因型为m/m。CYP2D6*10B m/m组的MR明显大于wt/m组和野生型组(wt/wt)。结论 ASA-PCR法有快速、准确的优点,可用于CYP2D6中速代谢的检测与研究。

  11. Genetic polymorphism of cytochrome P450 2D6 in Chinese population detected by gene chips%基因芯片法测定中国人群细胞色素P450 2D6的基因多态性

    李芹; 王睿; 许力; 文思远; 王升启

    2006-01-01

    目的:根据细胞色素P450 2D6基因序列的多态性分布特点,针对在中国人群药物代谢中具有潜在作用的突变位点C188T和G4268C,设计寡核苷酸探针,制备寡核苷酸芯片,探讨基因芯片技术应用于CYP2D6基因分型的可行性,观察中国人群细胞色素P450 2D6的基因多态性.方法:实验于2005-02/08进行.以克隆并已测序的细胞色素P450 2D6基因重组质粒作为标准样品,扩增产物与芯片进行杂交,制备基因芯片,测定312名中国健康志愿者(已签署知情同意书)细胞色素P4502D6基因分型,并使用直接测序法对结果进行验证.结果:312名全部进入结果分析.①312名中国健康志愿者中CYP2D6*2和CYP2D6*10的变异频率分别为CYP2D6*2W*10W 8.3%,*2H*10W 13.5%,*2M*10W 10.6%,*2M*10H 17.0%,*2M*10M 34.6%,*2H*10H 9.6%,*2H*10M 64%.②对部分样本采用直接测序的方法进行进一步确证,结果完全吻合.结论:①CYP2D6*2和CYP2D6*10突变型等位基因在中国人群中出现的频率较高.②基因芯片法简便、快捷,适用于中国人群细胞色素P4502D6基因分型研究.

  12. No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT)

    Daniels, J.; Williams, J.; Asherson, P.; McGuffin, P.; Owen, M. [Univ of Wales College of Medicine, Cardiff (United Kingdom)

    1995-02-27

    It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48 bp repeat within the 3{prime} untranslated region of DAT. 18 refs., 2 tabs.

  13. Escitalopram er en svag hæmmer af CYP2D6-katalyserede O-demetylering af (+)-tramadol, men ikke mindsker hypoalgesic virkning i eksperimentelle smerter

    Noehr-Jensen, L; Zwisler, S T; Larsen, F;

    2009-01-01

    Tramadol er O-demethylerede til den aktive metabolit (+)-O-desmethyltramadol ((+)- M1) via CYP2D6, et enzym, der er svagt hæmmes af escitalopram. Vi har undersøgt muligheden for en farmakokinetisk (PK) og farmakodynamiske (PD) virkningen af escitalopram på tramadol metabolisme. Femten raske...... 1,95 mikromol / LH efter escitalopram (P = 0,0027). Den gennemsnitlige ÄúÊÇ (1-12) af CPT var 4.140 og 4.388 cm.s efter placebo og escitalopram (p = 0,71). Selvom escitalopram er en svag hæmmer af CYP2D6, er det ikke forringer den analgetiske virkning af tramadol....

  14. Study of simple super-critical fluids (CO2, C2D6) through neutron scattering, Raman spectroscopy and molecular dynamic simulations

    Super-critical fluids are largely used in industrial sectors. However the knowledge of the physical phenomena in which they are involved stays insufficient because of their particular properties. A new model of adjusting molecular structures is proposed, this model has been validated through neutron scattering experiments with high momentum transfer on C2D6. The experimental representation of the critical universal function for C2D6 and CO2 has been obtained through the neutron echo spin and by relying on structure measurements made through neutron elastic scattering at small angles. Raman spectroscopy and molecular dynamics simulation have been used to feature structure and dynamics. Scattering as well as microscopic molecular density fluctuations have been analysed

  15. CYP2D6*10等位基因多态性对文拉法辛血药浓度的影响%Effect of CYP2D6*10 gene polymorphism on blood concentration of venlafaxine

    杨丽蓉; 刘天龙; 刘小雷

    2013-01-01

    目的 旨在研究细胞色素P450酶2D6*10(CYP2D6* 10)基因多态性对文拉法辛血药浓度的影响.方法 随机选择65例抑郁症患者为研究对象,提取其外周血中的DNA并利用特异性的引物对其进行扩增,对得到的扩增产物进行酶切,通过电泳表征酶切结果并分析65例抑郁患者CYP2D6*10基因的基因类型.根据所选择患者基因类型的不同,将其分为3组,即A组:纯合突变(CYP2D6*10/*14),B组:杂合体[CYP2D6*1(*2)/*14]及C组:野生型纯合体[CYP2D6*1(*2)/*5];各组患者口服文拉法辛225mg后,使用高效液相色谱仪测定患者文拉法辛(VL)和O-去甲文拉法辛(ODVL)的血药浓度以研究文拉法辛在不同基因携带者体内的代谢情况.通过汉密尔顿抑郁量表(HAMD)和药物不良反应量表(TESS)来明确文拉法辛对不同CYP2D6*10基因携带者的治疗效果和产生不良反应情况.结果 电泳结果显示,在65名患者中,纯合突变(CYP2D6*10/*14)为29例(44.6%),杂合体([CYP2D6*1(*2)/*14]为17例(26.1%),野生型纯合体[CYP2D6*1(*2)/*5]为19例(29.3%);3组间CvL CODVL及CODVL/CVL比较均具有显著地差异(P<0.05);根据CODVI/CVL值可知,A组、B组及C组对文拉法辛的代谢类型分别为快型(EM)、中型(IM)及慢型(PM).各组间TESS评分和HAMD评分差异具有统计学意义(P< 0.05).结论 不同CYP2D6* 10基因是通过决定抑郁症患者对文拉法辛的代谢类型而影响其血药浓度.%Objective To determine the effect of CYP2D6*10 gene polymorphism on blood concentration of venlafaxine. Methods A total of 65 patients with dysthymia disorders were selected as the case group and DNA extracted from their peripheral blood was amplified by PCR. The PCR products were digested by restriction endonuclease (HphI) and their CYP2D6*10 genotypes were determined by electrophoresis. According to different genotypes, 65 patients were divided into 3 groups: group A: CYP2D6*l0 /*14, group B: [ CYP2D6*1 (*2 ) /*14 ], and

  16. A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

    Ke, Alice Ban; Nallani, Srikanth C.; Zhao, Ping; Rostami-Hodjegan, Amin; Isoherranen, Nina; Unadkat, Jashvant D.

    2013-01-01

    Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age–dependent changes in materna...

  17. Genetic polymorphisms of CYP2D6*10 and the effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in infertile men with idiopathic oligozoospermia*

    Tang, Kai-Fa; Zhao, Yi-li; Ding, Shang-shu; Wu, Qi-Fei; Wang, Xing-yang; Shi, Jia-qi; SUN, FA; Xing, Jun-Ping

    2015-01-01

    Tamoxifen citrate, as the first line of treatment for infertile men with idiopathic oligozoospermia, was proposed by the World Health Organization (WHO), and testosterone undecanoate has shown benefits in semen values. Our objective was to assess the effectiveness of treatment with tamoxifen citrate and testosterone undecanoate in infertile men with idiopathic oligozoospermia, and whether the results would be affected by polymorphisms of CYP2D6*10. A total of 230 infertile men and 147 control...

  18. Genetic polymorphisms of CYP2D6*10 and the effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in infertile men with idiopathic oligozoospermia

    Kai-fa TANG; Yi-li ZHAO; Shang-shu DING; Qi-fei WU; Xing-yang WANG; Jia-qi SHI; Fa SUN; Jun-ping XING

    2015-01-01

      结论:CYP2D6*10基因突变型特发性少精男性不育患者接受他莫昔芬联合十一酸睾酮疗效较基因野生型组差。%Tamoxifen citrate, as the first line of treatment for infertile men with idiopathic oligozoospermia, was proposed by the World Health Organization (WHO), and testosterone undecanoate has shown benefits in semen values. Our objective was to assess the effectiveness of treatment with tamoxifen citrate and testosterone un-decanoate in infertile men with idiopathic oligozoospermia, and whether the results would be affected by polymor-phisms of CYP2D6*10. A total of 230 infertile men and 147 controls were included in the study. Patients were treated with tamoxifen citrate and testosterone undecanoate. Sex hormone, sperm parameters, and incidence of spontaneous pregnancy were detected. There were no significant differences between the control and patient groups with respect to CYP2D6*10 genotype frequencies (P>0.05). The follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were raised, and sperm concentration and motility were increased at 3 months and became significant at 6 months, and they were higher in the wild-type al ele (C/C) than in the heterozygous variant al ele (C/T) or homozygous variant allele (T/T) subgroups (P<0.05). In addition, the percentage of normal morphology was raised at 6 months, and represented the highest percentage in the C/C subgroup (P<0.05). The incidence of spontaneous pregnancy in the C/C subgroup was higher than that in the C/T or T/T subgroups (P<0.01). This study showed that the CYP2D6*10 variant genotype demonstrated worse clinical effects in infertile men with idiopathic oligozoospermia.

  19. Consequences of CYP2D6 polymorphism for the disposition and dynamics of tolterodine : a novel drug in the treatment of urinary bladder overactivity

    Brynne, Niclas

    1998-01-01

    The pharmacokinetics and pharmacological effects of tolterodine were studied in man following administration of increasing oral and intravenous single-doses. The influence of metabolic phenotype in extensive and poor metabolizers of debrisoquine was determined. The effect of tolterodine on the major drug metabolizing cytochrome P450 (CYP) isozymes 1A2, 2C19, 2D6 and 3A4 was studied in vivo by measurements of metabolic ratios of probe drugs. Changes in tolterodine disposition...

  20. Role of Pharmacogenetics in Improving the Safety of Psychiatric Care by Predicting the Potential Risks of Mania in CYP2D6 Poor Metabolizers Diagnosed With Bipolar Disorder

    Sánchez-Iglesias, Santiago; García-Solaesa, Virginia; García-Berrocal, Belén; Sanchez-Martín, Almudena; Lorenzo-Romo, Carolina; Martín-Pinto, Tomás; Gaedigk, Andrea; González-Buitrago, José Manuel; Isidoro-García, María

    2016-01-01

    Abstract One of the main concerns in psychiatric care is safety related to drug management. Pharmacogenetics provides an important tool to assess causes that may have contributed the adverse events during psychiatric therapy. This study illustrates the potential of pharmacogenetics to identify those patients for which pharmacogenetic-guided therapy could be appropriate. It aimed to investigate CYP2D6 genotype in our psychiatric population to assess the value of introducing pharmacogenetics as...

  1. Association of polymorphism of CYP2D6 and CYP2C9 genes encoding P-450 proteins of cytochrome with arterial hypertension

    Saratsev A.V.

    2012-12-01

    Full Text Available Gene polymorphisms of cytochrome P-450 CYP2 encoding proteins of cytochrome P-450 are essential forantihy-pertensive drugs metabolism. Purpose: We study the associations of functionally defective allele variants of CYP2D6 gene and CYP2C9 gene with the degree of arterial hypertension (AH. Materials and methods: Samples of DNA of leukocytes of blood of 150 patients with AH without the associated clinical conditions (56% of women at the age of 20-59 years have been investigated. For the study of polymorphism of genes the pharmacogenetic biochip developed in the Institute of Molecular Biology n.a. V. A. Engelgardt has been used. Comparison of frequencies of occurrence of signs has been carried out on the basis of chi-square criterion. Results: It has been revealed that homozygotes by mutant A1075C, C430T alleles of CYP2C9gene and G1934A of CYP2D6 gene have been significantly more common among patients with hypertension III (p=0.01. Conclusion: The research works on genes of system of P-450 cytochrome have important clinical value for rationalization of pharmacotherapy of hypertension. The increased frequency of occurrence of mutant allele of CYP2D6 and CYP2C9 genes in patients with hypertension III requires special attention to the problem of efficiency and safety of application of hypotensive drugs for the patients.

  2. 用回归分割法预测4味中药对CYP2D6代谢的抑制作用

    郑春松; 陈立武; 杜建; 叶蕻芝

    2007-01-01

    细胞色素P4502D6(CYP2D6)是人体中重要的药物代谢酶,参与临床近百种药物的代谢,包括多种抗心律失常药、β受体阻滞剂、抗高血压药、抗抑郁药以及抗肿瘤药等。某些毒性或致癌物也可被CYP2D6代谢解毒或激活。除影响外源性化学物质的代谢外,CYP2D6还与某些疾病呈相关性。黄芪、女贞子、山药、白花蛇舌草有很好的抗肿瘤作用.目前研究很多,

  3. 细胞色素P450 2D6酶基因多态性与氟西汀临床效应的相关性研究%Correlation between polymorphism of cytochrome P450 2D6 gene and clinical response to fluoxetine

    侯静; 林建荣; 郑东; 何凤贞; 谭静卿; 陆欣乔; 黄煜坤; 李洁仪; 庞振泰; 林振强

    2002-01-01

    目的研究中国人P450 2D6酶(CYP2D6)基因多态性与氟西汀临床效应之间的关系.方法用氟西汀对108例抑郁患者(抑郁症89例,精神分裂症后抑郁7例,分裂情感性精神病抑郁型4例,强迫性神经症2例,焦虑性神经症1例,抑郁性神经症4例,分裂样精神病(伴抑郁症状)1例)进行治疗,用汉密尔顿抑郁量表(HAMD)和治疗中需处理的副反应症状量表(TESS)评定疗效和副反应,用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)分析患者CYP2D6基因型.结果 (1)PCR-RFLP分析表明,在108例抑郁患者中,CYP2D6基因型为 wt/wt者26例,wt/Ch者55例,Ch/Ch者26例, wt/A者1例,未发现B等位基因.CYP2D6等位基因频率分别为CYP2D6wt(50%),CYP2D6Ch(49.5%), CYP2D6A(0.5%). (2)入组时,不同基因型的患者之间HAMD基础评分的差异无显著性(P>0.05).经氟西汀治疗4周和8周后,不同CYP2D6基因型患者的HAMD量表评分比治疗前降低,差异均有非常显著性(P=0.000);8周后减分率达80%左右,而TESS评分较低.在不同基因型的患者之间,治疗后的HAMD评分、HAMD减分率及TESS评分的差异均无显著性(P>0.05).患者治疗前后的HAMD评分及HAMD减分率、TESS评分等与CYP2D6基因型及CYP2D6突变等位基因数目的相关关系均无显著性(P>0.05).结论未发现中国人CYP2D6基因多态性与氟西汀临床效应之间有关联.

  4. CYP2D6 Genetic Polymorphisms in Chinese Healthy and Schizophrenia Populations%中国健康人群与精神分裂症患者CYP2D6(C100T)遗传多态性的相关研究

    周健; 李虓; 王刚; 陈雪彦; 康熙雄

    2008-01-01

    目的 探讨中国健康人群与精神分裂症患者细胞色素P450 2D6(CYP2D6)遗传多态性的相关性.方法 应用PCR与DNA测序相结合的方法对88名精神分裂症患者(男40例,女48例;平均年龄40.38±13.45岁)与93名健康志愿者(男40例,女53例,平均年龄43.60±12.05岁)进行了CYP2D6的基因多态性分析,根据CYP2D6(C100T)将精神分裂症患者和健康志愿者基因型分为三组(C/C,C/T,T/T).结果 在CYP2D6(C100T)的基因型和等位基因型检测中,精神分裂症患者和健康志愿者组间的基因型和等位基因没有显著性差异(X2=0.202,P>0.05;X2=0.066,P>0.05).结论 CYP2D6(C100T)可能不是中国精神分裂症患者的一个易感因素.

  5. 他汀类药物降脂治疗的CYP2D6基因多态性及其与高脂血症的关系%Statins therapy in CYP2D6 gene polymorphism and hyperlipidemia

    李居怡; 王健; 王奕; 甘利明; 黄文静; 邓艾平

    2016-01-01

    目的:观察他汀类药物降脂治疗相关的基因多态性位点CYP4502D6* 10(CYP2D6*10)在宁夏地区的分布和对辛伐他汀降脂疗效的影响及其与高脂血症的关系.方法:采用等位基因特异扩增技术,测定150例健康回族人和200例高脂血症患者CYP2D6基因型并分析基因型与血脂水平、辛伐他汀调脂疗效的关系.结果:CYP2D6* 10基因在宁夏地区的突变频率为47.6%,CYP2D6*10等位基因与高脂血症无显著相关性,服用辛伐他汀8周后CC基因型较CT及TT基因型个体总胆固醇(TC)水平明显降低,差异有统计学意义.结论:CYP2D6* 10基因多态性存在种族和地域的差异,CYP2D6* 10基因多态性对TC水平有显著影响,该基因多态性可能成为辛伐他汀调脂疗效的预测因子.

  6. Extracellular Protease Activity of Enteropathogenic Escherechia coli on Mucin Substrate

    SRI BUDIARTI

    2007-03-01

    Full Text Available Enteropathogenic Escherichia coli (EPEC causes gastrointestinal infections in human. EPEC invasion was initiated by attachment and aggressive colonization on intestinal surface. Attachment of EPEC alter the intestine mucosal cells. Despite this, the pathogenic mechanism of EPEC infectior has not been fully understood. This research hypothesizes that extracellular proteolytic enzymes is necessary for EPEC colonization. The enzyme is secreted into gastrointestinal milieu and presumably destroy mucus layer cover the gastrointestinal tract. The objective of this study was to assay EPEC extracellular protease enzyme by using mucin substrate. The activity of EPEC extracellular proteolytic enzyme on 1% mucin substrate was investigated. Non-pathogenic E. coli was used as a negative control. Positive and tentative controls were Yersinia enterocolitica and Salmonella. Ten EPEC strains were assayed, seven of them were able to degrade mucin, and the highest activity was produced by K1.1 strain. Both positive and tentative controls also showed the ability to digest 0.20% mucin.

  7. 利培酮治疗与细胞色素P4502D6/C188T酶基因多态性的关联分析%Genetic analysis of the cytochrome P450-2D6(CYP2D6)locus:screening influence of risperidone on clinical outcomes in schizophrenia

    王飚; 杨晓敏; 江三多; 钱伊萍; 汪栋祥; 江开达

    2004-01-01

    目的研究利培酮临床效应的个体差异与其代谢酶细胞色素P450 2D6(cytochrome P450 2D6, CYP2D6)酶基因多态性的相关性.方法对88例符合CCMD-3精神分裂症诊断标准的患者和96例健康对照者作病例-对照分析.精神分裂症患者给予利培酮治疗8周,用阳性和阴性症状量表(positive and negative symptom scale, PANSS)评分评价利培酮疗效.采用聚合酶链反应扩增及限制性片段长度多态性(PCR-RFLP)技术对CYP2D6 exon Ⅰ的C188T位点突变进行检测,分析利培酮临床效应与其主要代谢酶CYP2D6/C188T酶基因多态性的相关性. 结果中国上海地区人群的CYP2D6/C188T突变率(弱代谢型)为36.3%,病例组和正常对照组间基因型频率总体分布比较无显著差异(χ2=1.15, df=2, P>0.05),两组间的等位基因频率之间比较也无显著性差异(χ2=0.78, df=1, P>0.05).进行性别及有否家族史分组后分析,亦无差异存在,且CYP2D6/C188T突变与利培酮临床效应之间并无相关性(χ2=1.12, df=2; χ2=0.03, df=1, P>0.05). 结论未发现中国人CYP2D6/C188T多态性与利培酮临床效应的个体差异有相关性.

  8. CYP2D6和UGT1A6基因多态性与慢性苯中毒的危险性%Association of Genetic Polymorphism of CYP2D6 and UGT1A6 with Risks of Chronic Benzene Poisoning

    顾寿永; 张忠彬; 曹多志; 万俊香; 高晓玲; 金锡鹏; 夏昭林

    2005-01-01

    目的探讨CYP2D6基因和UGT1A6基因多态性与慢性苯中毒易感性的关系.方法采用病例一对照研究,选择152名苯中毒工人为病例组,152名接触苯而无中毒表现的工人为对照组.采用PCR-RFLP技术检测CYP2D6第9外显子g.4268位点和UGT1A6第1外显子t.181位点的多态性.结果携带CYP2D6 g.4268 C/C基因型的个体较携带有CYP2D6 g.4268 G/G或G/C基因型的个体发生苯中毒的危险性高1.72倍(95%CI:1.8~2.78,P=0.03);在不吸烟的人群中,携带CYP2D6 g.4268 C/C基因型的个体比携带G/G或G/C基因型的个体发生苯中毒的风险性高1.75倍(95%CI:1.03~2.94,P=0.04);在不饮酒的人群中,携带CYP2D6 g.4268 C/C基因型个体比携带CYP2D6 g.4268 G/G和G/C基因型的个体发生苯中毒的危险性高1.82倍(95%CI:1.09~3.03,P=0.02).UGT1A6 t.181的各基因型在病例组和对照组的分布频率差异无显著性(P>0.05).结论携带CYP2D6 g.4268 C/C基因型的个体对苯中毒可能易感.

  9. Substrate modulation of enzyme activity in the herpesvirus protease family

    Lazic, Ana; Goetz, David H.; Nomura, Anson M.; Marnett, Alan B.; Craik, Charles S.

    2007-01-01

    The herpesvirus proteases are an example in which allosteric regulation of an enzyme activity is achieved through the formation of quaternary structure. Here, we report a 1.7 Å resolution structure of Kaposi’s Sarcoma herpesvirus protease in complex with a hexapeptide transition state analogue that stabilizes the dimeric state of the enzyme. Extended substrate binding sites are induced upon peptide binding. In particular, 104 Å2 of surface are buried in the newly formed S4 pocket when tyrosin...

  10. Direct determination of phosphatase activity from physiological substrates in cells.

    Zhongyuan Ren

    Full Text Available A direct and continuous approach to determine simultaneously protein and phosphate concentrations in cells and kinetics of phosphate release from physiological substrates by cells without any labeling has been developed. Among the enzymes having a phosphatase activity, tissue non-specific alkaline phosphatase (TNAP performs indispensable, multiple functions in humans. It is expressed in numerous tissues with high levels detected in bones, liver and neurons. It is absolutely required for bone mineralization and also necessary for neurotransmitter synthesis. We provided the proof of concept that infrared spectroscopy is a reliable assay to determine a phosphatase activity in the osteoblasts. For the first time, an overall specific phosphatase activity in cells was determined in a single step by measuring simultaneously protein and substrate concentrations. We found specific activities in osteoblast like cells amounting to 116 ± 13 nmol min(-1 mg(-1 for PPi, to 56 ± 11 nmol min(-1 mg(-1 for AMP, to 79 ± 23 nmol min(-1 mg(-1 for beta-glycerophosphate and to 73 ± 15 nmol min(-1 mg(-1 for 1-alpha-D glucose phosphate. The assay was also effective to monitor phosphatase activity in primary osteoblasts and in matrix vesicles. The use of levamisole--a TNAP inhibitor--served to demonstrate that a part of the phosphatase activity originated from this enzyme. An IC50 value of 1.16 ± 0.03 mM was obtained for the inhibition of phosphatase activity of levamisole in osteoblast like cells. The infrared assay could be extended to determine any type of phosphatase activity in other cells. It may serve as a metabolomic tool to monitor an overall phosphatase activity including acid phosphatases or other related enzymes.

  11. Genetic polymorphisms of CYP2D6*10 and the effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in infertile men with idiopathic oligozoospermia*

    Tang, Kai-fa; Zhao, Yi-li; Ding, Shang-shu; Wu, Qi-fei; Wang, Xing-yang; Shi, Jia-qi; Sun, Fa; Xing, Jun-ping

    2015-01-01

    Tamoxifen citrate, as the first line of treatment for infertile men with idiopathic oligozoospermia, was proposed by the World Health Organization (WHO), and testosterone undecanoate has shown benefits in semen values. Our objective was to assess the effectiveness of treatment with tamoxifen citrate and testosterone undecanoate in infertile men with idiopathic oligozoospermia, and whether the results would be affected by polymorphisms of CYP2D6*10. A total of 230 infertile men and 147 controls were included in the study. Patients were treated with tamoxifen citrate and testosterone undecanoate. Sex hormone, sperm parameters, and incidence of spontaneous pregnancy were detected. There were no significant differences between the control and patient groups with respect to CYP2D6*10 genotype frequencies (P>0.05). The follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were raised, and sperm concentration and motility were increased at 3 months and became significant at 6 months, and they were higher in the wild-type allele (C/C) than in the heterozygous variant allele (C/T) or homozygous variant allele (T/T) subgroups (P<0.05). In addition, the percentage of normal morphology was raised at 6 months, and represented the highest percentage in the C/C subgroup (P<0.05). The incidence of spontaneous pregnancy in the C/C subgroup was higher than that in the C/T or T/T subgroups (P<0.01). This study showed that the CYP2D6*10 variant genotype demonstrated worse clinical effects in infertile men with idiopathic oligozoospermia. PMID:25743120

  12. Genetic polymorphisms of CYP2D6*10 and the effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in infertile men with idiopathic oligozoospermia.

    Tang, Kai-fa; Zhao, Yi-li; Ding, Shang-shu; Wu, Qi-fei; Wang, Xing-yang; Shi, Jia-qi; Sun, Fa; Xing, Jun-ping

    2015-03-01

    Tamoxifen citrate, as the first line of treatment for infertile men with idiopathic oligozoospermia, was proposed by the World Health Organization (WHO), and testosterone undecanoate has shown benefits in semen values. Our objective was to assess the effectiveness of treatment with tamoxifen citrate and testosterone undecanoate in infertile men with idiopathic oligozoospermia, and whether the results would be affected by polymorphisms of CYP2D6*10. A total of 230 infertile men and 147 controls were included in the study. Patients were treated with tamoxifen citrate and testosterone undecanoate. Sex hormone, sperm parameters, and incidence of spontaneous pregnancy were detected. There were no significant differences between the control and patient groups with respect to CYP2D6*10 genotype frequencies (P>0.05). The follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were raised, and sperm concentration and motility were increased at 3 months and became significant at 6 months, and they were higher in the wild-type allele (C/C) than in the heterozygous variant allele (C/T) or homozygous variant allele (T/T) subgroups (P<0.05). In addition, the percentage of normal morphology was raised at 6 months, and represented the highest percentage in the C/C subgroup (P<0.05). The incidence of spontaneous pregnancy in the C/C subgroup was higher than that in the C/T or T/T subgroups (P<0.01). This study showed that the CYP2D6*10 variant genotype demonstrated worse clinical effects in infertile men with idiopathic oligozoospermia. PMID:25743120

  13. Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 Polymorphisms in Breast Carcinoma

    Gabbouj Sallouha

    2008-04-01

    Full Text Available Abstract Background Xenobiotic Metabolizing Enzymes (XMEs contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients. Methods The authors used polymerase chain reaction and restriction enzyme digestion to characterize the variation of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene in a total of 560 unrelated subjects (246 controls and 314 patients. Results The mEH (C/C mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk (p = 0.02; p = 0.01, respectively. For NAT2 the association was more pronounced among postmenopausal patients (p = 0.006. A significant association was found between CYP2D6 (G/G wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04. Association studies of genetic markers with the rates of breast carcinoma specific overall survival (OVS and the disease-free survival (DFS revealed among all breast carcinoma patients no association to DFS but significant differences in OVS only with the mEH gene polymorphisms (p = 0.02. In addition, the mEH wild genotype showed a significant association with decreased OVS in patients with axillary lymph node-negative patients (p = 0.03 and with decreasesd DFS in patients with axillary lymph node-positive patients (p = 0.001. However, the NAT2 intermediate acetylator genotype was associated with decreased DFS in axillary lymph node-negative patients. Conclusion The present study may prove that polymorphisms of some XME genes may predict the onset of breast carcinoma as well as survival after treatment.

  14. Interaction of drug metabolizing cytochrome P450 2D6 poor metabolizers with cytochrome P450 2C9 and 2C19 genotypes modify the susceptibility to head and neck cancer and treatment response

    Yadav, Sunishtha S.; Ruwali, Munindra [Developmental Toxicology Division, Indian Institute of Toxicology Research (Formerly: Industrial Toxicology Research Centre), Council CSIR, P.O. Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India); Pant, Mohan C.; Shukla, Pragya [Department of Radiotherapy, C.S.M. Medical University, Shahmina Road, Lucknow 226 001 (India); Singh, Ram L. [Department of Biochemistry, Dr. R.M.L. Awadh University, Faizabad 224 001, U.P. (India); Parmar, Devendra, E-mail: parmar_devendra@hotmail.com [Developmental Toxicology Division, Indian Institute of Toxicology Research (Formerly: Industrial Toxicology Research Centre), Council CSIR, P.O. Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India)

    2010-02-03

    The present case-control study attempted to investigate the association of poor metabolizer (PM) genotypes of cytochrome P450 2D6 (CYP2D6*4 and CYP2D6*10) with squamous cell carcinoma of head and neck (HNSCC) and treatment response in patients receiving chemotherapy or combination of chemo- and radiotherapy. Cases with the PM genotypes of CYP2D6 displayed a significantly increased risk for HNSCC as compared to wild type genotypes. The risk was found to further increase in cases (up to 4.8) carrying combination of PM genotypes of CYP2D6, CYP2C9 (CYP2C9*2) or CYP2C19 (CYP2C19*2), suggesting that synergism amongst the PM genotypes of drug metabolizing CYPs leads to impairment in the detoxification of the tobacco carcinogens. A small increase in the risk in tobacco (chewers or smokers) or alcohol users in cases with CYP2D6*4 allele while no change or even a small decrease in risk in cases with CYP2D6*10 allele when compared to non-tobacco or alcohol users have suggested that CYP2D6 genotypes alone do not appear to interact significantly with environmental risk factors in modifying the susceptibility to HNSCC. Furthermore, most of the cases carrying PM genotypes of CYP2D6 did not respond to the treatment. Moreover, higher prevalence of non-responders among cases carrying combination of CYP2D6*4 or CYP2D6*4, CYP2C9*2 and CYP2C19*2 have demonstrated that interaction of PM genotypes may not only significantly modify the susceptibility to HNSCC but also the treatment response.

  15. 氨苄西林与双黄连注射液单用及配伍时对大鼠CYP2D6的影响%Effects on CYP2D6 by the Single Use of Ampicillin and Shuanghuanglian or Combination of Both

    王欢; 吴东媛; 杜智敏

    2008-01-01

    目的 通过氨苄西林和双黄连注射液的大鼠体内、外实验,观察两种药物分别给药及合用时对大鼠CYP2D6的影响.方法 对照组和实验组大鼠分别经尾静脉注射给予0.9%氯化钠溶液、双黄连注射液、氨苄西林、双黄连注射液联合氨苄西林,均给药1周.高效液相色谱法测定大鼠尿样及肝微粒体中CYP2D6探针药物右美沙芬的代谢率,观察氨苄西林、双黄连注射液分别单用及合用时对大鼠CYP2D6活性的影响.通过Western blot法测定其对大鼠肝微粒体CYP2D6蛋白表达的调控.结果 实验组大鼠分别给予双黄连注射液、氨苄西林及双黄连注射液配伍氨苄西林时,尿样中右美沙芬代谢率与对照组差异无显著性(P>0.05);实验组大鼠肝微粒体中加入右美沙芬(0.324 mmol·L-1),右美沙芬代谢率与对照组差异无显著性(P>0.05);各实验组与对照组CYP2D6蛋白表达差异无显著性.结论 双黄连注射液、氨苄西林单用和两药配伍使用均不影响CYP2D6酶的活性,与同时使用经CYP2D6代谢的其他药物不会产生相互作用.

  16. 26种中药提取物对CYP3A4和CYP2D6代谢的抑制作用

    Iwata; H; 郑晓燕(摘译); 阴赪宏(校)

    2005-01-01

    研究认为,细胞色素P450(CYP)酶与药物相互作用。本次在NADPH-生成体系存在的情况下,以单味中药甲醇提取物对人肝细胞微粒体进行预培养,检测26种中药对CYP3A4和CYP2D6的抑制作用。

  17. Untersuchung zu unerwünschten Arzneimittelwirkungen von Metoprolol in Abhängigkeit vom CYP2D6-Genotyp bei ambulanten Patienten

    Pröhmer, Anne Marie Theres

    2008-01-01

    Diese prospektive klinische Studie wurde mit dem Ziel durchgeführt, den Einfluss des polymorph exprimierten Cytochrom P450 (CYP) 2D6 auf erwünschte und unerwünschte Wirkungen von Metoprolol in einem ambulanten Setting zu untersuchen. Die mittels eines Tagebuchs abgefragten unerwünschten Arzneimittelwirkungen (UAW) umfassten zentralnervöse und kardiovaskuläre Beschwerden, die sexuelle Funktion und Lebensqualität des Patienten, sowie zusätzlich bei den Patienten mit diagnostizierter Psoriasis v...

  18. CYP2D6*10 polymorphism and response to donepezil in patients with Alzheimer's disease%阿尔茨海默病CYP2D6*10基因多态性与多奈哌齐疗效

    郑雪丽; 苗雅; 钟远; 万丽丽

    2012-01-01

    目的 研究阿尔茨海默病(AD)患者CYP2D6* 10基因多态性对多奈哌齐疗效的影响.方法 筛选AD患者110例(AD组)和健康体检者124例(对照组),应用限制性片段长度多态性-聚合酶链反应(RFLP-PCR)方法对两组患者进行CYP2D6*10基因多态性测定.AD组给予多奈哌齐治疗6个月,于服药前后,应用简易精神状态量表( MMSE)和阿尔茨海默病评定量表认知分量表(ADAS-Cog)进行认知功能测定;应用高效液相色谱-质谱法测定患者血浆中多奈哌齐的稳态血药浓度.结果 AD组与对照组CYP2D6*10的基因型和等位基因频率分布差异无统计学意义(P>0.05);AD组CYP2D6*10基因突变型(T/T型与C/T型)的血药浓度、MMSE和ADAS-Cog评分与野生型(C/C型)相比,差异均有统计学意义(P< 0.05).结论 多奈哌齐对阿尔茨海默病CYP2D6* 10基因突变型患者的疗效优于野生型患者.%Objective To analyze the relation of CYP2D6* 10 polymorphism with response to donepezil in patients with Alzheimer's disease(AD). Methods A total of 110 AD patients (AD group) and 124 healthy individuals (control group) were recruited for the study. RFLP-PCR was applied to analyze the CYP2D6*10 gene polymorphisms. Besides, the AD patients were administrated with donepezil 5-10 mg/d for 6 months and evaluated by cognition scales (MMSE and ADAS-Cog) before and after therapy. The steady plasma concentration (Cp) of donepezil was measured by HPLC-MS. Results There was no statistical difference in genotypes and allele frequency of CYP2D6* 10 between AD group and control group. However, significant differences were found in AD patients on steady concentration of donepezil and cognition scores (MMSE and ADAS-Cog) between CYP2D6*10 mutant genotypes (T/T and C/T group) and wild type (C/C group) (P < 0.05). Conclusions Donepezil is more effective for AD patients carrying CYP2D6*10 mutants than those carrying wild type.

  19. Influence of CYP2D6 genetic polymorphism on pharmacokinetics of metoprolol in Chinese population%中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响

    李芹; 王睿; 郭雅; 裴斐

    2008-01-01

    目的:研究中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响.方法:使用基因芯片技术测定中国健康志愿者CYP2D6的基因型,按照分型结果将志愿者分为四组,第1组:CYP2D6*2W*10W,第2组:CYP2D6*2H*10W或CYP2D6*2M*10W,第3组:CYP2D6*2M*10H,第4组:CYP2D6*2M*10M,每组筛选10人,共40人.各组志愿者单次口服 100 mg 美托洛尔后,使用HPLC方法测定血和尿中美托洛尔及其代谢产物α-羟基美托洛尔(HM)的浓度,研究其在不同基因型志愿者体内的药代过程.结果:第2组美托洛尔及其HM的主要药动学参数与第1组相比均没有统计学差异.第3组美托洛尔的t1/2、AUC、Cmax显著高于第1组(P<0.05);而HM的t1/2延长 47.3%,AUC降低 56.0%(P<0.05).第4组美托洛尔的t1/2、AUC、Cmax均显著高于第1组(P<0.05)和第3组(P<0.05);HM的t1/2、AUC、Cmax与第1组和第3组相比均有统计学差异(P<0.05),且呈现基因剂量效应.第3组和第4组的口服清除率和肾清除率均低于第1组,而0~24 h 代谢比率分别为第1组的 1.82 倍和 3.96 倍.结论:CYP2D6*2对于美托洛尔的药代动力学过程没有影响;但CYP2D6*10可降低酶活性,且CYP2D6*10纯合子变异比杂合子变异对美托洛尔药代动力学的影响更大,呈现基因剂量效应.

  20. The correlation between ACE and CYP2D6 polymorphism and the effect of perindopril%心衰患者 ACE 及 CYP2 D6遗传多态性与培哚普利疗效的关联性研究

    彭俊; 黄自明; 郭观华

    2015-01-01

    Objective To investigate the correlation between ACE and CYP 2D6 polymorphism and the effect of perindopril.Methods The genotype was determined by PCR in 158 patients.The differences of left ventricular end-diastolic diameters ( LVDD) , left ventricular ejection fractions ( LVEF) and AngⅡlevel before and after perindo-pril treatment were detected .Results The patients with DD/CC, DD/CT and DD/TT phenotype had a great de-crease in LVDD and AngⅡ after perindopril treatment .Conclusion ACE polymorphisms correlates to the effect of perindopril treatment .CYPD2D6 polymorphism does not correlate to the perindopril treatment .%目的:探讨心衰患者ACE及CYP2D6遗传多态性与培哚普利疗效的关联性。方法选取158例心衰患者,应用PCR方法检测其ACE及CYP2D6多态性,给予培哚普利治疗,对治疗前后的左室舒张末期内径( LVDD)、左室射血分数( LVEF)和血浆血管紧张素Ⅱ( AngⅡ)进行检测。结果 DD/CC、DD/CT和DD/TT型患者经治疗后,LVDD明显缩小,且血浆AngⅡ水平下降的幅度最大。结论 ACE基因的多态性与培哚普利的治疗效果有关联性,CYP2D6基因多态性对培哚普利的疗效无明显影响。

  1. CYP1A1和CYP2D6基因多态性对白血病发生的影响%Genetic polymorphisms of CYP1A1 and CYP2D6 and their impact on leukemia morbidity

    李文凯; 刘清霞; 陈放知; 骆亚萍; 陈慧娟; 夏嘉志; 陈汉春

    2008-01-01

    目的 分析细胞色素P450 CYP1A1和CYP2D6的多态性基因型在湖南地区白血病患者和健康人群中的分布及其对白血病发生的影响.方法 采用PCR及PCR-RFLP技术分析多态性基因型频率.结果 CYP1A1和CYP2D6基因的野生型、杂合突变型及纯合突变型的分布频率在急性淋巴细胞性白血病、急性非淋巴细胞性白血病、慢性粒细胞性白血病患者组与健康对照组之间无显著性差异;携带一个突变等位基因型的个体患白血病的风险与相应野生型携带者比较均无显著性差异;急性非淋巴细胞性白血病患者组的CYP1A1杂合突变型与CYP2D6杂合突变型的联合基因型频率高于健康对照组.结论 单独的CYP1A1或CYP2D6基因的多态性变异与白血病易感性不相关;CYP1A1杂合突变与CYP2D6杂合突变的联合基因型增加患急性非淋巴细胞性白血病的风险.

  2. Secretory Phospholipase A(2) Activity toward Diverse Substrates

    Madsen, Jesper Jonasson; Linderoth, Lars; Subramanian, Arun Kumar;

    2011-01-01

    an inverted ester. The latter were included to study head group-enzyme interactions. Our simulation results show that the lipids are optimally placed into the binding cleft and that water molecules can freely reach the active site through a well-defined pathway; both are indicative that these...... substrates are efficiently hydrolyzed, which is in good agreement with our experimental data. The phospholipid analogue with three alkyl side chains forms aggregates of different shapes with no well-defined sizes due to its cone-shape structure. Phosphatidylglycerol and phosphatidylcholine head groups...

  3. 细胞色素P4502D6基因多态性和药物相互作用%Genetic polymorghism of CYP2D6 and drug interactions

    李芹; 王睿

    2006-01-01

    细胞色素P4502D6(CYP2D6)是一种重要的P450系氧化代谢酶,参与多种重要药物的代谢.CYP2D6具有基因多态性,对药物的代谢呈现明显的个体差异.而且CYP2D6能被多种药物竞争性抑制和诱导,药物联用时易产生相互作用.本文从CYP2D6的基因多态性与代谢表型、底物竞争作用、代谢酶的诱导和抑制等方面,探讨CYP2D6基因多态性与药物相互作用的关系.

  4. 乳腺癌患者CYP2D6多态性与Endoxifen血药浓度的相关性分析%Association between CYP2D6 polymorphism and plasma concentration of Endoxifen in breast cancer patients

    杨汐; 罗波; 吴斌

    2013-01-01

    目的:研究乳腺癌术后服用他莫昔芬(TAM)辅助治疗绝经前、雌激素受体(ER)阳性患者CYP2D6基因多态性与TAM活性代谢产物Endoxifen血药浓度的相关性,及其与TAM不良反应发生的相关性.方法:57例乳腺癌术后经TAM辅助治疗的患者(绝经前、ER阳性),采用Tetra-primer ARMS PCR检测其CYP2D6基因型,采用LC-MS/MS测定所有患者体内TAM及其活性代谢产物Endoxifen的血药浓度;根据患者自述标记存在治疗不良反应的个体.结果:CYP2D6* 10/* 10型和*1/* 10型受试者体内Endoxifen的血药浓度值分别为(23.55±4.01)和(25.90±3.93) ng/mL,均显著低于*1/*1型受试者(34.82±5.95) ng/mL,差异有统计学意义,P<0.01;但*10/* 10型和*1/* 10型之间Endoxifen的浓度值差异无统计学意义,P>0.05.CYP2D6* 1/*1型组自述无任何不良反应的比例(22.2%)低于突变组(62.5%),且差异有统计学意义,P<0.05.结论:CYP2D6基因多态性与Endoxifen血药浓度的差异及TAM治疗不良反应的发生有关;根据CYP2D6基因型,可指导绝经前、ER阳性乳腺癌患者术后的TAM个体化用药.

  5. Active substrate integrated terahertz waveguide using periodic graphene stack

    Dong, Yanfei; Liu, Peiguo; Yu, Dingwang; Yi, Bo; Li, Gaosheng

    2015-11-01

    The transmission properties of a substrate integrated waveguide (SIW) based on periodic graphene stacks have been theoretically investigated in the terahertz (THz) region. The effects of the dielectric-graphene-dielectric structure of the stack on the propagation properties are shown to be significant and different from the conventional active SIW based on active components. By varying the graphene chemical potential, the cut-off frequency of the proposed waveguide can be dynamically tuned from 3 to 3.7 THz. Moreover, the tunable waveguide displays low leakage loss and single-mode propagation with -120 dB stop-band attenuation. These primary results are very promising for THz integration devices and SIW-based systems.

  6. Active substrate integrated terahertz waveguide using periodic graphene stack

    Yanfei Dong

    2015-11-01

    Full Text Available The transmission properties of a substrate integrated waveguide (SIW based on periodic graphene stacks have been theoretically investigated in the terahertz (THz region. The effects of the dielectric-graphene-dielectric structure of the stack on the propagation properties are shown to be significant and different from the conventional active SIW based on active components. By varying the graphene chemical potential, the cut-off frequency of the proposed waveguide can be dynamically tuned from 3 to 3.7 THz. Moreover, the tunable waveguide displays low leakage loss and single-mode propagation with −120 dB stop-band attenuation. These primary results are very promising for THz integration devices and SIW-based systems.

  7. Transient Response of Aerobic and Anoxic Activated Sludge Activities to Sudden Substrate Concentration Changes

    Sin, G.; Vanrolleghem, P.A.; Gernaey, Krist

    2004-01-01

    The state-of-the-art understanding of activated sludge processes as summarized in activated sludge models (ASMs) predicts an instantaneous increase in the biomass activity (which is measured, e.g., by the corresponding respiration rate OUR, NUR, etc.) under sudden substrate concentration changes....

  8. Optically active vibrational modes of PPV derivatives on textile substrate

    In this work, MEH-PPV and BDMO-PPV films were deposited by spin-coating on “dirty” textile substrates of canvas, nylon, canvas with resin, jeans and on glass and the temperature dependence of the optical properties of them was studied by photoluminescence and Raman (300 K) techniques. The temperature dependence of the energy, of the half line width at half height of the purely electronic peak, of the integrated PL intensity and of the Huang-Rhys factor, S=I(01)/I(00), were obtained directly from the PL spectrum. For an analysis of the vibrational modes involved, Raman measurements were performed on substrates with and without polymers deposited and the results compared with those found in the literature. The films of MEH-PPV and BDMO-PPV showed optical properties similar to those films deposited on other substrates such as glass, metals, etc. It was observed an inversion of the first vibrational band in relation to the purely electronic peak with increasing temperature in the films deposited on nylon and canvas. The vibrational modes obtained by Raman were used to compose the simulation of the PL line shape of BDMO-PPV films on canvas and nylon, using a model proposed by Lin [29]. - Highlights: ► MEH-PPV and BDMO-PPV films were deposited by spin-coating on dirty textile. ► Their properties were studied by photoluminescence and Raman techniques. ► We observed inversion of first vibrational band in relation to purely electronic peak. ► Optically active vibrational modes of PPV derivatives were studied.

  9. β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的影响%Effectes of β1-adrenergic receptor and CYP2D6 gene polymorphism on metoprolol antihypertension therapy

    徐承华; 杨玉雯; 曹蘅

    2011-01-01

    AIM: To investigate effects of β1-adrenergic receptor and CYP2D6 gene polymorphism on metoprolol antihypertension therapy. METHODS: 120 cases of patients with essential hypertension were detected by β1 -adrenergic receptor and CYP2D6 gene polymorphism, 118 patients with Arg 389 allele in β1- adrenergic re-ceptor gene chosen from 120 essential hypertension patients were divided into three phenotype groups according to CYP2D6 gene mutations: the poor metabolism group(PM, 55 cases), intermediate metabolism group (IM, 36 cases)and extensive metabolism group(EM, 27 cases). The subjects of PM, IM and EM were administratedwith metoprolol for the same doseQOO mg/d), taking orally twice a day. Blood pressures, heart rates and side effects were observed during 4-week following-up. RESULTS: Blood pressure and heart rate in group PM, IM and EM were decreased, especially, obviously decreased in group PM, however, the incidence of side effect was significantly increased in group PM. CONCLUSION: The genetic polymorphism of β1- ad-renergic receptor and CYP2D6 was associated with the efficiency of metoprolol antihyperten-sion therapy.%目的:探讨β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的影响.方法:将2008年10月至2009年10月在安徽省皖南地区收集的120例原发性高血压患者进行岛肾上腺素能受体(β1-AR)和代谢酶细胞色素2136(CYP2D6)基因多态性检测,将β1-AR 389位携带Arg的118例患者按照CYP2D6基因表型分为弱代谢组(PM组,55例)、中等代谢组(IM组,36例)和强代谢组(EM组,27例),给予相同剂量(100 mg/d)美托洛尔,均分2次口服降压治疗,共随访4周,观察血压、心率和不良反应等指标.结果:PM、IM、EM组血压和心率均下降,尤以PM组血压和心率降幅最大,但不良反应发生率明显增加.结论:β1肾上腺素受体和CYP2D6基因多态性与美托洛尔降压疗效有一定相关性.

  10. Genetic polymorphism analysis of cytochromeP450 CYP2D6 and CYP2C19 in Han and Uyghur breast cancer patients in Xinjiang%新疆汉族与维吾尔族乳腺癌CYP2D6和CYP2C19基因多态性差异研究

    2016-01-01

    目的 探讨新疆汉族与维吾尔族绝经前乳腺癌患者CYP2D6和CYP2C19基因频率分布及他莫昔芬代谢类型以指导临床合理用药.方法 选取2011-06-01-2013-12-01新疆医科大学附属肿瘤医院绝经前激素受体阳性乳腺癌患者中汉族125例和维吾尔族121例,对CYP450中常见突变位点利用TaqMan(R)-MGB技术进行基因检测并确定他莫昔芬代谢类型.结果 CYP2D6(* 1/* 10)、CYP2D6(* 10/* 10)及CYP2C19(* 1/*1)基因型在汉族、维吾尔族两组患者中表达差异有统计学意义,x2值分别为1.123、9.746和5.935,P值分别为0.029、0.002和0.015;而CYP2D6(* 1/*5)、CYP2D6(* 5/*5)、CYP2D6(* 5/* 10)、CYP2C19(* 3/*3)基因型在两组患者中均无表达,差异无统计学意义,P>0.05.两组中CYP2D6(* 1/*1)、CYP2C19(* 1/*2)、CYP2C19(* 2/*2)、CYP2C19(* 1/*3)和CYP2C19(* 2/*3)基因型差异无统计学意义,P>0.05.汉族患者他莫昔芬快、中、慢代谢型者比例分别为72.0%、24.0%和4.0%,维吾尔族分别为76.9%、17.4%和5.7%,P>0.05.结论 汉族、维吾尔族乳腺癌患者中CYP2C19*2、CYP2C19*3基因频率均差异无统计学意义;而CYP2D6* 10等位基因的频率差异有统计学意义;他莫昔芬的代谢类型均以快代谢类型为主,两组之间差异无统计学意义.

  11. Genetic polymorphism of CYP2D6 in Karnataka and AndhraPradesh population in India%CYP2D6在印度卡纳塔克邦和安得拉邦人群中的遗传多态性

    Benny K ABRAHAM, C ADITHAN; P USHA KIRAN; Mohammed ASAD; K KOUMARAVELOU

    2000-01-01

    AIM: To study the prevalence of cytochrome P-450 2D6 (CYP2D6) polymorphism in Karnataka ( KA ) and Andhra Pradesh (AP) population. METHODS: Two hundred and eleven healthy human volunteers participated in the study (100 from KA and 111 from AP). At bed time, after voiding their bladder, the volunteers ingested 30 mg of dextromethorphan hydrobromide (DM). Urine samples were collected for 8 h. DM and its metabolite dextrorphan (DT) were estimated in the urine using HPLC. The metabolic ratio (DM/DT) was used for phenotyping. RESULTS: The prevalence of poor metabolisers (PM) in KA is 4 % and AP is 1.8 %.CONCLUSION: The frequency of PM phenotype in South Indian population is in between the Western and Oriental population.

  12. Effects of CYP2D6*10 genetic polymorphism on the protection of metoprolol for the elder during perioperative period%CYP2D6*10遗传基因多态性对美托洛尔在围术期保护老年患者心脏功能的影响

    刘芳; 张燕; 先小纲

    2014-01-01

    目的:探讨CYP2D6*10等位基因C188T单核苷酸多态性与美托洛尔(metoprolol,METO)在老年患者围术期心脏保护疗效的关系.方法:筛选323名应用METO预防围术期心血管风险的老年患者,采用PCR-RFLP法分析CYP2D6*10基因C188>T位点的单核苷酸多态性.患者用药后进行围术期临床跟踪,观测并评价METO治疗围术期血流动力学紊乱发生事件及个体服药后3h肌钙蛋白的变化.结果:本研究人群中CYP2D6* 10外显子C188>T位点的C、T等位基因频率分别为48.76%和51.24%,CYP2D6* 10基因野生型纯合子C/C、杂合子C/T、突变型纯合子T/T基因型人群分布分别为24.76%、47.98%和27.24%,其频率分布均符合Hardy-Weinberg平衡定律.统计结果显示基因型与心血管术后均有中等强度关联.对心肌梗死风险因子的散点图按照基因多态性分布情况进行分组后分析发现,其心血管风险增高与CYP2D6* 10遗传多态性存在相关的基因剂量效应.结论:CYP2D6* 10基因多态性(C188>T)可能导致METO在老年患者围术期中的心脏保护功能增强,同时还可能带来心动过缓的副作用.CYP2D6* 10突变与METO疗效密切相关,可致患者用药后收缩压显著改变,临床应关注CYP2D6遗传多态性对METO疗效的影响.

  13. An Experimental and Theoretical Study on the Kinetic Isotope Effect of C2H6 and C2D6 Reaction with OH

    Khaled, Fethi

    2015-10-30

    We report experimental and theoretical results for the deuterated kinetic isotope effect (DKIE) of the reaction of OH with ethane (C2H6) and deuterated ethane (C2D6). The reactions were investigated behind reflected shock waves over 800–1350 K by monitoring OH radicals near 306.69 nm using laser absorption. In addition, high level CCSD(T)/cc-pV(T,Q)Z//MP2/cc-pVTZ quantum chemical and statistical rate theory calculations were performed which agreed very well with the experimental findings. The results reported herein provide the first experimental evidence that DKIE for alkanes asymptotes to a value of 1.4 at high temperatures.

  14. 基因芯片技术对中国人群细胞色素P450 2D6基因多态性的研究

    李芹; 王睿

    2005-01-01

    目的:探讨基因芯片技术在细胞色素P450 2D6基因分型中应用的可行性,研究中国人群CYP2D6的基因多态性。方法建立寡核苷酸芯片测定CYP2D6基因型的方法,测定288例中国健康志愿者CYP2D6基因分型,并使用直接测序法对结果进行验证。结果:288例中国健康志愿者中CYP2D6*2和CYP2D6*10的变异频率分别高达52.8%和53.5%。对部分样本采用直接测序的方法进行进一步确证,结果完全吻合。结论:基因芯片法适用于中国人群CYP2D6基因分型研究。

  15. Substrate integrated ferrite phase shifters and active frequency selective surfaces

    Cahill, B M

    2002-01-01

    There are two distinct parts to this thesis; the first investigates the use of ferrite tiles in the construction of printed phase shifting transmission lines, culminating in the design of two compact electromagnetic controlled beam steered patch and slot antenna arrays. The second part investigates the use of active frequency selective surfaces (AFSS), which are later used to cover a uPVC constructed enclosure. Field intensity measurements are taken from within the enclosure to determine the dynamic screening effectiveness. Trans Tech G-350 Ferrite is investigated to determine its application in printed microstrip and stripline phase shifting transmission lines. 50-Ohm transmission lines are constructed using the ferrite tile and interfaced to Rogers RT Duroid 5870 substrate. Scattering parameter measurements are made under the application of variable magnetic fields to the ferrite. Later, two types of planar microwave beam steering antennas are constructed. The first uses the ferrites integrated into the Dur...

  16. Study on association of polymorphism of CYP450 2D6 with head and neck cancer and treatment response in patients receiving neoadjuvant chemotherapy paclitaxel, cisplatin, 5fu (TPF followed by chemoradiation

    Divyesh Kumar

    2014-04-01

    Results: Patients with CYP 2D6 1 showed good response to the therapy given, while CYP 2D6 4 and 10 were poor responders. Conclusion: There is a strong association of polymorphs of CYP 2D6 with occurrence of head and neck cancer. Response to treatment (TPF--CT-RT is polymorph graded. Our study thus provides an insight in to the concept of and ldquo;Right therapy to the right patient and rdquo;. [Int J Res Med Sci 2014; 2(2.000: 585-591

  17. Substrate regulation of ascorbate transport activity in astrocytes

    Astrocytes possess a concentrative L-ascorbate (vitamin C) uptake mechanism involving a Na(+)-dependent L-ascorbate transporter located in the plasma membrane. The present experiments examined the effects of deprivation and supplementation of extracellular L-ascorbate on the activity of this transport system. Initial rates of L-ascorbate uptake were measured by incubating primary cultures of rat astrocytes with L-[14C]ascorbate for 1 min at 37 degrees C. We observed that the apparent maximal rate of uptake (Vmax) increased rapidly (less than 1 h) when cultured cells were deprived of L-ascorbate. In contrast, there was no change in the apparent affinity of the transport system for L-[14C]ascorbate. The increase in Vmax was reversed by addition of L-ascorbate, but not D-isoascorbate, to the medium. The effects of external ascorbate on ascorbate transport activity were specific in that preincubation of cultures with L-ascorbate did not affect uptake of 2-deoxy-D-[3H(G)]glucose. We conclude that the astroglial ascorbate transport system is modulated by changes in substrate availability. Regulation of transport activity may play a role in intracellular ascorbate homeostasis by compensating for regional differences and temporal fluctuations in external ascorbate levels

  18. Substrate-Competitive Activity-Based Profiling of Ester Prodrug Activating Enzymes.

    Xu, Hao; Majmudar, Jaimeen D; Davda, Dahvid; Ghanakota, Phani; Kim, Ki H; Carlson, Heather A; Showalter, Hollis D; Martin, Brent R; Amidon, Gordon L

    2015-09-01

    Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific prodrug sensitivities necessary for evaluating preclinical animal models and potential drug-drug interactions. Despite significant adoption of prodrug methodologies for enhanced pharmacokinetics, functional annotation of prodrug activating enzymes is laborious and often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically similar enzyme class in native proteomes. The serine hydrolase enzyme family is broadly reactive with reporter-linked fluorophosphonates, which have shown to provide a mechanism-based covalent labeling strategy to assay the activation state and active site occupancy of cellular serine amidases, esterases, and thioesterases. Here we describe a modified ABPP approach using direct substrate competition to identify activating enzymes for an ethyl ester prodrug, the influenza neuraminidase inhibitor oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase 1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates. Saturating concentrations of oseltamivir lead to a four-fold reduction in the observed rate constant for CES1 inactivation by fluorophosphonates. WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir hydrolysis activity in human cell homogenates, confirming CES1 is the primary prodrug activating enzyme for oseltamivir in human liver and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited mouse but not human CES1, providing a series of probes for analyzing prodrug activation mechanisms in different preclinical models. Overall, we present a substrate-competitive activity-based profiling approach for broadly surveying candidate prodrug hydrolyzing enzymes and outline the kinetic parameters for activating enzyme discovery, ester prodrug design, and

  19. Substrate-competitive activity-based profiling of ester prodrug activating enzymes

    Xu, Hao; Majmudar, Jaimeen D.; Davda, Dahvid; Ghanakota, Phani; Kim, Ki H.; Carlson, Heather A.; Showalter, Hollis D.; Martin, Brent R.; Amidon, Gordon L.

    2015-01-01

    Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific prodrug sensitivities necessary for evaluating pre-clinical animal models and potential drug-drug interactions. Despite significant adoption of prodrug methodologies for enhanced pharmacokinetics, functional annotation of prodrug activating enzymes is laborious and often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically similar enzyme class in native proteomes. The serine hydrolase enzyme family is broadly reactive with reporter-linked fluorophosphonates, which have shown to provide a mechanism-based covalent labeling strategy to assay the activation state and active site occupancy of cellular serine amidases, esterases, and thioesterases. Here we describe a modified ABPP approach using direct substrate competition to identify activating enzymes for an ethyl ester prodrug, the influenza neuraminidase inhibitor oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase 1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates. Saturating concentrations of oseltamivir lead to a 4-fold reduction in the observed rate constant for CES1 inactivation by fluorophosphonates. WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir hydrolysis activity in human cell homogenates, confirming CES1 is the primary prodrug activating enzyme for oseltamivir in human liver and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited mouse, but not human CES1, providing a series of probes for analyzing prodrug activation mechanisms in different preclinical models. Overall, we present a substrate-competitive activity-based profiling approach for broadly surveying candidate prodrug hydrolyzing enzymes and outline the kinetic parameters for activating enzyme discovery, ester prodrug design and preclinical

  20. Anthelmintics Are Substrates and Activators of Nematode P Glycoprotein▿

    Kerboeuf, Dominique; Guégnard, Fabrice

    2011-01-01

    P glycoproteins (Pgp), members of the ABC transporter superfamily, play a major role in chemoresistance. In nematodes, Pgp are responsible for resistance to anthelmintics, suggesting that they are Pgp substrates, as they are in mammalian cells. However, their binding to nematode Pgp and the functional consequences of this interaction have not been investigated. Our study showed that levamisole and most of the macrocyclic lactones (MLs) are Pgp substrates in nematodes. Ivermectin, although a v...

  1. Substrate integrated ferrite phase shifters and active frequency selective surfaces

    There are two distinct parts to this thesis; the first investigates the use of ferrite tiles in the construction of printed phase shifting transmission lines, culminating in the design of two compact electromagnetic controlled beam steered patch and slot antenna arrays. The second part investigates the use of active frequency selective surfaces (AFSS), which are later used to cover a uPVC constructed enclosure. Field intensity measurements are taken from within the enclosure to determine the dynamic screening effectiveness. Trans Tech G-350 Ferrite is investigated to determine its application in printed microstrip and stripline phase shifting transmission lines. 50-Ohm transmission lines are constructed using the ferrite tile and interfaced to Rogers RT Duroid 5870 substrate. Scattering parameter measurements are made under the application of variable magnetic fields to the ferrite. Later, two types of planar microwave beam steering antennas are constructed. The first uses the ferrites integrated into the Duroid as microstrip lines with 3 patch antennas as the radiating elements. The second uses stripline transmission lines, with slot antennas as the radiating sources etched into the ground plane of the triplate. Beam steering is achieved by the application of an external electromagnet. An AFSS is constructed by the interposition of PIN diodes into a dipole FSS array. Transmission response measurements are then made for various angles of electromagnetic wave incidence. Two states of operation exist: when a current is passed through the diodes and when the diodes are switched off. These two states form a high pass and band stop space filter respectively. An enclosure covered with the AFSS is constructed and externally illuminated in the range 2.0 - 2.8GHz. A probe antenna inside the enclosure positioned at various locations through out the volume is used to establish the effective screening action of the AFSS in 3 dimensional space. (author)

  2. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers

    Aarnoutse, Rob E; Kleinnijenhuis, Johanneke; Koopmans, Peter P; Touw, Daan J; Wieling, Jaap; Hekster, Yechiel A; Burger, David M

    2005-01-01

    OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose

  3. Proteolytic activity of prostate-specific antigen (PSA towards protein substrates and effect of peptides stimulating PSA activity.

    Johanna M Mattsson

    Full Text Available Prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3 exerts chymotrypsin-like proteolytic activity. The main biological function of PSA is the liquefaction of the clot formed after ejaculation by cleavage of semenogelins I and II in seminal fluid. PSA also cleaves several other substrates, which may explain its putative functions in prostate cancer and its antiangiogenic activity. We compared the proteolytic efficiency of PSA towards several protein and peptide substrates and studied the effect of peptides stimulating the activity of PSA with these substrates. An endothelial cell tube formation model was used to analyze the effect of PSA-degraded protein fragments on angiogenesis. We showed that PSA degrades semenogelins I and II much more efficiently than other previously identified protein substrates, e.g., fibronectin, galectin-3 and IGFBP-3. We identified nidogen-1 as a new substrate for PSA. Peptides B2 and C4 that stimulate the activity of PSA towards small peptide substrates also enhanced the proteolytic activity of PSA towards protein substrates. Nidogen-1, galectin-3 or their fragments produced by PSA did not have any effect on endothelial cell tube formation. Although PSA cleaves several other protein substrates, in addition to semenogelins, the physiological importance of this activity remains speculative. The PSA levels in prostate are very high, but several other highly active proteases, such as hK2 and trypsin, are also expressed in the prostate and may cleave protein substrates that are weakly cleaved by PSA.

  4. Analysis of SNP genetic polymorphism in CYP3A4 and CYP2D6 in Chinese Han population%中国汉族人群CYP2D6、CYP3A4 SNP位点基因多态性分析

    杨栋; 万立华; 涂政; 石屹; 胡兰

    2014-01-01

    目的:通过对药物代谢酶CYP2D6和CYP3A4的相关单核苷酸多态性(single nucleotide polymorphism,SNP)筛选检测,获得其在中国汉族人群中遗传多态性分布的相关数据.方法:筛选11个关于CYP2D6、CYP3A4基因的SNP位点,取192份中国汉族无关个体健康自愿者的血液样本获得基因组DNA,根据单碱基延伸技术通过GenomeLabTM SNPstream(R)基因分型系统进行SNP分型.结果:本次检测的11个SNP位点在研究人群中全部具有多态性(最小等位基因频率>0.01),其中7个SNP(RS28624811、RS28670611、RS9623531、RS5758589、RS3735451、RS2246709、RS2404955、RS4646440)位点的等位基因频率在此人群与白种人相比差异具有统计学意义(P<0.01).结论:汉族人群可能有继承特定的遗传信息,导致与其他人群具有不同药物代谢率.

  5. Do CVD grown graphene films have antibacterial activity on metallic substrates?

    Dellieu, Louis; Reckinger, Nicolas; Didembourg, Christian; Letesson, Jean-Jacques; Sarrazin, Michael; Deparis, Olivier; Matroule, Jean-Yves; Colomer, Jean-François

    2014-01-01

    Accurate assessment of the antibacterial activity of graphene requires consideration of both the graphene fabrication method and, for supported films, the properties of the substrate. Large-area graphene films produced by chemical vapor deposition were grown directly on copper substrates or transferred on a gold substrate and their effect on the viability and proliferation of the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli were assessed. The viability and the proliferation of both bacterial species were not affected when they were grown on a graphene film entirely covering the gold substrate, indicating that conductivity plays no role on bacterial viability and graphene has no antibacterial activity against S. aureus and E. coli. On the other hand, antibacterial activity was observed when graphene coated the copper substrates, resulting from the release of bactericidal cupric ions in inverse proportion to the graphene surface coverage.

  6. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients.

    Wyen, C.; Fuhr, U.; Frank, D.; Aarnoutse, R.E.; Klaassen, T.; Lazar, A.; Seeringer, A.; Doroshyenko, O.; Kirchheiner, J.C.; Abdulrazik, F.; Schmeisser, N.; Lehmann, C.; Hein, W.; Schomig, E.; Burger, D.M.; Fatkenheuer, G.; Jetter, A.

    2008-01-01

    This study aimed to quantify the inhibition of cytochrome P450 (CYP3A), CYP2D6, and P-glycoprotein in human immunodeficiency virus (HIV)-infected patients receiving an antiretroviral therapy (ART) containing ritonavir boosted lopinavir, and to identify factors influencing ritonavir and lopinavir pha

  7. Epidermal growth factor stimulates substrate-selective protein-tyrosine-phosphatase activity.

    Hernández-Sotomayor, S M; Arteaga, C L; Soler, C. (Carlos); Carpenter, G

    1993-01-01

    This study investigates the regulation of protein-tyrosine-phosphatase (PTPase; EC 3.1.3.48) activity by epidermal growth factor (EGF). Cytosol from EGF-treated A-431 human epidermoid carcinoma cells was used as a source of PTPase activity, and tyrosine-phosphorylated ErbB2, EGF receptor, phospholipase C-gamma 1, and the Ras GTPase-activating protein were used as substrates to monitor PTPase activity. EGF stimulated PTPase activity that was selective toward these substrates, as it dephosphory...

  8. Identification of transglutaminase 2 kinase substrates using a novel on-chip activity assay.

    Jung, Se-Hui; Kong, Deok-Hoon; Jeon, Hye-Yoon; Ji, Su-Hyun; Han, Eun-Taek; Park, Won Sun; Hong, Seok-Ho; Kim, Min-Soo; Kim, Young-Myeong; Ha, Kwon-Soo

    2016-08-15

    Transglutaminase 2 (TG2) is an enzyme that plays a critical role in a wide variety of cellular processes through its multifunctional activities. TG2 kinase has emerged as an important regulator of apoptosis, as well as of chromatin structure and function. However, systematic investigation of TG2 kinase substrates is limited due to a lack of a suitable TG2 kinase activity assays. Thus, we developed a novel on-chip TG2 kinase activity assay for quantitative determination of TG2 kinase activity and for screening TG2 kinase substrate proteins in a high-throughput manner. Quantitative TG2 kinase activity was determined by selective detection of substrate protein phosphorylation on the surface of well-type amine arrays. The limit of detection (LOD) of this assay was 4.34μg/ml. We successfully applied this new activity assay to the kinetic analysis of 27 TG2-related proteins for TG2 kinase activity in a high-throughput manner and determined Michaelis-Menten constants (Km) of these proteins. We used the Km values and cellular locations of the TG2-related proteins to construct a substrate affinity map for TG2 kinase. Therefore, this on-chip TG2 kinase activity assay has a strong potential for the systematic investigation of substrate proteins and will be helpful for studying new physiological functions. PMID:27040940

  9. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen

    Chamnanphon M

    2013-05-01

    Full Text Available Montri Chamnanphon,1 Khunthong Pechatanan,2 Ekapob Sirachainan,3 Narumol Trachu,4 Wasun Chantratita,5 Ekawat Pasomsub,5 Wilai Noonpakdee,6 Insee Sensorn,1,7 Chonlaphat Sukasem11Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 2Department of Medicine, Phramongkutklao College of Medicine, 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 5Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 6Department of Biochemistry, Faculty of Science, Mahidol University, 7Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, ThailandPurpose: To investigate the impact of CYP2D6 and CYP2C19 polymorphisms in predicting tamoxifen efficacy and clinical outcomes in Thai breast cancer patients.Methods: Polymorphisms of CYP2D6 and CYP2C19 were genotyped by the AmpliChip™ CYP450 Test (Roche Molecular Diagnostics, Branchburg, NJ, USA for 57 patients, who were matched as recurrent versus nonrecurrent breast cancers (n = 33 versus n = 24, respectively, with a 5-year follow-up.Results: Based on the genotype data, five CYP2D6 predicted phenotype groups were identified in this study including homozygous extensive metabolizer (13 of 57, 22.80%, extensive/intermediate metabolizer (23 of 57, 40.40%, extensive/poor metabolizer (3 of 57, 5.30%, homozygous intermediate metabolizer (14 of 57, 24.50%, and intermediate/poor metabolizer (4 of 57, 7.00%, and three CYP2C19 genotype groups including homozygous extensive metabolizer (27 of 57, 47.40%, extensive/intermediate metabolizer (27 of 57, 47.40%, and homozygous poor metabolizer (3 of 57, 5.30%. The CYP2D6 variant alleles were *10 (52 of 114, 45.60%, *5 (5 of 114, 4.40%, *41 (2 of 114, 1.80%, *4 (1 of 114, 0

  10. 浙南地区女性人群CYP2D6及MDR1基因多态性对曲马多镇痛效果的影响

    马光泛; 陈千煌

    2013-01-01

      目的探讨CYP2D6*10等位基因及MDR1 C3435T基因多态性对浙南地区女性人群术后曲马多镇痛效果的影响.方法收集行子宫肌瘤剥除手术患者194例,手术结束前30 min肌肉注射曲马多,采用患者自控镇痛(PCA)模式进行术后镇痛.抽取外周血,采用聚合酶链反应-限制性条带长度多态性方法(PCR-RFLP),分析患者CYP2D6*10等位基因及MDR1 C3435T基因多态性,比较不同基因型患者之间曲马多的累积量,记录镇痛起效时间、持续时间、VAS及不良反应.结果 CYP2D6*10等位基因频率为52.84%,术后2、6、12h曲马多累积量及术后2、6hVAS的比较,m/m型明显高于w/w型和m/w型,差异有统计学意义(P0.05).结论在浙南地区女性人群中,CYP2D6*10等位基因对曲马多镇痛效果有显著影响,MDR1 C3435T等位基因对曲马多镇痛效果无显著影响.%Objective To investigate the association of CYP2D6*10 and MDR1 C3435T polymorphisms with analgesic ef-ficacy of tramadol in woman patients of Southern Zhejiang province. Methods One hundred and ninety four patients with hys-termyoma undergoing uterine myomatectomy from August 2010 to March 2012. Patients were given with loading dose of tramadol intramuscularly 30 minutes before the ending of surgery and received the postoperative patient-control ed analgesia (PCA). Samples of peripheral blood were col ected for DNA isolation. Polymorphisms of CYP2D6*10 and MDR1 C3435T were detected with PCR-RFLP analysis. The differences of tramadol consumption in the genotype groups were monitored and the starting time and duration of analgesia, VAS scores and adverse reaction were observed. Results The al elic frequency of CYP2D6 was 52.84%. The tramadol consumption at 2、6h and 12h after surgery and VAS at 2h and 6h after surgery in m/m type (n=50) were higher than those in w/w (n=39) and m/w (n=105) type (P<0.05). Variant al eles C3435T in MDR1 gene was seen in frequency of 38.14%. There were no significant