Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymorphisms in drug-metabolizing genes may lead to the production of dysfunctional proteins and consequently affect therapeutic efficacy and toxicity of drugs. Different frequencies of polymorphic alleles among the races have been postulated to account for the observed ethnic variations in drug responses. In the current study, we aimed to estimate the frequencies of 14 polymorphisms in eight genes (TPMT, NQO1, MTHFR, GSTP1, CYP1A1, CYP2D6, ABCB1, and SLC19A1) in the Singapore multiracial populations by screening 371 cord blood samples from healthy newborns. To improve genotyping efficacy, we designed an oligonucleotide array based on the principle of allele-specific primer extension (AsPEX) that was capable of detecting the 14 polymorphisms simultaneously. Cross-validation using conventional polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assays demonstrated 99% concordant results. Measurements on the fluorescent intensity displayed clear distinctions among different genotypes. Statistical analyses showed significantly different allele distributions in several genes among the three races, namely Chinese, Malays, and Indians. Comparing the allelic frequencies in Chinese with previous studies in Caucasian populations, NQO1 609C>T and SLC19A1 80G>A were distinctly different, whereas close similarity was observed for MTHFR 677C>T. We have demonstrated an array-based methodology for rapid multiplex detection of genetic polymorphisms. The allelic frequencies reported in this study may have important therapeutic and prognostic implications in the clinical use of relevant drugs.
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PMID:Genotyping of eight polymorphic genes encoding drug-metabolizing enzymes and transporters using a customized oligonucleotide array. 1711 62

The pharmacogenetics of either individual patients or tumors has been used to aid the progress of personalized medicine to generate antitumor drugs (eg, trastuzamab and erlotinib) that are active against tumors expressing particular growth factor receptors. Outside the field of cancer therapeutics, pharmacogenetic tests have been introduced to detect patient genotypes with the aim of individualizing existing treatments. For example, the analysis of thiopurine S-methyltransferase genotypes enables the prediction of toxicity in patients to be treated with either 6-mercaptopurine or azathioprine, while the uridine 5'-diphosphoglucuronosyl-transferase 1A1 genotype may predict irinotecan toxicity. There is a large body of information concerning cytochrome P450 (CYP) polymorphisms and their relationship with drug toxicity and response; however, currently, there is limited use of CYP genotypes to individualize treatments. It is now well recognized that the CYP2C9 genotype, when combined with the genotype for vitamin K epoxide reductase complex subunit 1, is predictive of dose requirement for oral anticoagulants, a fact that is likely to have clinical utility. There is also potential to individualize treatments with certain drugs on the basis of CYP2D6, CYP2C19 and CYP3A5 genotypes. Studies on genes encoding drug receptors in relation to individualized prescription have been limited but there is increasing information on the relationship between response to beta2-adrenoceptor agonists and the genotype for the beta2-adrenoceptor gene. The introduction of pharmacogenetic tests into routine healthcare requires both a demonstration of cost-effectiveness and the availability of appropriate accessible testing systems.
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PMID:Individualized drug therapy. 1726 38

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study -- at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance.
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PMID:Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment. 1822 12

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.
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PMID:[Pharmacogenomics in routine medical care]. 2010 57

Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research.
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PMID:Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project. 2088 55

The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.
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PMID:Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. 2117 26

Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.
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PMID:Pharmacogenetics in Ghana: reviewing the evidence. 2185 25

Pharmacogenetics has substantially added to our understanding of the variability of drug response. A number of single gene markers have been established and are ready to use in clinical practice. Here we review the validity and utility of markers in a number of genes (CYP2D6, CYP2C19, CYP2C9, VKORC1, TPMT, UGT1A1, OATP1B1, KRAS and HLA locus) for therapy decisions. As drug response is a complex trait in the majority of cases, most of the identified functional variants will only explain a limited part of the variability of drug response. In this sense, a phenotype is the product of many low-penetrance variations. Technical progress has not only improved the cost-effectiveness of screening for single gene markers, but offers the possibility of generating vast amounts of genome-wide single nucleotide polymorphism (SNP) or sequence data for each patient. The latest challenge is to incorporate these amounts of data into pharmacogenetic decision support. We discuss here the challenges associated with choosing the correct therapy for patients who present to their physicians with personal genome data.
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PMID:Pharmacogenetic screening for drug therapy: from single gene markers to decision making in the next generation sequencing era. 2222 55

There are several hurdles to the clinical implementation of pharmacogenetics. One approach is to employ pre-prescription genotyping, involving interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the Drug Metabolizing Enzymes and Transporters (DMET) Plus array (1,931 variants in 225 genes) with that of orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates >98% and were in Hardy-Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method, and a total of 19,942 single-nucleotide polymorphism (SNP)-patient sample pairs were evaluated. The concordance rate was 99.9%, with only 28 genotype discordances observed. For the genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance rate of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples, with the results in good concordance with those of several lower-throughput genotyping methods.
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PMID:Concordance of DMET plus genotyping results with those of orthogonal genotyping methods. 2352 92

Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future.
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PMID:Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. 2308 72


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