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)

This brief review discusses the relationship between genetic polymorphism of drug metabolizing enzyme and drug's safety and efficacy. When elimination occurs via a single metabolic pathway, individual differences in metabolic rates can lead to large differences in drug and metabolite concentrations in the blood. Genetic polymorphism leads to subpopulation of patients with decreased, absent or even increased activities of certain reactions (e.g., CYP2C19, CYP2D6, CYP2C9, N-acetyltransferase, thiopurine methyltransferase polymorphism). The consequences of a genetic polymorphism include not only altered kinetics of specific drug substrate but idiosyncratic adverse drug reactions. Having these information will aid in determining dosage of certain medications to the patients with an inherited abnormality of drug metabolizing enzyme. Pharmacogenetics already has influenced therapeutics.
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PMID:[Individualization of drug therapy and pharmacogenetics]. 954 39

The role of drug metabolism in drug discovery (lead compound selection) and the traditional role of identifying the enzymes involved in biotransformation pathways (reaction phenotyping) have both relied heavily on the availability and use of a human liver bank. The assessment of drug metabolizing enzyme activity and variability in a series of individual human livers is essential when characterizing the enzymes involved in metabolic pathways (i.e. correlation analysis). In this regard, a human liver bank of 21 samples (14 males, six females, and one unknown) was characterized with respect to the activity of several important drug metabolizing enzymes. The total CYP450 content of the livers ranged from 0.06 to 0.46 nmol/mg microsomal protein. The fold variations found in specific enzyme contents were as follows: CYP1A2 (3x), CYP2A6 (21x), CYP2C9 (8x), CYP2C19 (175x), CYP2D6 (18x), CYP2E1 (5x), CYP3A4 (18x), FMO (2.5x), UDPGT (4x), NAT (7x), COMT (5x), ST (5x), TPMT (3x), and GST (2.5x). In general, the fold variation of the Phase II enzymes was lower compared with the Phase I enzymes, with the exceptions of CYP1A2, CYP2E1, and FMO. Similar data were reviewed from other established liver banks and compared with regard to the relative variability observed in drug metabolizing capacities found in this study.
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PMID:Characterization of Phase I and Phase II hepatic drug metabolism activities in a panel of human liver preparations. 1035 59

We have developed an allele-specific fluorogenic 5' nuclease chain reaction assay for detecting polymorphisms in the following human drug-metabolizing enzyme genes: CYP2C9 (CYP2C9*2 and *3), CYP2C19 (CYP2C19*2 and *3), CYP2D6 (CYP2D6*4, *10, *14, *18, and *21(C8)), N-acetyltransferase 2 (NAT2*5B, *6A, and *7B), thiopurine methyltransferase (TPMT*3C), and aldehyde dehydrogenase2 (ALDH2*2). This method is a marriage of two emerging technologies, the use of allele-specific amplification primers for target DNA and hybridization of the TaqMan probe. The TaqMan probe is labeled with both a fluorescent reporter dye and a quencher dye. Genotypes are separated according to the different threshold cycles of the wild-type and mutant primers. All assays are performed using a single thermocycling protocol. This genotyping method is rapid and highly sensitive and yields a high throughput. It could be applied toward automated large-scale genotyping.
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PMID:High throughput detection of drug-metabolizing enzyme polymorphisms by allele-specific fluorogenic 5' nuclease chain reaction assay. 1104 Dec 38

Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations. Routine genotyping before drug therapy may enable the identification of responders, nonresponders, or patients at increased risk of toxicity. Automated, high-throughput detecting methods for single-nucleotide polymorphisms (SNPs) are highly desirable in many clinical laboratories. The aim of this study is to develop a high-throughput genotyping method for detecting SNPs influencing drug response in the Japanese population. We have developed three real-time PCR assays for detecting SNPs in the human drug-metabolizing enzymes and drug targets. The assay for simultaneously detecting CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A5, NAT2, TPMT, DPYD, UGT1A1, ALDH2, ADH2, MDR1, CETP, DCP-1, ADRB2, HTR2A, INPP1, SDF1, and mitochondrial DNA polymorphisms takes less than 1.5 h. With the clinical application of NAT2 genotyping, we found statistically significant difference between the incidence of adverse drug reactions (ADRs) and the NAT2 genotype. The incidence of the ADRs was significantly higher in the slow type than the in other two types, as 5 of the 6 patients were of the slowtype, and the other was the intermediatetype, while no patients of the rapidtype has developed any ADRs.
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PMID:[Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications]. 1213 41

There is increasing information available on the existence of polymorphisms in genes encoding xenobiotic metabolizing enzymes and the functional significance of many of these. In addition to genes long recognized as being polymorphic, such as CYP2D6, CYP2C19 and CYP2C9, there is now information available on the existence of polymorphisms in other cytochrome P450 genes such as CYP2A6, CYP2B6 and CYP2C8. With respect to phase II metabolism, polymorphisms in GSTM1, GSTT1, NAT2 and TPMT are well understood but information is also emerging on other GST polymorphisms and on polymorphisms in the UDP-glucuronosyltransferases and sulfotransferases. The availability of comprehensive information on the occurrence and functional significance of polymorphisms affecting drug metabolism should facilitate their application to pharmacogenomic profiling.
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PMID:Pharmacogenetics of the major polymorphic metabolizing enzymes. 1258 28

The metabolism of MK-0767, (+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide, a thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor alpha/gamma agonist, was studied in liver microsomes and hepatocytes from humans and rat, dog, and rhesus monkey, to characterize the enzyme(s) involved in its metabolism. The major site of metabolism is the TZD ring, which underwent opening catalyzed by CYP3A4 to give the mercapto derivative, M22. Other metabolites formed in NADPH-fortified liver microsomes included the TZD-5-OH derivative (M24), also catalyzed by CYP3A4, and the O-desmethyl derivative (M28), whose formation was catalyzed by CYP2C9 and CYP2C19. Metabolite profiles from hepatocyte incubations were different from those generated with NADPH-fortified microsomal incubations. In addition to M22, M24, and M28, hepatocytes generated several S-methylated metabolites, including the methyl mercapto (M25), the methyl sulfoxide amide (M16), and the methyl sulfone amide (M20) metabolites. Addition of the methyl donor, S-adenosyl methionine, in addition to NADPH, to microsomal incubations enhanced the turnover and resulted in metabolite profiles similar to those in hepatocyte incubations. Collectively, these results indicated that methyltransferases played a major role in the metabolism of MK-0767. Using enzyme-specific inhibitors, it was concluded that microsomal thiol methyltransferases play a more important role than the cytosolic thiopurine methyltransferase. Baculovirus-expressed human flavin-containing monooxygenase 3, as well as CYP3A4, oxidized M25 to M16, whereas further oxidation of M16 to M20 was catalyzed mainly by CYP3A4. Esterases were involved in the formation of the methyl sulfone carboxylic acids, minor metabolites detected in hepatocytes.
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PMID:In vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide], a peroxisome proliferator-activated receptor alpha/gamma agonist. I. Role of cytochrome P450, methyltransferases, flavin monooxygenases, and esterases. 1531 44

Pharmacogenetics as one of the areas of clinical pharmacology addresses hereditary factors involved in individually different responses to drugs. Clinical trials combined with molecular genetics seek for underlying reasons influencing efficacy and toxicity of drugs. The declared goal of pharmacogenetics is to provide physicians with knowledge and tools to allow an individualized patient-directed pharmacotherapy. This concept is best evolved for clinical practice in the field of drug-metabolizing enzymes, especially for the cytochromes P450 (CYP) 2D6, CYP2C19 and thiopurine S-methyltransferase (TPMT). Patients with inherited enzyme deficiencies are at risk to accumulate excessive drug concentrations when treated with standard doses which may lead to adverse drug reactions or even to life-threatening conditions. Genetic factors are also involved in drug-target interactions (e. g. receptors). Prospective controlled clinical trials are needed to evaluate the benefit of pharmacogenetics for therapy outcome and to define its role in clinical practice.
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PMID:[Implications of pharmacogenetics in every-day practice]. 1617 May 12

There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenetics aims to identify individuals predisposed to a high risk of toxicity and low response from standard doses of anti-cancer drugs. This review focuses on the clinical significance of polymorphisms in drug-metabolising enzymes (cytochrome P450 [CYP] 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase [UGT] 1A1, glutathione S-transferase, sulfotransferase [SULT] 1A1, N-acetyltransferase [NAT], thiopurine methyltransferase [TPMT]) and drug transporters (P-glycoprotein [multidrug resistance 1], multidrug resistance protein 2 [MRP2], breast cancer resistance protein [BCRP]) in influencing efficacy and toxicity of chemotherapy. The most important example to demonstrate the influence of pharmacogenetics on anti-cancer therapy is TPMT. A decreased activity of TPMT, caused by genetic polymorphisms in the TPMT gene, causes severe toxicity with mercaptopurine. Dosage reduction is necessary for patients with heterozygous or homozygous mutation in this gene. Other polymorphisms showing the influence of pharmacogenetics in the chemotherapeutic treatment of cancer are discussed, such as UGT1A1*28. This polymorphism is associated with an increase in toxicity with irinotecan. Also, polymorphisms in the DPYD gene show a relation with fluorouracil-related toxicity; however, in most cases no clear association has been found for polymorphisms in drug-metabolising enzymes and drug transporters, and pharmacokinetics or pharmacodynamics of anti-cancer drugs. The studies discussed evaluate different regimens and tumour types and show that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumours in response to different drugs. The clinical application of pharmacogenetics in cancer treatment will therefore require more detailed information of the different polymorphisms in drug-metabolising enzymes and drug transporters. Larger studies, in different ethnic populations, and extended with haplotype and linkage disequilibrium analysis, will be necessary for each anti-cancer drug separately.
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PMID:Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. 1650 59

The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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PMID:Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. 1696 50

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


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