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 have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
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PMID:Metabolic polymorphisms. 836 90

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 are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.
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PMID:Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I. 1239 93

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

Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs.
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PMID:Clinical relevance of pharmacogenetics. 1470 61

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

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


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