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

Significant fractions of health budgets must be spent for treatment of drug side effects and for inefficient drug therapy. Hereditary variants in drug metabolizing enzymes, drug transporters, and drug targets are important determinants of drug response and toxicity and may therefore aid in selection and dosage of drugs. Today there is extensive knowledge of genetic polymorphisms of cytochrome P450 (CYP) enzymes 2A6, 2C9, 2C19, and 2D6; of phase-2 enzymes such as thiopurine S-methyltransferase; and more recently of drug transporters such as the MDR-1 gene-product P-glycoprotein, affecting a significant share of currently used drugs. However, application of pharmacogenetic knowledge to clinical routine is limited in current practice. To promote the application of pharmacogenetic knowledge in clinical routine, research on genotype-based dose adjustments is still necessary - as is the promotion of faster and cheaper genotype analyses. Furthermore, the benefits of CYP genotype-directed drug therapy should be evaluated in properly designed prospective studies. Once such steps have been successfully taken, drug therapy could well become more prevention-directed and patient-tailored than it is possible today, replacing the current "one drug in one dose for one disease" strategy by a more individualized approach.
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PMID:How to manage individualized drug therapy: application of pharmacogenetic knowledge of drug metabolism and transport. 1109 42

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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PMID:Pharmacokinetic considerations in the treatment of inflammatory bowel disease. 1170 60

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

The goal of chemotherapy is the elimination of tumor cells from the host. This is achieved by the use of therapeutic agents that are often more harmful to normal tissues than to the targeted tumor. Many chemotherapeutic agents are designed to damage cell replication machinery either directly at the level of DNA or indirectly, by inhibiting enzymes involved with DNA repair and synthesis. Novel therapeutic agents that exert their effects at signal transduction pathways have advanced chemotherapy; however, a role for the classic chemotherapeutic agents remains. These classic agents are associated with tumor cell resistance, toxicity, and occasionally secondary neoplasia. Current practices for the dosing of therapeutic agents rely on height and body surface measurements or drug monitoring and Bayesian adaptive control. Pharmacogenetics is emerging as an alternate approach to managing chemotherapy that may prevent undertreatment while avoiding overtreatment and associated toxicities. By determining the polymorphic genetic makeup of the host and, in some instances, the altered genetic expression of the tumor, chemotherapy can be tailored for interindividual response and toxicity avoidance. Chemotherapy is particularly applicable to the pharmacogenetic approach to tailored therapy for a number of reasons. The margin of safety is low with chemotherapeutic agents. Some drugs require biotransformation for activation. Drug activation correlates with toxicity. The pathways of drug clearance or inactivation exhibit polymorphic differences. Interindividual, race-specific, and age-related responses to chemotherapeutic agents are common. Last, drug resistance can be inherent to the tumor as a result of the suppression of apoptosis. Variations in response and toxicity to a specific drug can be caused by alterations in drug-metabolizing enzymes or receptor expression. These effects can be classed as pharmacokinetic and pharmacogenetic differences. Some of the genes known to display polymorphic differences include FLT3 receptor tyrosine kinase, FCG3RA IgG FC receptor, thymidylate synthase, methylenetetrahydrofolate reductase, thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, aldehyde dehydrogenase, glutathione S-transferase, uridine diphosphate glyuronosyl transferases, N-acetyl transferases, cytochrome P450, and the DNA repair enzymes XPD and XRCC1. To be successful a pharmacogenetic approach to individualized chemotherapy must selectively take advantage of a determination of direct enzyme activity, gene expression, and genotype.
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PMID:Pharmacogenetics in cancer chemotherapy: balancing toxicity and response. 1522 71

It is widely claimed that pharmacogenetics may form the basis of 'personalized medicine'. We sought to determine the current utilization of pharmacogenetic testing for drug metabolizing enzymes (DMEs). The hypothesis was that these tests were rarely performed clinically. Questionnaires were sent to 629 individuals representing laboratories, hospitals and universities throughout Australia and New Zealand. The questionnaires asked which facilities performed pharmacogenetic tests for selected DMEs, and details about the tests, if performed. The overall response rate was 81.1% (510/629); three respondents declined to participate. Clinical genotyping and phenotyping tests for DMEs could be performed by 10 (2.0% of 507) and 18 (3.6%) facilities, respectively. The most frequently performed genetic tests were for thiopurine methyltransferase (approximately 400 times in 2003) and pseudocholinesterase (approximately 250 times). The frequency of phenotyping exceeded genotyping by five- and eight-fold, respectively. One centre performed CYP2D6 phenotyping frequently (approximately 4200 times in 2003) for perhexiline. Genotyping and phenotyping tests for other cytochrome P450 enzymes, N-acetyltransferase-2 and dihydropyrimidine dehydrogenase were effectively never undertaken for clinical purposes. Pharmacogenetic tests for DMEs are currently performed rarely in clinical practice, despite repeated claims that they may benefit patient care. The only tests performed with any regularity in Australasia are for thiopurine methyltransferase and pseudocholinesterase, and CYP2D6 phenotyping in one centre for patients on perhexiline. The low clinical utilization reflects a poor evidence base, unestablished clinical relevance and, in the few cases with the strongest rationale, a slow translation to the clinical setting.
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PMID:Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice? 1586 39

Iatrogenic malignancies represent a devastating and often fatal long-term effect of therapy administered for a prior condition, usually a primary cancer. Earlier diagnosis and the development of more effective cancer treatments over the last 30 years have considerably improved the long-term survival of patients. However, the burgeoning number of cancer survivors has led to a parallel increase in the number of cases of iatrogenic malignancy. Consequently, understanding host susceptibility factors, such that high-risk patients can be identified, has become a priority. However, this task is made difficult by the heterogeneity of iatrogenic malignancies. Nevertheless, the identification of polymorphic loci and pathways predicted to modify dose (e.g., glutathione S-transferases, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase, cytochrome P450, and thiopurine S-methyltransferase) or determine cellular outcome (e.g., nucleotide excision DNA repair, base excision DNA repair, DNA mismatch repair, and cell death signaling) after therapy has provided insight into how host genetics may impact on the risk of developing iatrogenic malignancy.
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PMID:Genetic susceptibility to iatrogenic malignancy. 1614 1

Drug metabolism enzymes (DME) play a significant role in drug detoxification and activation, which exert important effect on drug efficacy and sensitivity to toxicity. There is difference in expression and activity of DME between in tumor tissue and in non-tumor tissue. DME related with tumor chemotherapy are cytochrome P450 (CYP), glutathione-S-transferase (GST), uridine diphospho-glucuronosyltransferase (UGT), thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD). The enzymes above are inducible and genetic polymorphic, thus with variable activity in individuals.
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PMID:[Cancer chemotherapy and drug metabolism enzyme]. 1640 65

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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