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

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

The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.
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PMID:Predicting drug response and toxicity based on gene polymorphisms. 1589 Feb 68

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

Different functional alleles for each subtype of cytochrome P450 (CYPs), thiopurine S-methyltransferase (TPMT), glutathione S-transferase (GST) and sulfotransferase (SULT) enzymes, have been identified. In this review, the genetic polymorphisms of drug-metabolizing enzymes in the Japanese population and their effects on metabolic activity are described in detail.
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PMID:Brief review of polymorphic drug-metabolizing enzymes in Japanese populations: development of a higher-throughput genotyping method and proposed applications. 1935 33