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)

1. Methyl conjugation is an important pathway in the biotransformation of many drugs and xenobiotic compounds. 'Pharmacogenetic' variation exists in the activities of many methyltransferase enzymes, and experiments with the drug-metabolizing enzyme thiopurine methyltransferase (TPMT) offer a model for one approach that has proven useful in the study of methyltransferase pharmacogenetics. 2. TPMT catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. This enzyme activity is present in the human red blood cell (RBC), and RBC TPMT activity is controlled by a common genetic polymorphism that regulates also the enzyme activity in all other human tissues that have been studied. 3. Subjects with inherited low levels of TPMT activity are at increased risk for thiopurine drug-induced myelotoxicity, while patients with high TPMT activities may be 'undertreated' with these drugs. 4. TPMT activity in tissue from selected strains of inbred mice also is regulated by a genetic polymorphism. These mice provide an animal model for use in the study of pharmacological or toxicological consequences of inherited differences in TPMT activity. 4. Other methyltransferase enzymes including thiol methyltransferase, catechol O-methyltransferase, and histamine N-methyltransferase also are present in the human RBC, are regulated by inheritance, and are responsible for individual variation in drug metabolism. Enhanced understanding of the pharmacogenetics of methylation may make it possible to understand and predict individual variation in the biotransformation, toxicity and therapeutic effect of compounds that undergo methyl conjugation.
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PMID:Methylation pharmacogenetics: thiopurine methyltransferase as a model system. 144 97

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
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PMID:Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. 1033 Oct 75

1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other. 2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable "model system" for studies of the ways in which variation in DNA sequence might influence function. 3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers. 4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research-both basic mechanistic and clinical translational research-principles that have been applied to a series of genes encoding methyltransferase enzymes.
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PMID:Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. 1680 86

S-adenosylmethionine (AdoMet or SAM)-dependent methyltransferases belong to a large and diverse family of group-transfer enzymes that perform vital biological functions on a host of substrates. Despite the progress in genomics, structural proteomics, and computational biology, functional annotation of methyltransferases remains a challenge. Herein, we report the synthesis and activity of a new AdoMet analogue functionalized with a ketone group. Using catechol O-methyltransferase (COMT, EC 2.1.1.6) and thiopurine S-methyltransferase (TPMT, EC 2.1.1.67) as model enzymes, this robust and readily accessible analogue displays kinetic parameters that are comparable to AdoMet and exhibits multiple turnovers with enzyme. More importantly, this AdoMet surrogate displays the same substrate specificity as the natural methyl donor. Incorporation of the ketone group allows for subsequent modification via bio-orthogonal labeling strategies and sensitive detection of the tagged ketone products. Hence, this AdoMet analogue expands the toolbox available to interrogate the biochemical functions of methyltransferases.
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PMID:Enzyme-catalyzed transfer of a ketone group from an S-adenosylmethionine analogue: a tool for the functional analysis of methyltransferases. 2019 37

Phase II biotransformation enzymes conjugate xenobiotics using small, organic donor molecules, such as glutathione, UDP-glucuronic acid, S-adenosyl-L-methionine, acetyl coenzyme A and amino acids (primarily glycine). These reactions generally resulted in detoxification by the loss of pharmacological activity and by quickening the elimination of xenobiotics from the body, however Bioactivation is also known to be occurred. Historically, it was placed more emphasis on research of phase I than of phase II enzymes. Nevertheless, it is well known that conjugation enzymes play an important role in drug and toxicant disposition since they can dramatically alter pharmacokinetics and therefore therapeutic efficacy and toxicity of drugs. In this context surprisingly, the exact regulation mechanism of phase II conjugation enzymes expression is not fully understood. However, available experimental data suggest that several transcriptional factors are involved in this process. In the current review, we characterize and summarize our knowledge about regulation of the most important phase II enzymes, such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), arylamine N-acetyltransferases (NATs), catechol O-methyltransferase (COMT) and thiopurine S-methyltransferase (TPMT) by different steroid hormones.
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PMID:Regulation of phase II biotransformation enzymes by steroid hormones. 2140 12

Ototoxicity is a debilitating side effect of platinating agents with substantial interpatient variability. We sought to evaluate the association of thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from the St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P = 0.013) and craniospinal irradiation (P = 0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid-tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wild-type mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.
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PMID:The role of inherited TPMT and COMT genetic variation in cisplatin-induced ototoxicity in children with cancer. 2464 35

Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.
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PMID:Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts. 2555 97