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)

Thiopurine drugs are used in the treatment of inflammatory bowel disease--as are sulphasalazine and its metabolite 5-aminosalicylic acid (ASA). S-Methylation catalyzed by thiopurine methyltransferase (TPMT) is a major pathway in the metabolism of thiopurines. The hypothesis was tested that TPMT might be inhibited by sulphasalazine or isomers of ASA. Sulphasalazine as well as 3-, 4- and 5-ASA inhibited recombinant human TPMT, with IC50 values of 78, 99, 2600 and 1240 microM, respectively. Kinetic studies demonstrated that the inhibition of TPMT by sulphasalazine and ASA isomers was non-competitive with regard to the thiopurine substrate, 6-MP, and was uncompetitive with regard to the methyl donor for the reaction, S-adenosyl-L-methionine. Our observations raise the possibility of a clinically significant drug-drug interaction in patients treated simultaneously with sulphasalazine and thiopurine drugs.
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PMID:Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. 764 Jan 56

6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR.
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PMID:Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts. 799 28

6-Mercaptopurine (6MP) and methotrexate are the backbone of continuation therapy for childhood acute lymphoblastic leukemia (ALL). In studies of oral 6MP and methotrexate, indices of chronic systemic exposure to active metabolites of these agents, namely, red blood cell (RBC) concentrations of methotrexate polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have positively correlated with event-free survival (EFS). Our objective was to evaluate whether MTXPGs, TGNs, and the dose intensity of administered methotrexate and 6MP were prognostic in the setting of a treatment protocol in which all treatment was coordinated through a single center, and the weekly doses of methotrexate were given parenterally. On protocol Total XII, 182 children achieved remission and received weekly methotrexate 40 mg/m2 parenterally and daily oral 6MP, interrupted every 6 weeks during the first year by pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine methyltransferase (TPMT) measurements, along with complete dose intensity information (dose received divided by protocol dose per week) for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate analyses, only higher dose intensity of 6MP and of weekly methotrexate were significant predictors of overall EFS (P =.006 and. 039, respectively). The occurrence of neutropenia was associated with worse outcome (P =.040). In a multivariate analysis, only higher dose intensity of 6MP (P =.020) was a significant predictor of EFS, with lower TPMT activity (P =.096) tending to associate with better outcome. 6MP dose intensity was also associated (P =.007) with EFS among patients with homozygous wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to missed weeks of therapy and not to reductions in daily dose. We conclude that increased dose-intensity of oral 6MP is an important determinant of EFS in ALL, particularly among those children with a homozygous wild-type TPMT phenotype. However, increasing intensity of therapy such that neutropenia precludes chemotherapy administration may be counterproductive.
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PMID:Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. 1021 75

6-Mercaptopurine and its prodrug counterpart, azathioprine, have proven efficacy in the induction and maintenance of remission, fistula closure, and steroid sparing in patients with Crohn's disease. Long-term follow-up has demonstrated the safety of the purine analogues, with no increased risk of malignancy. For patients with Crohn's disease intolerant or unresponsive to azathioprine or 6-mercaptopurine, methotrexate has emerged as an effective alternative. In patients with severe ulcerative colitis, intravenous cyclosporine is highly efficacious in the short term, and with the addition of azathioprine or 6-mercaptopurine to oral cyclosporine, long-term remission rates of 60% to 70% can be achieved. Azathioprine or 6-mercaptopurine therapy is effective in patients with steroid-dependent or steroid-refractory colitis and is valuable in maintaining remission. Neither methotrexate nor cyclosporine has been shown to be effective for maintenance therapy in patients with ulcerative colitis. Current data are insufficient to recommend routine use of genetic or enzymatic testing of thiopurine methyltransferase or measurements of blood 6-thioguanine metabolites to guide 6-mercaptopurine or azathioprine dosing.
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PMID:Immunomodulator Therapy in Inflammatory Bowel Disease. 1146 77

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.
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PMID:Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine. 1168 11

The purpose of this study was to determine the frequency of thiopurine methyltransferase (TPMT) polymorphisms in a multiracial Asian population and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Six hundred unrelated cord blood samples from 200 Chinese, Malay, and Indian healthy newborns were collected at the National University Hospital, Singapore; an additional 100 children with ALL were analyzed for five of the commonly reported TPMT variant alleles using polymerase chain reaction/restriction fragment length polymorphism and allele-specific polymerase chain reaction-based assays. In the cord blood study, the TPMT*3C variant was detected in all three ethnic groups; Chinese, Malays, and Indians had allele frequencies of 3%, 2.3%, and 0.8%, respectively. The TPMT*3A variant was found only among the Indians at a low allele frequency of 0.5%. The TPMT*6 variant was found in one Malay sample. Among the children with ALL, two white and one Chinese were heterozygous for the TPMT*3A variant and showed intermediate sensitivity to 6-mercaptopurine during maintenance therapy. Three Chinese patients and one Malay patient were heterozygous for the TPMT*3C variant. Mercaptopurine sensitivity could be validated in only one out of four TPMT*3C heterozygous patients. The overall allele frequency of the TPMT variants in this multiracial population was 2.5%. The TPMT*3C was the most common variant allele; TPMT*3A and TPMT*6 were rare. These results support the feasibility of performing TPMT genotyping in all children diagnosed with acute leukemia to minimize toxicity from thiopurine chemotherapy.
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PMID:Thiopurine methyltransferase polymorphisms in a multiracial asian population and children with acute lymphoblastic leukemia. 1214 79

High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m(2)/24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m(2)/week) and 6MP (75 mg/m(2)/day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir < or =60 x 10(9)/l and/or a neutrophil nadir < or =0.7 x 10(9)/l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 x 10(9)/l (range: 6-214) to 133 x 10(9)/l (range: 21-305; P<0.001) and the median neutrophil nadir from 0.5 x 10(9)/l (range: 0.0-1.4) to 0.9 x 10(9)/l (range: 0.2-3.2; P<0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (P < 0.001). The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.
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PMID:Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia. 1283 23

There is great heterogeneity in a patient's response to medications, often requiring empirical strategies to define the appropriate drug therapy for each patient. Pharmacogenomics aims to elucidate further the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosage for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. For example, polymorphism in thiopurine methyltransferase (TPMT) results in altered degradation of the commonly prescribed agent 6-mercaptopurine. This genetic variant has significant clinical implications because patients with functionally relevant homozygous mutations in the TPMT gene experience extreme or fatal toxicity after administration of normal doses of 6-MP. In addition, patients heterozygous for mutations in TPMT require slight dosage reduction of 6-MP and experience a greater degree of systemic toxicity from the agent. This and other examples of genetic polymorphism relevant to the treatment of cancer are highlighted to illustrate the promise and pitfalls of the exciting area of cancer therapeutics, with the potential of providing a stronger scientific basis to optimize drug therapy on the basis of each patient's genetic constitution.
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PMID:Cancer pharmacogenomics: SNPs, chips, and the individual patient. 1453 51

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) remain the mainstay of immunomodulator therapy for the maintenance of steroid-free remission in patients with inflammatory bowel disease (IBD). Traditional dosing strategies for initiation of thiopurines are often based on weight or empirically chosen. Dosing based on an understanding of an inherited difference in drug disposition and metabolism may provide a safer alternative. The thiopurine methyltransferase (TPMT) enzyme plays a pivotal role in the metabolism of 6-MP and AZA and is critical to the determination of thiopurine toxicity. The therapeutic benefits of thiopurines correlate best with concentration of the active 6-thioguanine (6-TGN) metabolites. Reports suggest that therapeutic response can be maximized when patients achieve therapeutic 6-TGN levels. Pharmacogenetic dosing based on TPMT and pharmacokinetic dosing based on 6-TGN levels may offer a safety and efficacy advantage over traditional dosing strategies and provide a novel mechanism for optimizing immunomodulator therapy in IBD.
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PMID:Optimizing immunomodulator therapy for inflammatory bowel disease. 1460 61

Although the mouse has great potential for pharmacogenomic discovery, little is known about variation in drug response or genetic variation in pharmacologically relevant genes between inbred mouse strains. We therefore assessed variation in gene sequence, mRNA expression and protein activity of thiopurine methyltransferase (TPMT) in multiple inbred mouse strains. TPMT activity was measured by high-performance liquid chromatography detection of 6-MMP produced by incubation of liver homogenates with 6-MP. Genetic variation was assessed by resequencing and single nucleotide polymorphism (SNP) genotyping using pyrosequencing technology. mRNA expression was measured by real-time polymerase chain reaction. We observed an almost five-fold variation in TPMT activity, with strains falling into distinct low and high activity groups. This pattern of TPMT activity was highly correlated with expression of TPMT mRNA among strains, and high TPMT expression is dominant in F1 hybrids. To correlate genotype with phenotype, 29 SNPs and one insertion/deletion were genotyped throughout the TPMT gene and upstream 10 kb. Only two haplotypes were observed across all 30 polymorphisms, corresponding to the low and high activity groups. These results suggest that differential mouse TPMT activity is due to variation in mRNA expression. In addition, the identified pattern of low haplotype diversity suggests that the mouse is likely to be useful for pharmacogenomic discovery by associating haplotype blocks with drug response phenotypes among inbred strains.
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PMID:Analysis of variation in mouse TPMT genotype, expression and activity. 1508 69


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