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)

This review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing is discussed for individualisation of thiopurine therapy, particularly to avoid severe adverse effects. Both azathioprine and mercaptopurine are pro-drugs that undergo extensive metabolism. The catabolic enzyme thiopurine S-methyltransferase (TPMT) is polymorphically expressed, and currently 23 genetic variants have been described. On the basis of an excellent phenotype-genotype correlation for TPMT, genotyping has become a safe and reliable tool for determination of a patient's individual phenotype. Thiopurine-related adverse drug reactions are frequent, ranging from 5% up to 40%, in both a dose-dependent and -independent manner. IBD patients with low TPMT activity are at high risk of developing severe haematotoxicity if pharmacogenetically guided dosing is not performed. Based on several cost-benefit analyses, assessment of TPMT activity is recommended prior to thiopurine therapy in patients with IBD. The underlying mechanisms of azathioprine/mercaptopurine-related hepatotoxicity, pancreatitis and azathioprine intolerance are still unknown. Although the therapeutic response appears to be related to 6-thioguanine nucleotide (6-TGN) concentrations above a threshold of 230-260 pmol per 8 x 10(8) red blood cells, at present therapeutic drug monitoring of 6-TGN can be recommended only to estimate patients' compliance.Drug-drug interactions between azathioprine/mercaptopurine and aminosalicylates, diuretics, NSAIDs, warfarin and infliximab are discussed. The concomitant use of allopurinol without dosage adjustment of azathioprine/mercaptopurine leads to clinically relevant severe haematotoxicity due to elevated thiopurine levels. Several studies indicate that thiopurine therapy in IBD during pregnancy is safe. Thus, azathioprine/mercaptopurine should not be withdrawn in strictly indicated cases of pregnant IBD patients. However, breastfeeding is contraindicated during azathioprine/mercaptopurine therapy. Use of azathioprine/mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or corticosteroid-refractory IBD, particularly Crohn's disease, is evidence based. To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/mercaptopurine treatment are required to identify novel candidate genes.
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PMID:Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. 1771 77

Genetic data on the thiopurine S-methyltransferase (TPMT) polymorphism were obtained in population samples from Cabinda and Mozambique (located in the western and eastern coasts of sub-Saharan Africa, respectively). The overall frequency of TPMT-deficient alleles was 5.6% in Mozambique and 6.3% in Cabinda. Accordingly, one out of the 103 individuals from Cabinda tested had a genotype associated with TPMT deficiency, yielding a frequency that is threefold higher than heretofore reported in any population. In addition, in both Cabinda or Mozambique, TPMT*8 accounted for a significant proportion of non-functional alleles (nearly 40% in Cabinda). Since the substitution defining TPMT*8 seems to be highly specific of sub-Saharan Africa populations and given the fact it has not been integrated into the set of single nucleotide polymorphisms routinely tested for TPMT, a re-design of molecular screenings should be considered in the future in order to avoid serious underestimates of TPMT deficiency when the enzymatic profiles in populations are unknown.
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PMID:Do the distribution patterns of polymorphisms at the thiopurine S-methyltransferase locus in sub-Saharan populations need revision? Hints from Cabinda and Mozambique. 1747 18

Prospective clinical pharmacogenetic testing of the thiopurine S-methyltransferase gene remains to be realized despite the large body of evidence demonstrating clinical benefit for the patient and cost effectiveness for health care systems. We describe an entirely microchip-based method to genotype for common single nucleotide polymorphisms in the thiopurine S-methyltransferase gene that lead to serious adverse drug reactions for patients undergoing thiopurine therapy. Restriction fragment length polymorphism and allele-specific polymerase chain reaction have been adapted to a microfluidic chip-based polymerase chain reaction and capillary electrophoresis platform to genotype the common *2, *3A, and *3C functional alleles. In total, 80 patients being treated with thiopurines were genotyped, with 100% concordance between microchip and conventional methods. This is the first report of single nucleotide polymorphism detection using portable instrumentation and represents a significant step toward miniaturized for personalized treatment and automated point-of-care testing.
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PMID:Microfluidic platform for single nucleotide polymorphism genotyping of the thiopurine S-methyltransferase gene to evaluate risk for adverse drug events. 2843 80

Cancer chemotherapy is characterized by a broad range of efficacy and toxicity among patients. Most anticancer drugs show wide interindividual variability in pharmacokinetics and have narrow therapeutic windows. Since drug metabolism is often an essential determinant of interindividual variability in pharmacokinetics, pharmacogenomic studies of drug-metabolizing enzymes are expected to rationalize cancer chemotherapy in terms of patient, treatment, and dosage selection. Candidate gene approaches to pharmacogenomics are based on existing knowledge in clinical pharmacology, used to select the target(s) to be analyzed. So far, the candidate gene approach has provided important clues for pharmacogenomic-based personalized chemotherapy with 6-mercaptopurine (6-MP), solely metabolized by thiopurine S-methyltransferase (TPMT), and irinotecan, mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1). Reduced activity of TPMT caused by polymorphisms in the TPMT gene and decreased activity of UGT1A1 caused by UGT1A1*28 are related to severe toxic effects of 6-MP and irinotecan, respectively. In response to these findings, the Food and Drug Administration in the United States has supported clinical pharmacogenetic testing by revising the package inserts for these anticancer drugs. The genome wide approach to pharmacogenomics has gradually evolved with continued progress in genome sciences and technologies. This approach can disclose previously unknown relations of factors, as well as identify potential multigenetic associations. The genome wide approach can also identify genes underlying the phenotypic effects of anticancer drugs. This approach may play a complemental role to the candidate gene approach in the future of cancer pharmacogenomics. This review describes recent progress in pharmacogenomics in the field of cancer chemotherapy.
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PMID:Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. 1769 17

Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher risk of hematologic toxicity and leukemogenesis. We present such a patient who was a slow metabolizer for azathioprine, and developed a rapidly lethal form acute myeloid leukemia after relatively low dose exposure to the drug. There was prominent hemophagocytic activity in the bone marrow, and cytogenetic analysis showed a complex karyotype with monosomy 7, but no involvement of chromosome 8.
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PMID:Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency. 1769 2

Environmental chemicals may be involved in the etiology of breast cancer. Among them, organophosphorous compounds are the most widely used pesticides because of their extensive use in agriculture, medicine and industry. The risk of breast cancer is associated with prolonged exposure to female hormones and is attributed to estrogen since prolonged stimulation by steroid hormones may increase cell division. The aim of the present study was to identify the differentially expressed genes encoding enzymes that are important to drug transport and metabolism in parathion- and estrogen-treated human breast epithelial cell lines using cDNA microarrays. MCF-l0F, an immortalized human breast epithelial cell line was treated with parathion and estrogen, either alone or in combination, and malignant cells were developed through a series of sequential steps. Differential expression from the drug metabolism gene array showed that 17 genes were found to be altered either by parathion or estrogen alone, or the combination of both. Among the genes altered by parathion in comparison to the control were CHST5, CHST6 and CHST7 (sulfotransferases); CYP2F1, CYP3A7 and CYP4F3 (CYPs); GSTP1, GSTT2 and MGST1 (GSTs); MT1X (metallothionein); TPMT (methyltransferase); UGT1A1 and UGT2B (UDP glycosyltransferases). The same genes were down-regulated in estrogen alone including several metallothioneins (MT1A, MT1E, MT1H, MT1L and MT2A). The combination of parathion and estrogen induced down-regulation of three sulfotransferases, CYP2F1 and CYP4F3, MGST1, all metallothioneins and TPMT genes. There was no change in CYP3A7, GSTP1, GSTT2, UGT1A1 and UGT2B genes in the presence of both substances. It can be concluded from this study that organophosphorous pesticides such as parathion in the presence of estradiol induced changes in human drug metabolism gene expression in breast cells.
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PMID:Human drug metabolism genes in parathion-and estrogen-treated breast cells. 1798 97

Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5'-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.
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PMID:Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. 1804 78

We report a case of an allergic hypersensitivity reaction on azathioprine presenting with colitis. Allergic reactions on azathioprine are common in patient with inflammatory bowel disease. The clinic of the allergic reaction on azathioprine in our patient was atypical in the way it mimicked an acute exacerbation of inflammatory bowel disease. The pathogenesis of the allergic reaction is still unclear. Although re-challenge can be life-threatening and should always be done with precautions, it may definitively proof the causal association with the drug and decide for definitive cessation In allergic reactions there is no link with TPMT activity but other genetically predispositions are proposed.
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PMID:Azathioprine induced colitis: a case report and review of the literature. 1807 43

The genetic profile based on autosomal markers, four microsatellite DNA markers (D8S315, FES, D8S592, and D2S1328) and two minisatellite DNA markers (TPMT and PDGFA), were analyzed in six endogamous populations to examine the effect of geographic and linguistic affiliation on the genetic affinities among the groups. The six populations are from three different states of India and are linguistically different. Marathas from western India speak Marathi, an Indo-European language. Arayas, Muslims, Ezhavas, and Nairs from Kerala state of South India speak Malayalam, and Iyers from Tamil Nadu state speak Tamil. Genomic DNA was extracted from peripheral blood samples of random, normal, healthy individuals. Locus-specific PCR amplification was carried out, followed by electrophoresis of the amplicons and genotyping. All the loci were highly polymorphic and followed Hardy-Weinberg equilibrium, except for loci D8S315 and PDGFA in Iyers and Marathas, respectively. All six loci had high heterozygosity (average heterozygosity ranged from 0.73 to 0.76) and high polymorphism information content (0.57-0.90). The extent of gene differentiation among the six populations (G(ST) = 0.030) was greater than that for four Kerala populations (G(ST) = 0.011), suggesting proximity between the four Kerala populations. This result conforms with the cultural and linguistic background of the populations. The extent of diversity found among the populations probably resulted from the strict endogamous practices that they follow.
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PMID:Genetic polymorphism of six DNA loci in six population groups of India. 1807 6

Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and consequently, the development of toxicity secondary to thiopurines. Methods A total of 108 DNA samples from volunteer donors and 39 from patients with acute lymphoblastic leukemia (ALL) were analyzed. Genomic DNA from peripheral blood leukocytes was isolated by standard methods. TPMT gene fragments were amplified by PCR for exons 5, 7, and 10. Thereafter, these were analyzed by DHPLC for the most frequent mutant TPMT alleles. Results No elution profiles on DHPLC analysis, different from those previously reported, were documented. Frequency of functional allele polymorphisms was 17.6%, being the most frequent *3A (n = 13; 4.4%), followed by *3B (n = 5; 1.7%), *3C (n = 5; 1.7%), and *2 (n = 3; 1.0%). From 39 ALL patients, 22 were treated with thiopurines, and five from 10 with a functional polymorphism developed hematological toxicity (4 mild, 1 severe in a patient referred to our Hospital after developing pancytopenia while on treatment with thiopurine). Conclusions This is the first analysis of the polymorphisms at this gene in Mexican population. Since a direct relation has been documented within functional polymorphisms and enzyme activity, and DHPLC is a highly sensitive, rapid and efficient method, feasible to realize in any phase during the treatment of ALL patients, the routine typing of TPMT polymorphisms in the patients with ALL has been set in our Institution.
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PMID:Thiopurine S-methyltransferase gene (TMPT) polymorphisms in a Mexican population of healthy individuals and leukemic patients. 1818 16


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