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)

Inflammatory bowel disease (IBD), with its two subforms of Crohn disease and ulcerative colitis, is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition. The first risk gene underlying susceptibility to Crohn disease has been identified as CARD15 (located on chromosome 16q12, encoding NOD2). Three single nucleotide polymorphisms in the leucine rich region (LRR) of this gene are strongly and independently associated with Crohn disease susceptibility and explain up to 20% of the total genetic predisposition for Crohn disease. These variants have been consistently replicated as associated with a particular sub-phenotype characterized by small bowel (ileum) involvement and early age at onset. Presently, genetic testing for the CARD15 variants has only a modest relevance in clinical practice. The most attractive use of genetic testing is for the prediction of response to therapy. Most therapies only show efficacy in subgroups of patients and no clinical parameters are available to distinguish, prior to therapy, whether the patients will be responders or non-responders, or if the patients will experience adverse effects. The pharmacogenetic basis of toxicity is well known for azathioprine: several thiopurine methyltransferase (TPMT) polymorphisms that are associated with reduced activity of this thiopurine drug metabolizing enzyme result in cytotoxic and immunosuppressive adverse effects of azathioprine. Genetic screening, which has found its way into routine clinical diagnostics, allows the identification of the patients who will not tolerate a standard dose of the drug. The extensive search for genetic predictors of response to the anti-tumor necrosis factor treatment with infliximab, which results in a remission rate of 30-40%, has, however, failed to identify a variation associated with a differential response.
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PMID:Genetic testing in Crohn disease: utility in individualizing patient management. 1607 58

Azathioprine is a frequently used immunosuppressant for managing inflammatory bowel disease (IBD). In recent years the hepatotoxic profile of thiopurines has been recognised. We report the case of a 40-year-old man with Crohn's disease treated with azathioprine. After taking azathioprine (2.2 mg/kg daily) for two years, his liver function tests were found to be elevated. Moreover, a myelodepression was established as platelet and leucocytes counts were lowered. The 6-thioguaninenucleotide level was 738 picomoles/8 x 10(8) per red blood cell, which is well above the proposed upper limit of efficacy and associated with an increased risk of developing a myelodepression. Genotyping of the enzyme thiopurine methyltransferase revealed no mutant alleles. The ultrasonography and CT scan showed signs of portal hypertension (spleen 17 cm and widened splenic vein). A liver biopsy was performed and an incomplete septal liver cirrhosis was found. An upper endoscopy revealed oesophageal varices (grade 2 to 3). Autoimmune and viral liver diseases were ruled out by laboratory parameters. After cessation of therapy, all laboratory parameters normalised. Therefore, azathioprine is believed to be the causative factor for inducing the liver cirrhosis. Continuous monitoring of patients taking thiopurines is mandatory. The role of 6-thioguaninenucleotide levels in inducing myelotoxicity and hepatotoxicity is discussed.
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PMID:Myelotoxicity and hepatotoxicity during azathioprine therapy. 1639 13

6-Thioguanine (6-TG) seems to be an attractive alternative in both AZA- and 6-MP-intolerant and -resistant IBD populations. However, little is known of 6-TG pharmacokinetics, metabolite levels, and their correlation with drug efficacy and toxicity in IBD patients. This study reports the 6-TG pharmacokinetics in a population of IBD patients and the predictive value of metabolite concentrations. Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations were measured in 28 IBD patients at t = 1, 2, 4, and 8 weeks after starting 6-TG, 20 mg once daily. Outcome measures included mean 6-TGN concentrations (+/-95% confidence interval [CI95%]) and their associations with TPMT genotype, 6-TG dose, and hematological, hepatic, pancreatic, and efficacy parameters during the 8 week period. Steady-state 6-TGN concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days, and measured 856 (CI95% 715-997) pmol/8 x 10 RBCs. Large interpatient variability occurred at all time-points. No correlation was found between steady-state 6-TGN concentrations and drug dose per kilogram body weight. No significant differences in 6-TGN concentrations were found between patients with adverse events and patients without any event. Also, mean 6-TGN concentrations did not differ in patients with active disease versus patients in remission. In IBD patients on 6-TG treatment, large interindividual differences in metabolite concentrations occur. In our population, we could not demonstrate a clear relationship between 6-TGN concentrations on one hand and toxicity and efficacy on the other, as exist in AZA- and 6-MP-treated patients.
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PMID:Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. 1641 93

Inherited variations in the nucleotide sequence of genes influence how individual patients respond to drugs. Most commonly, clinically significant genetic variations consist of single nucleotide polymorphisms (SNPs) within genes that affect drug disposition or drug targets. Up to now, relatively few clinically important examples of inherited traits that affect drug responses have been studied in detail. However, one of the well-characterized examples is highly relevant to inflammatory bowel disease therapeutics, that of thiopurine methyltransferase pharmacogenetics. Individuals with 2 normal alleles of the gene encoding thiopurine methyltransferase metabolize and clear thiopurines such as azathioprine and 6-mercaptopurine rapidly. Individuals with 1 normal and 1 variant allele are intermediate, whereas those with 2 variant alleles clear thiopurines very slowly. Intermediate and slow metabolizers are predisposed to have high active thiopurine drug levels and develop bone marrow suppression. Genomic era technology permits determination of large numbers of SNPs in large numbers of individuals. This capability is allowing the field of pharmacogenomics to become one of the most productive interfaces in translational biomedical research at present. By using high-throughput SNP genotyping, combined with careful phenotypic characterization of disease, pharmacogenomic research carries the potential of identifying individual biomarkers that predict the relative likelihood of benefit or risk from a therapeutic intervention. If this promise can be realized, pharmacogenomics will deliver the opportunity for personalized medicine.
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PMID:Pharmacogenomics in inflammatory bowel disease. 1643

The volume of research undertaken on the genetic susceptibility of inflammatory bowel disease (IBD) has been tremendous, and over 10 chromosomal regions have been identified by genome-wide scanning. Fine-mapping approaches and candidate gene studies have already led to the identification of several susceptibility genes, including CARD15 (NOD2), DLG5, novel organic cation transporter (OCTN) 1 and 2, and CARD4 (NOD1). The CARD15 gene is the most understood at present and explains around 20% of the genetic predisposition to Crohn's disease. Although the clinical implications of genetic testing are limited at present, genetic research has advanced our understanding of the clinical heterogeneity and the complex interactions between genetic and environmental risk factors in IBD. Genes also interfere with the metabolism of drugs and may influence the clinical response and drug-related toxicity. Ultimately, researchers and clinicians aim to personalize medicine based on a patient's genotype, although azathioprine (thiopurine methyltransferase polymorphisms) is the only drug to date where pharmacogenetics has shown clinical relevance in IBD. In the future, it is anticipated that genetic markers will be implemented in an integrated molecular diagnostic and prognostic approach to managing our patients.
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PMID:Review article: genetic susceptibility and application of genetic testing in clinical management of inflammatory bowel disease. 1696 37

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

We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 +/- 6 U/mL, but differed depending on the disease (P<.001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0-13.7) in 11.9%; or high (>or=13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0-0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.
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PMID:Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. 1733 11

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 thiopurine drugs-azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine-are widely used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease, and solid organ transplant rejection. However, thiopurine drugs have a relatively narrow therapeutic index and are capable of causing life-threatening toxicity, most often myelosuppression. Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67), an enzyme that catalyzes S-methylation of these drugs, exhibits a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at risk for excessive toxicity after receiving standard doses of thiopurine medications. This report reviews the recent advances in the knowledge of the mechanism of action as well as the molecular basis and interethnic variations of TPMT and inosine triphosphate pyrophosphatase (ITPase; EC 3.6.1.19), another enzyme implicated in thiopurine toxicity. In addition, an update on pharmacokinetics, metabolism, drug-drug interactions, safety, and tolerability of thiopurine drugs is provided.
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PMID:Clinical pharmacology and pharmacogenetics of thiopurines. 1850 37


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