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)

Azathioprine is a purine analogue used as an immunosuppressive and immunomodulator agent in various mammals, including cats. Several adverse reactions have been reported and have limited the use of the drug in the cat. Adverse reactions to azathioprine in humans have been correlated with reduced activity of thiopurine methyltransferase (TPMT) in erythrocytes. The purpose of this preliminary study was to determine if cats have TPMT activity in their erythrocytes and to compare the values obtained with the normal range for humans and the normal range for dogs in a preliminary report. Activity of the enzyme was measured in blood samples drawn from 41 cats. Blood also was taken from 5 dogs. The mean erythrocyte TPMT activity in the cats was 2.4 +/- 0.4 nmol (range, 1.2-3.9 nmol) per hour per milliliter of red blood cells (U/mL RBC) or 2-8 nmol per hour per gram of hemoglobin (U/g Hb). This range was far lower than the normal human range (8-15 U/mL RBC; 16-33 U/g Hb) and was of monopolar distribution. This observation apparently precludes any diagnostic purpose in assaying erythrocyte TPMT in this species. Erythrocyte TPMT activity in the 5 dogs ranged from 5.5 to 13.1 U/mL RBC (11-27 U/g Hb), which was comparable with normal and carrier ranges for humans, but proof of TPMT genetic polymorphism in either species will require genotyping studies.
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PMID:Demonstration of thiopurine methyltransferase activity in the erythrocytes of cats. 1101 21

6-thioguanine (6TG) is undergoing investigation for use in the maintenance phase of acute lymphoblastic leukemia (ALL). Just as with 6-mercaptopurine (6MP), it is be expected that 6TG would cause pancytopenia in individuals with inherited thiopurine methyltransferase (TPMT) deficiency. We report the first case of severe and prolonged pancytopenia caused by 6-thioguanine in an 8-year-old boy with ALL and inherited TPMT deficiency. Neutropenia lasted 67 days, whereas anemia and thrombocytopenia did not recover for 96 days. To obviate this life-threatening complication, clinicians should consider assaying TPMT activity before initiating therapy with 6MP and, particularly, 6TG in children with ALL.
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PMID:Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. 1103 57

We have developed an allele-specific fluorogenic 5' nuclease chain reaction assay for detecting polymorphisms in the following human drug-metabolizing enzyme genes: CYP2C9 (CYP2C9*2 and *3), CYP2C19 (CYP2C19*2 and *3), CYP2D6 (CYP2D6*4, *10, *14, *18, and *21(C8)), N-acetyltransferase 2 (NAT2*5B, *6A, and *7B), thiopurine methyltransferase (TPMT*3C), and aldehyde dehydrogenase2 (ALDH2*2). This method is a marriage of two emerging technologies, the use of allele-specific amplification primers for target DNA and hybridization of the TaqMan probe. The TaqMan probe is labeled with both a fluorescent reporter dye and a quencher dye. Genotypes are separated according to the different threshold cycles of the wild-type and mutant primers. All assays are performed using a single thermocycling protocol. This genotyping method is rapid and highly sensitive and yields a high throughput. It could be applied toward automated large-scale genotyping.
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PMID:High throughput detection of drug-metabolizing enzyme polymorphisms by allele-specific fluorogenic 5' nuclease chain reaction assay. 1104 Dec 38

Knowledge about the clinical pharmacology of medical therapy of inflammatory bowel disease has incrementally advanced. Small studies with mesalamine have suggested that intestinal mucosal concentrations of mesalamine may predict clinical response to mesalamine therapy. Increased expression of glucocorticoid receptor beta and increased expression of the multidrug resistance drug pump P-glycoprotein 170 have been proposed as markers of drug resistance to glucocorticoids. A baseline determination of thiopurine methyltransferase phenotype or genotype may predict early leukopenia in patients treated with azathioprine or 6- mercaptopurine. Serial measurement of erythrocyte 6-thioguanine nucleotides may be useful in tailoring the dose of these medications. A loading dose of intravenous azathioprine does not accelerate the time to response in patients with steroid-treated Crohn's disease; however, standard azathioprine may work more quickly than previously reported. Methotrexate, 15 to 25 mg/wk, is effective for the treatment of Crohn's disease (active or in remission), and there is no significant difference in the erythrocyte concentrations of methotrexate polyglutamate in patients with inflammatory bowel disease receiving 15 mg, compared with 25 mg, subcutaneously on a weekly basis.
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PMID:Clinical pharmacology of inflammatory bowel disease therapies. 1107 44

The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of drugs used both in the treatment of acute leukaemia (6-mercaptopurine and 6-thioguanine) and as an immunosuppressant in patients with autoimmune diseases or following organ transplantation (azathioprine). Studies of enzyme activity in red blood cells have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. Patients with biallelic mutations and undetectable enzyme activity suffer life-threatening myelosuppression when treated with conventional doses of these drugs. Patients with intermediate activity have an increased risk of drug-associated toxicity. In the Caucasian populations studied to date, intermediate activity is associated with mutations at two sites of the TPMT gene, G460A and A719G (designated TPMT*3A), in 80% of cases. Detection of these mutations has, to date, been based on the analysis of restriction digests of PCR products. In order to simplify this process we have investigated the ability of denaturing high pressure liquid chromatography (DHPLC) to detect the A719G mutation. DHPLC of PCR products from 15 known heterozygotes (TPMT*3A/TPMT*1) and 18 known homozygotes (TPMT*1/TPMT*1) gave a clear pattern difference between the groups and 100% concordance with the results of restriction digests. These results suggest DHPLC represents a valuable technique for accurate and rapid detection of pharmacologically important mutations in the TPMT gene.
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PMID:The use of denaturing high-pressure liquid chromatography for the detection of mutations in thiopurine methyltransferase. 1117 62

Thiopurine drugs are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best examples of the potential importance of pharmacogenetics for clinical medicine. Specifically, it is now known that patients with inherited very low levels of TPMT activity are at greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of these drugs, while subjects with very high activity may be undertreated. Furthermore, recent reports indicate that TPMT may be the target for clinically significant drug interactions and that this common genetic polymorphism might be a risk factor for the occurrence of therapy-dependent secondary leukemia. In parallel with these clinical reports, the molecular basis for the TPMT polymorphism has been determined as a result of cloning and characterization of the human TPMT cDNA and gene. Those advances led to the description and characterization of a series of single nucleotide polymorphisms that result in low levels of enzyme activity as well as a polymorphic variable number tandem repeat within the 5'-flanking region of the TPMT gene that may "modulate" level of enzyme activity. As a result of these observations, the TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is developed and applied to clinical medicine.
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PMID:Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. 1125 60

The susceptibility of recombinant human thiopurine methyltransferase (hTPMT) to thiol-disulfide exchange was investigated. The enzyme was incubated in buffers of the redox couple GSH and GSSG. The values of the chosen concentrations and concentration ratios of the redox couple equaled those expected to occur in vivo. Activity measurements of the enzyme over time in these buffers at 30 degrees C indicated that thiol-disulfide exchange may be a part of the posttranslational modulation of hTPMT activity. Activity varied between 5% and 100%, with the lowest activities in buffers of low [GSH]/[GSSG] concentration ratios and of low total concentration of the redox couple. A thiol-disulfide exchange mechanism involving a mixed disulfide was proposed. Titration of the protein thiol groups with Ellmann's reagent (5,5'-dithiobis[2-nitrobenzoic acid]) revealed that at least two protein thiols were readily accessible for conjugation with the reagent, while others were conjugated more slowly. The previous model of hTPMT constructed by our group was in accordance with the experimental results. Inspection of the model indicated that one of the protein thiols subject to slow thiol-disulfide exchange may be situated at the binding site of the co-substrate of the enzyme and thus be responsible for the glutathione/glutathione disulfide modulation of the activity of hTPMT.
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PMID:Effect of the glutathione/glutathione disulfide redox couple on thiopurine methyltransferase. 1126 55

Polymorphisms at three loci in the thiopurine methyltransferase (TPMT) gene are known to be responsible for azathioprine and 6-mercaptopurine (6MP) toxicity. Among them, only TPMT*3C variant allele with A719G mutation was found in 15/522 (2.9%; 17/1044 alleles; 1.6%) Japanese individuals including two homozygotes. The allele frequency was different from that in Caucasians, and investigation of TPMT polymorphisms with consideration of ethnic differences before administration of azathioprine or 6MP may provide clinically useful information.
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PMID:Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. 1133 44

Azathioprine (AZA) is characterized by a high interindividual variability in bioavailability and metabolism. AZA is converted into 6-thioguanine nucleotides (6-TGN) to which the immune modifier activity is attributed. The 6-TGN levels are known to be affected by the activity of the key enzyme, thiopurine methyltransferase (TPMT), which is under genetic dependence. The authors measured a significantly lower TPMT activity in 53 women with systemic lupus erythematosus (SLE) (12.2 +/- 2.4 pmol/h/ml RBC; P < 0.01) when compared with 30 healthy control participants (13.15 +/- 3.1 pmol/h/ml RBC) but not with 28 patients with other dysimmune diseases (non-SLE; 13.0 +/- 3.0 pmol/h/ml RBC; P = 0.10). To evaluate the impact of TPMT activity on the concentrations of AZA metabolites, we measured the TPMT activity and 6-TGN levels in a subgroup of 26 patients in remission and treated with a stable dose of AZA (mean value: 1.9 +/- 0.5 mg/kg/day) for at least six months (n = 13 with SLE and n = 13 with other dysimmune diseases, ie, non-SLE). In such a subgroup, no correlation between 6-TGN levels and TPMT activity was observed. However, patients with SLE presented lower TPMT activity and higher 6-TGN levels (215 +/- 123 versus 140 +/- 75 pmol/8 x 10(8) RBC in non-SLE patients; P < 0.04). It must be noted that transient increase in 6-methylmercaptopurine levels (6-MMP), a putative toxic metabolite (up to 21.7 nmol/8 x 10(8) RBC), was more frequently observed in the non-SLE group (P < 0.01). Even if a relationship was observed between low TPMT activity and 6-TGN levels in SLE, its clinical impact appears to be limited as far as regular hematologic controls are performed.
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PMID:High 6-thioguanine nucleotide levels and low thiopurine methyltransferase activity in patients with lupus erythematosus treated with azathioprine. 1134 81

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


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