Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The commonly used immunosuppressive regimen after solid organ transplantation consists of cyclosporine A, azathioprine and steroids. Azathioprine, which is known to carry the risk of severe myelosuppression, is catabolized in vivo by xanthine oxidase and thiopurine methyltransferase, an enzyme which exhibits a common genetic polymorphism; 11% of Caucasians are heterozygous and 0.3% are homozygous with respect to thiopurine methyltransferase deficiency. Toxicity and immunosuppressive effects have been attributed to the 6-thioguanine nucleotides generated from azathioprine. We have studied thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in erythrocytes from 39 heart and kidney recipients. Erythrocyte thiopurine methyl-transferase was determined by a radioenzymatic assay and erythrocyte 6-thioguanine nucleotide concentration with HPLC. Thiopurine methyltransferase activity [median (range, 10th-90th percentile)] was significantly (p < 0.05) higher in patients (n = 39) receiving azathioprine [285 (218-362) vs. 262 (160-352) mU/I erythrocytes] than in healthy blood donors as controls (n = 120). When stratified according to thiopurine methyltransferase phenotype, one patient homozygous for the low allele exhibited an excessive erythrocyte 6-thioguanine nucleotide concentration (2210 pmol/0.8 x 10(9) erythrocytes). Heterozygous patients had significantly higher 6-thioguanine nucleotide concentrations median: 435 pmol/0.8 x 10(9) erythrocytes) compared with concentrations in patients homozygous for the high allele (median: 86 pmol/0.8 x 10(9) erythrocytes; p < 0.01), although the azathioprine dosage did not differ (p = 0.66). Erythrocyte thiopurine methyltransferase determination therefore identifies patients at high risk of accumulating 6-thioguanine nucleotides. The monitoring of this enzyme may contribute to the safer management of immunosuppressive therapy with azathioprine. Alternative regimens such as cyclosporin A/mycophenolate mofetil or tacrolimus should also be considered for this patient group.
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PMID:Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. 872 7

The commonly used immunosuppressive regimen after orthotopic heart transplantation consists of cyclosporine (CsA), azathioprine (AZA), and steroids. Although AZA therapy is generally regarded as unproblematic, its use can be associated with severe side effects, particularly myelosuppression. Since AZA is a prodrug, which must first be metabolized to its active metabolites, AZA therapy, in contrast to CsA therapy, cannot be controlled by measuring blood levels of this drug. Because of the myelosuppressive properties of the AZA metabolites, the 6-thioguanine nucleotides (6-TGN), the white blood cell count is usually monitored in patients on AZA therapy, and AZA is discontinued if neutropenia appears. In a group of 20 consecutive heart recipients, 6-TGN concentrations ranged from < 30 to 2,211 pmol/8 x 10(8) red blood cells (RBCs); levels < or = 450 pmol/8 x 10(8) RBCs were not associated with AZA-induced myelosuppression. Three cases of neutropenia were experienced, two of them with a fatal outcome. One patient died in septicemia owing to total myelosuppression. In this case an excessively high erythrocyte 6-TGN concentration (2,211 pmol/8 x 10(8) RBCs) was associated with a complete deficiency of thiopurine methyltransferase (TPMT), one of the main AZA detoxifying enzymes. The second patient, who had high RBC TPMT activity, developed neutropenia during rehabilitation, and AZA was withdrawn. Coincidentally, in this case the CsA blood level was only 132 g/L, and the RBC 6-TGN level was very low (maximum 46 pmol/8 x 10(8) RBCs). This patient rapidly developed cardiogenic shock with clinical signs of acute rejection and was given a second transplant on an emergency basis, but finally died from rejection of the second graft. Retrospectively, it was determined that neutropenia in this patient was not related to AZA toxicity. A high 6-TGN level (698 pmol/8 x 10(8) RBCs) was also seen in a third patient with mild neutropenia, who required allopurinol, an inhibitor of xanthine oxidase, the other major detoxifying enzyme for AZA. In this patient AZA therapy could be individually adapted by RBC 6-TGN monitoring. Based on our experience, we suggest that RBC 6-TGN monitoring allows for better individualization of treatment with AZA and may help avoid fatal complications.
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PMID:Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine? 873 60

Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) and thioguanine (6-TG)] have a well-established role as immunosuppressive agents in a variety of chronic inflammatory conditions, haematological neoplasia and in transplant rejection. Despite good overall clinical response rates, particularly when used as steroid sparing agents, adverse effects are a limiting problem leading to withdrawal in up to a quarter of patients. Severe myelosuppression is the most serious toxicity occurring early or occasionally later during treatment. An understanding of the competing pathways involved in the metabolism of thiopurines has important implications for predicting some of the more severe toxicity seen with these drugs. Thiopurine methyl transferase (TPMT) is an enzyme catalysing the methylation of 6-MP, competing with xanthine oxidase (XO) and hypoxanthine guanine phosphoribosyl transferase (HGPRT) to determine the amount of 6-MP metabolised to cytotoxic thioguanine nucleotides. Allelic polymorphisms in the TPMT gene predict the activity of the enzyme such that 1 in 10 of the population are heterozygous and have approximately 50% of normal activity, whilst 1 in 300 are completely deficient. As a result, these individuals are at high risk of severe myelosuppression. Conversely, individuals with very high levels of TPMT activity are hyper-methylators in whom clinical response is less likely. Prior knowledge of TPMT status avoids exposure of individuals with zero TPMT to potentially fatal treatment with AZA or 6-MP and provides one of the best examples of predictive pharmacogenetics in therapeutics. This article reviews literature on the role of TPMT measurement prior to treatment with thiopurines and provides some guidance to the use of TPMT as a guide to tailoring thiopurine therapy.
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PMID:Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? 1529 37

Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH.
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PMID:Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review. 2834 71