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)

Azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine (TG) are thiopurine drugs. These agents are indicated for the treatment of various diseases including hematologic malignancies, inflammatory bowel disease (IBD), rheumatoid arthritis, and as immunosuppressants in solid organ transplants. Thiopurine drugs are metabolized, in part, by thiopurine methyltransferase (TPMT). TPMT displays genetic polymorphism resulting in null or decreased enzyme activity. At least 20 polymorphisms have been identified, of which, TPMT *2, *3A, *3B, *3C, and *4 are the most commonly studied. These polymorphisms have been associated with increased myelosuppression risk. TPMT genotyping may be useful to predict this risk.
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PMID:Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. 2159 64

Pharmacogenetics is the growing field of study of genetic variations underlying interindividual differences in drug response. Inherited polymorphisms in genes coding for drug-metabolizing enzymes, transporters, and targets influence toxicity as well as efficacy associated with the medication. Thiopurines are agents widely used in hematologic malignancies, transplantation, and chronic inflammatory conditions. Myelosuppression is the commonly encountered dose-limiting toxicity. Polymorphisms in the thiopurine S-methyltransferase gene (TPMT), the predominant inactivating enzyme for thiopurines in hematopoietic tissue, are correlated with enzymatic activity of TPMT, thiopurine metabolism, and risk of clinical toxicity. In this chapter, we present TPMT genotype assessment that allows for prescribing pharmacogenetically guided doses to enhance patient safety and drug efficacy.
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PMID:Thiopurine S-methyltransferase pharmacogenetics in childhood acute lymphoblastic leukemia. 2366 6

Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results. For calcineurin inhibitors like cyclosporine and in particular tacrolimus however, cytochrome P450 3A4 and 3A5 variants were found to significantly affect the pharmacokinetics. Genetic variants in genes encoding relevant pharmacodynamic proteins, however, lacked compelling evidence to affect the clinical outcome. This chapter reviews the current evidence on the association of pharmacogenetic traits to dose finding and clinical outcome of small-molecule immunosuppressants. Moreover this chapter critically summarizes suitability to apply pharmacogenetics in clinical practice in order to optimize immunosuppressant therapy.
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PMID:The Pharmacogenetics of Immune-Modulating Therapy. 2980 78