Thiopurine methyltransferase, genetic polymorphism

Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989 7 1816-1823. Erratum itv.JClin Oncol 1990 8 567. Lennard L, Lewis IJ, Michelagnoli M et al. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia 6-mercaptopurine dosage strategies. MedPediatr Oncol 1997 29 252-255. Lennard L, Van Loon JA, Weinshilboum RM. Pharmaeogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

Lennard L, Richards S, Cartwright CS et al. UK MRC/NCRl Childhood Leukaemia Working Party. The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther 2006 80 375-383. 

Corominas H, Domenech M, Laiz A, Gich I, Geli C, Diaz C et al (2003) Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients Rheumatology 42(l) 40-45... 

Leonard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukaemia 2000 14 567-572. 

Tai HI, Krynetski EY, Schuetz EG, Ya-shinevski Y, Evans WE. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in human (TPMT 3A, TPMT 2) mechanism for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci USA 1997 94 6444-6449. 

In addition to being cleared by xanthine oxidase (see sec. III.D), 6-mercaptopurine is cleared by S-methylation catalyzed by the genetically polymorphic thiopurine methyltransferase (134). This enzyme is inhibited by the chug sulfasalazine, leading to bone marrow suppression as a result of increased 6-mercaptopurine concentrations (135,136). 

Krynetski EY, Tai HE, Yates CR, Eessing MY, Loennechen T, Schuetz JD et al. Genetic polymorphism of thiopurine S-methyltransferase Clinical importance and molecular mechanisms. Pharmacogenetics 1996 6 279-90. 

As discussed in Chapter 14/ genetic polymorphisms for the Phase I enzymes (CYP2D6 and CYP2C19) and the Phase II enzymes (N-acetyltransferase and the methyltransferases thiopurine methyltransferase/ catechol O-methyl transferase/ and thiol methyltransferase) may significantly alter exposure to relevant drug substrates. Evaluation of the frequency... 

Azathoiprine is metabolised to 6-mercaptopurine (see p. 608), which is responsible for many, but not all, of its actions as an inhibitor of purine synthesis. The cellular immune response is impaired, notably the function of both B and T lymphocytes. As a result of a genetic polymorphism, approximately 1 in 300 Caucasian people have very low levels of thiopurine methyltransferase (TPMT) the enzyme that metabolises 6-mercaptopurine these individuals are at high risk of toxicity to normal doses of azathioprine. 

Thiopurines are metabolized by thiopurine methyltransferase, whose activity is controlled by a common genetic polymorphism in the short arm of chromosome 6. Patients with low or intermediate activity who take azathioprine or 6-mercaptopurine are at risk of myelosup-pression caused by excess accumulation of the active thiopurine metabolite 6-thioguanine nucleotide. Benzoic acid derivatives, such as mesalazine and its precursors, and prodrugs (sulfasalazine, olsalazine, and balsalazide) inhibit thiopurine methyltransferase activity in vitro. This action could explain the increase in whole blood concentrations of 6-thioguanine nucleotide, leading to leukopenia. 

Clinical response to mercaptopurine is related to whole-blood concentrations of the metabolite 6-thioguanine, and hepatotoxic-ity is correlated with another metabolite, 6-methylmercaptopurme. Metabolic inactivation of azathioprine and mercaptopurine occurs by thiopurine S-methyltransferase, which exhibits genetic polymorphism. Enzyme-deficient patients are at greater risk of bone marrow suppression from these agents. Determination of enzyme activity may be necessary to determine which patients require lower doses of these agents. 

S-Methylation is also an important pathway in the biotransformation of many sulfur-containing drugs. At least two separate enzymes, thiol methyltrans-ferase (TMT) and thiopurine methyltransferase (TPMT) are known to catalyze S-methylation in humans [87], TMT, a membrane-bound enzyme, catalyzes the S-methylation of captopril, D-penicillamine, and other aliphatic sulfhydryl compounds such as 2-mercaptoethanol. On the other hand TPMT, a cytosolic enzyme, catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including 6-mercaptopurine and other thiopurines. Recently, S-methyltransferase has been shown to play a critical role in the metabolism of the antipsychotic drug, ziprasi-done, in humans [72, 88]. Both TPMT and TMT have been shown to be genetically polymorphic in humans. 

Krynetski E Y, Evans W E (2000). Genetic polymorphism of thiopurine S-methyltransferase Molecular mechanisms and clinical importance. Pharmacology. 61 136-146. 

Seki T, Tanaka T, Nakamura Y. Genomic structure and multiple single-nucleotide polymorphisms (SNPs) of the thiopurine 5-methyltransferase (TPMT) gene. J Hum Genet 2000 45 299-302. 

Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 1999 8 371-6. 

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