Thiopurine 5-methyltransferase polymorphisms

Yan L, Zhang S, Eiff B et al. Thiopurine methyltransferase polymorphic tandem repeat genotype-phenotype correlation analysis. Clin Pharmacol Ther 2000 68 210-219. 

Oh, K.T., Anis, A.H., and Bae, S.C. (2004) Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford). 43,156-163. 

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. 

Otterness D, Szumlanski C, Lennard L et al. Human thiopurine methyltransferase pharmacogenetics gene sequence polymorphisms. Clin Pharmacol Ther 1997 62 60-73. 

McLeod HL, Reeling MV, Liu Q et al. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995 85 1897-1902. 

Szumlanski C, Otterness D, Her C et al. Thiopurine methyltransferase pharmacogenetics human gene cloning and characterization of a common polymorphism. DNA Cell Biol 1996 15 17— 30. 

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. 

Schwab, M Schaffeler, E Marx, C Fischer, C., Lang, T., Behrens, C., Gregor, M., Eichelbaum, M., Zanger, U.U. and Kaskas, B.A. (2002) Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease impact of thiopurine s-methyltransferase polymorphism. Pharmacogenetics, 12, 429-438. 

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. 

Spire-Vayron de la Moureyre C, Debuy sere H, SabbaghN et al. Detection of known and new mutations in the thiopurine -methyltransferase gene by single-strand conformation polymorphism analysis. HumMutat 1998 12 177-185. 

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. 

Lennard L, Van Loon JA, Weinshilboum RM. Pharmaeogeneties of aeute azathioprine toxieity relationship to thiopurine methyltransferase genetie polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, Iven H, Schmeigelow K, Branum E, Brien J O , Weinshilboum R. Human thiopurine methyltransferase pharmacogenetics gene sequence polymorphisms. Clin Pharmacol Ther 1997 62 60-73. 

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). 

Wusk B, Kullak-Ublick GA, Rammert C et al. (2004) Thiopurine S-methyltransferase polymorphisms efficient screening method for patients considering taking thiopurine drugs. Eur J Clin Pharmacol 60 5-10... 

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. 

Naughton MA, Battaglia E, O Brien S, Walport MJ, Botto M. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology (Oxford) 1999 38(7) 640-4. 

Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics the cost effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatoiogical conditions treated with azathioprine. J Rheumatol 2002 29 2507-12. 

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... 

---