Thiopurine 5-methyltransferase

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. 

Although the pathway has not been established, relatively high yields of trimethyltin from inorganic tin have been observed in yeast concomitant with the degradation of butyltin compounds (Errecalde et al. 1995). Exceptionally, methionine transferase may carry out the methylation of Hg in Neurospora crassa (Landner 1971) and thiopurine methyltransferase the methylation of inorganic Se in Escherichia coli (Ranjard et al. 2003). 

Cournoyer B, S Watanabe, A Vivian (1998) A tellurite-resistance genetic determinant from pathogenic pseudomonads encodes a thiopurine methyltransferase evidence of a widely conserved family of methyltransferases. Biochim Biophys Acta 1397 161-168. 

Ranjard L, S Nazaret, B Coumoyer (2003) Freshwater bacteria can methylate selenium through the thiopurine methyltransferase pathway. Appl Environ Microbiol 69 3784-3790. 

Weinshilboum R. Thiopurine pharma-cogenomics clinical and molecular studies of thiopurine methyltransferase. Dmg Metab Dispos 2001 29[4 Pt 2] 601-605. 

Deininger M, Szumlanski CL, Otter-ness DM et al. Purine substrates for human thiopurine methyltransferase. Bio-chem Pharmacol 1994 48 2135-2138. 

Woodson LC, Ames MM, Selassie CD et al. Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 1983 24 471-478. 

McLeod HL, Coulthard S, Thomas AE et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999 105 696-700. 

Evans WE, Horner M, Chu YQ et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991 119 985-989. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

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

McLeod HL, Lin JS, Scott EP et al. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994 55 15-20. 

Thiopurine drugs in the treatment of childhood leukaemia the influence of inherited thiopurine methyltransferase activity on dmg metabolism and cytotoxicity. Br J Clin Pharmacol 1997 44 455-461. 

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. 

Otterness DM, Szumlanski CL, Wood TC et al. Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J Clin Invest 1998 101 1036-1044. 

Collie-Duguid ES, Pritchard SC, Pow-rie RH et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999 9 37-42. 

McLeod HL, Pritchard SC, Githang a J et al. Ethnic differences in thiopurine methyltransferase pharmacogenetics evi-... 

Coulthard SA, Howell C, Robson J et al. The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia. Blood 1998 92 2856-2862. 

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

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

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. 

Weinshilboum RM, Sladek SL. Mercap-topurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

McLeod HL, Lin J-S, Scott EP, Pui C-H, Evans WE. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994 55 15-20. McLeod HL, Miller DR, Evans WE. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993 1341 1151. 

Lennard L, Gibson BES, Nicole T, Lilleyman JS. Congenital thiopurine methyltransferase deficiency and 6-mer-captopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child 1993 69 577-579. 

Schutz E, Gummert J, Mohr F, Oel-lerich M. Azathioprine induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993 341 436. 

Jones DC, Smart C, Titus A, Blyden G, Dorvril M, Nwadike N. Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther 1993 53 348-353. 

Relling MV, Hancock HL, Rivera GK, Sandlund JT, Ribeiro RC, Krymetski EY et al. Intolerance to mercaptopurine therapy related to heterozygosity at the thiopurine methyltransferase gene locus. 

Ameyaw MM, Collie-Duguid ESR, Powrie RH, Ofori-Adjei D, McLeod HL. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 1999 8 367-370. 

McLeod HL, Pritchard SC, Githang a J, Indalo A, Ameyaw MM, Powrie RH, Booth L, Collie-Duguid ESR. Ethnic differences in thiopurine methyltransferase pharmacogenetics evidence for allele specificity in Caucasian and Kenyan subjects. Pharmacogenetics 1999 9 773-776. 

Weinshilboum, R., "Thiopurine Pharmacogenetics Clinical and Molecular Studies of Thiopurine Methyltransferase," Drug Metab. Dispos., 29, 601-605 (2001). 

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