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Gene Review

TPMT  -  thiopurine S-methyltransferase

Homo sapiens

Synonyms: Thiopurine S-methyltransferase, Thiopurine methyltransferase
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Disease relevance of TPMT

  • The autosomal recessive trait of thiopurine S-methytransferase (TPMT) deficiency is associated with severe hematopoietic toxicity when patients are treated with standard doses of mercaptopurine, azathioprine, or thioguanine [1].
  • RESULTS: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight) [2].
  • The ability of plasma from individual uremic patients to inhibit TPMT also correlated with its ability to inhibit two other drug metabolizing methyltransferases in the RBC, catechol-O-methyltransferase and phenol-O-methyltransferase, RBC TMT activity is not altered in patients with uremia [3].
  • There are large individual variations in inhibition of RBC TPMT by plasma from patients with renal failure [3].
  • METHODS: Seventy-two azathioprine treated paediatric inflammatory bowel disease patients, 47% girls, mean age 12.5 years (range 6.5-17.5), were assessed for TPMT and ITPA polymorphisms and for adverse events [4].
  • Fifty patients with inflammatory bowel disease with normal TPMT activity were all homozygous for six GCC repeats [(GCC)6] [5].

Psychiatry related information on TPMT


High impact information on TPMT


Chemical compound and disease context of TPMT


Biological context of TPMT


Anatomical context of TPMT

  • In the present study, we established that erythrocyte TPMT activity was significantly related to the amount of TPMT protein on Western blots of erythrocytes from patients with TPMT activities of 0.4-23 units/ml pRBC (rs = 0.99; P < 0.001) [21].
  • Northern blot analysis of RNA isolated from leukocytes of the deficient patient demonstrated the presence of TPMT mRNAs of comparable size to that in subjects with high TPMT activity [13].
  • Two patients with AZA-related bone marrow toxicity were found to have a TPMT deficiency, 1 partial and 1 total [14].
  • The TPMT cDNA ORF was then used to screen a human lymphocytes genomic DNA library in an attempt to clone the TPMT gene(s) in humans [22].
  • Therefore, it was important to clone a TPMT cDNA from a human drug-metabolizing organ such as the liver to determine whether its sequence matched that of the cDNA cloned from the T84 cell line [22].

Associations of TPMT with chemical compounds

  • If they receive standard doses of thiopurine medications (for example, 75 mg/m2 body surface area per day), TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, which leads to severe and possibly fatal myelosuppression [19].
  • TPMT is a cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including medications such as mercaptopurine and thioguanine [21].
  • The plasma of uremic patients reversibly inhibits RBC TPMT activity to a greater extent than normal plasma does and contains higher concentrations of endogenous methyl acceptors than normal plasma [3].
  • The first pharmacogenetic trait identified was monogenic, and concerned the prototypic example of thiopurine methyltransferase (TPMT) implicated in azathioprine metabolism [23].
  • Geldanamycin treatment of COS-1 cells transfected with FLAG-tagged wild-type also resulted in a time and geldanamycin concentration-dependent decrease in TPMT activity and protein, which was compatible with results obtained in the RRL [24].
  • Leukocyte genetic TPMT testing revealed that the patient had homozygous polymorphisms associated with the absence of TPMT activity and severe azathioprine-induced myelotoxicity [25].

Regulatory relationships of TPMT


Other interactions of TPMT


Analytical, diagnostic and therapeutic context of TPMT

  • Detection of TPMT mutations in genomic DNA by PCR coincided perfectly with genotypes detected by complementary DNA sequencing [19].
  • TPMT genotype was determined in all individuals with TPMT activity indicative of a heterozygous genotype (</=10.1 U/ml pRBC, n = 23African-Americans, n = 21 Caucasians) and a control group with TPMT activity indicative of a homozygous wild-type genotype (>10.2 U/ml pRBC, n = 23 African-Americans, n = 21 Caucasians) [33].
  • RBC TPMT activity is not affected by hemodialysis [3].
  • Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype [34].
  • Analysis of recent data suggests that by optimizing the AZA dose on the basis of TPMT status testing (with a substantial reduction in dose for patients homozygous for mutant TPMT alleles), a reduction in drug-induced morbidity and cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events [35].


  1. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Tai, H.L., Krynetski, E.Y., Yates, C.R., Loennechen, T., Fessing, M.Y., Krynetskaia, N.F., Evans, W.E. Am. J. Hum. Genet. (1996) [Pubmed]
  2. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Hindorf, U., Lindqvist, M., Peterson, C., Söderkvist, P., Ström, M., Hjortswang, H., Pousette, A., Almer, S. Gut (2006) [Pubmed]
  3. Thiol S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors. Pazmiño, P.A., Sladek, S.L., Weinshilboum, R.M. Clin. Pharmacol. Ther. (1980) [Pubmed]
  4. Pharmacogenetics of thiopurine therapy in paediatric IBD patients. De Ridder, L., Van Dieren, J.M., Van Deventer, H.J., Stokkers, P.C., Van der Woude, J.C., Van Vuuren, A.J., Benninga, M.A., Escher, J.C., Hommes, D.W. Aliment. Pharmacol. Ther. (2006) [Pubmed]
  5. Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. Roberts, R.L., Gearry, R.B., Bland, M.V., Sies, C.W., George, P.M., Burt, M., Marinaki, A.M., Arenas, M., Barclay, M.L., Kennedy, M.A. Pharmacogenet. Genomics (2008) [Pubmed]
  6. Purine substrates for human thiopurine methyltransferase. Deininger, M., Szumlanski, C.L., Otterness, D.M., Van Loon, J., Ferber, W., Weinshilboum, R.M. Biochem. Pharmacol. (1994) [Pubmed]
  7. Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Ganiere-Monteil, C., Medard, Y., Lejus, C., Bruneau, B., Pineau, A., Fenneteau, O., Bourin, M., Jacqz-Aigrain, E. Eur. J. Clin. Pharmacol. (2004) [Pubmed]
  8. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Cuffari, C., Dassopoulos, T., Turnbough, L., Thompson, R.E., Bayless, T.M. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. (2004) [Pubmed]
  9. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Cheng, Q., Yang, W., Raimondi, S.C., Pui, C.H., Relling, M.V., Evans, W.E. Nat. Genet. (2005) [Pubmed]
  10. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Gardiner, S.J., Begg, E.J. Pharmacol. Rev. (2006) [Pubmed]
  11. Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Weinshilboum, R.M., Otterness, D.M., Szumlanski, C.L. Annu. Rev. Pharmacol. Toxicol. (1999) [Pubmed]
  12. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. Relling, M.V., Hancock, M.L., Rivera, G.K., Sandlund, J.T., Ribeiro, R.C., Krynetski, E.Y., Pui, C.H., Evans, W.E. J. Natl. Cancer Inst. (1999) [Pubmed]
  13. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Krynetski, E.Y., Schuetz, J.D., Galpin, A.J., Pui, C.H., Relling, M.V., Evans, W.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  14. Azathioprine-related bone marrow toxicity and low activities of purine enzymes in patients with rheumatoid arthritis. Kerstens, P.J., Stolk, J.N., De Abreu, R.A., Lambooy, L.H., van de Putte, L.B., Boerbooms, A.A. Arthritis Rheum. (1995) [Pubmed]
  15. Comprehensive screening of the thiopurine methyltransferase polymorphisms by denaturing high-performance liquid chromatography. Udaka, T., Torii, C., Takahashi, D., Mori, T., Aramaki, M., Kosaki, R., Tanigawara, Y., Takahashi, T., Kosaki, K. Genetic testing. (2005) [Pubmed]
  16. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Kumagai, K., Hiyama, K., Ishioka, S., Sato, H., Yamanishi, Y., McLeod, H.L., Konishi, F., Maeda, H., Yamakido, M. Pharmacogenetics (2001) [Pubmed]
  17. Consequences of binding an S-adenosylmethionine analogue on the structure and dynamics of the thiopurine methyltransferase protein backbone. Scheuermann, T.H., Keeler, C., Hodsdon, M.E. Biochemistry (2004) [Pubmed]
  18. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. Heneghan, M.A., Allan, M.L., Bornstein, J.D., Muir, A.J., Tendler, D.A. J. Hepatol. (2006) [Pubmed]
  19. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Yates, C.R., Krynetski, E.Y., Loennechen, T., Fessing, M.Y., Tai, H.L., Pui, C.H., Relling, M.V., Evans, W.E. Ann. Intern. Med. (1997) [Pubmed]
  20. Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation. Wang, L., Nguyen, T.V., McLaughlin, R.W., Sikkink, L.A., Ramirez-Alvarado, M., Weinshilboum, R.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  21. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Tai, H.L., Krynetski, E.Y., Schuetz, E.G., Yanishevski, Y., Evans, W.E. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  22. Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. Lee, D., Szumlanski, C., Houtman, J., Honchel, R., Rojas, K., Overhauser, J., Wieben, E.D., Weinshilboum, R.M. Drug Metab. Dispos. (1995) [Pubmed]
  23. Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives. Anglicheau, D., Legendre, C., Thervet, E. Transplantation (2004) [Pubmed]
  24. Thiopurine S-methyltransferase pharmacogenetics: chaperone protein association and allozyme degradation. Wang, L., Sullivan, W., Toft, D., Weinshilboum, R. Pharmacogenetics (2003) [Pubmed]
  25. Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase. Perri, D., Cole, D.E., Friedman, O., Piliotis, E., Mintz, S., Adhikari, N.K. Eur. Respir. J. (2007) [Pubmed]
  26. Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity. Arenas, M., Simpson, G., Lewis, C.M., Shobowale-Bakre, e.l.-.M., Escuredo, E., Fairbanks, L.D., Duley, J.A., Ansari, A., Sanderson, J.D., Marinaki, A.M. Clin. Chem. (2005) [Pubmed]
  27. Pharmacokinetic considerations in the treatment of inflammatory bowel disease. Schwab, M., Klotz, U. Clinical pharmacokinetics. (2001) [Pubmed]
  28. Pharmacogenomic discovery approaches: will the real genes please stand up? Walgren, R.A., Meucci, M.A., McLeod, H.L. J. Clin. Oncol. (2005) [Pubmed]
  29. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Stolk, J.N., Boerbooms, A.M., de Abreu, R.A., de Koning, D.G., van Beusekom, H.J., Muller, W.H., van de Putte, L.B. Arthritis Rheum. (1998) [Pubmed]
  30. Do ITPA and TPMT genotypes predict the development of side effects to AZA? Duley, J.A., Marinaki, A.M., Arenas, M., Florin, T.H. Gut (2006) [Pubmed]
  31. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Breen, D.P., Marinaki, A.M., Arenas, M., Hayes, P.C. Liver Transpl. (2005) [Pubmed]
  32. Clinical relevance of pharmacogenetics. Becquemont, L. Drug Metab. Rev. (2003) [Pubmed]
  33. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hon, Y.Y., Fessing, M.Y., Pui, C.H., Relling, M.V., Krynetski, E.Y., Evans, W.E. Hum. Mol. Genet. (1999) [Pubmed]
  34. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Otterness, D., Szumlanski, C., Lennard, L., Klemetsdal, B., Aarbakke, J., Park-Hah, J.O., Iven, H., Schmiegelow, K., Branum, E., O'Brien, J., Weinshilboum, R. Clin. Pharmacol. Ther. (1997) [Pubmed]
  35. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Clunie, G.P., Lennard, L. Rheumatology (Oxford, England) (2004) [Pubmed]
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