Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMTgene. A pseudogene for this locus is located on chromosome 18q.[5][6]
Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzyme's activity are correlated with variations in sensitivity and toxicity to such drugs. About 1/300 individual is deficient for the enzyme.[5]
Pharmacology
TPMT is best known for its role in the metabolism of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of 6MP leading to enhanced bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency, leukopenia & infection.[8][9][10] Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.[11]
Diagnostic use
Measurement of TPMT activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolised drug. Reuther et al. found that about 5% of all thiopurine therapies will fail due to toxicity. This intolerant group could be anticipated by routine measurement of TPMT activity. There appears to be a great deal of variation in TPMT mutation, with ethnic differences in mutation types accounting for variable responses to 6MP.[9][12]
Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[13] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[14]
^Genome Bioinformatics Group, Center for Biomolecular Science and Engineering. "Human Gene TPMT (uc003ncm.1)". UCSC Genome Browser. University of California Santa Cruz. Retrieved 2008-07-25.
^Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, Feroz-Zada Y, Visscher H, Brown AM, Rieder MJ, Rogers PC, Phillips MS, Carleton BC, Hayden MR (December 2009). "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nat. Genet. 41 (12): 1345–9. doi:10.1038/ng.478. PMID 19898482. S2CID 21293339.
^"Cisplatin". Science & Research (Drugs). United States Food and Drug Administration. Archived from the original on January 21, 2012.
Further reading
Reuther LO, Vainer B, Sonne J, Larsen NE (January 2004). "Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity". Eur. J. Clin. Pharmacol. 59 (11): 797–801. doi:10.1007/s00228-003-0698-8. PMID 14634700. S2CID 530045..
Krynetski EY, Tai HL, Yates CR, et al. (1997). "Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms". Pharmacogenetics. 6 (4): 279–90. doi:10.1097/00008571-199608000-00001. PMID 8873214.
Krynetski E, Evans WE (2003). "Drug methylation in cancer therapy: lessons from the TPMT polymorphism". Oncogene. 22 (47): 7403–13. doi:10.1038/sj.onc.1206944. PMID 14576848. S2CID 22198609.
Corominas H, Baiget M (2004). "Clinical utility of thiopurine S-methyltransferase genotyping". American Journal of Pharmacogenomics. 4 (1): 1–8. doi:10.2165/00129785-200404010-00001. PMID 14987117. S2CID 1954995.
Krynetskiy EY, Evans WE (2005). "Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward". Pharmacogenetics. 14 (7): 395–6. doi:10.1097/01.fpc.0000114753.08559.e9. PMID 15226671.
Coulthard SA, Matheson EC, Hall AG, Hogarth LA (2005). "The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment". Nucleosides Nucleotides Nucleic Acids. 23 (8–9): 1385–91. doi:10.1081/NCN-200027637. PMID 15571264. S2CID 627569.
Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development". Oncologist. 10 (2): 104–11. doi:10.1634/theoncologist.10-2-104. PMID 15709212.
Honchel R, Aksoy IA, Szumlanski C, et al. (1993). "Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA". Mol. Pharmacol. 43 (6): 878–87. PMID 8316220.
Glauser TA, Nelson AN, Zembower DE, et al. (1993). "Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase". J. Pharmacol. Exp. Ther. 266 (1): 23–32. PMID 8392551.
Szumlanski C, Otterness D, Her C, et al. (1996). "Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism". DNA Cell Biol. 15 (1): 17–30. doi:10.1089/dna.1996.15.17. PMID 8561894.
Leipold G, Schütz E, Haas JP, Oellerich M (1997). "Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis". Arthritis Rheum. 40 (10): 1896–8. doi:10.1002/art.1780401026. PMID 9336428.
Krynetski EY, Fessing MY, Yates CR, et al. (1998). "Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library". Pharm. Res. 14 (12): 1672–8. doi:10.1023/A:1012111325397. PMID 9453052. S2CID 22214838.
