Thiopurine methyltransferase orthiopurine S-methyltransferase (TPMT) is anenzyme that in humans is encoded by theTPMTgene. A pseudogene for this locus is located on chromosome 18q.[5][6]
Thiopurine drugs such as6-mercaptopurine are used aschemotherapeutic agents andimmunosuppressive 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]
TPMT is best known for its role in the metabolism of thethiopurine drugs such asazathioprine,6-mercaptopurine and6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of6MP leading to enhanced bone marrow toxicity which may causemyelosuppression, anemia, bleeding tendency,leukopenia & infection.[8][9][10] Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.[11]
Measurement of TPMT activity is encouraged prior to commencing the treatment of patients withthiopurine drugs such asazathioprine,6-mercaptopurine and6-thioguanine. Patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-inducedbone marrow toxicity due to accumulation of the unmetabolised drug. Reutheret 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 to6MP.[9][12]
Genetic variants of TPMT have also been associated withcisplatin-inducedototoxicity in children.[13] TPMT is now listed as a pharmacogenomicbiomarker 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. Retrieved2008-07-25.
^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.PMID19898482.S2CID21293339.
^"Cisplatin".Science & Research (Drugs). United States Food and Drug Administration. Archived fromthe original on January 21, 2012.
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.PMID14634700.S2CID530045..
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.PMID8873214.
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.PMID15226671.
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.PMID15571264.S2CID627569.
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.PMID15709212.
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.PMID8316220.
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.PMID8392551.
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.PMID8561894.
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.PMID9336428.
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.PMID9453052.S2CID22214838.
