Thiopurine methyltransferase explained

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.^{[1] [2]}

Function

Align:	left
thiopurine S-methyltransferase
Ec Number:	2.1.1.67
Cas Number:	67339-09-7
Go Code:	0008119

Thiopurine methyltransferase methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine. This enzyme metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct.^{[1] [3]}

Clinical significance

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.^[1]

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.^{[4] [5] [6]} Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.^[7]

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.^{[5] [8]}

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.^[9] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.^[10]

See also

• Cancer pharmacogenomics

References

Further reading

• 14634700 . 10.1007/s00228-003-0698-8 . 59 . 11 . Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity . January 2004 . Eur. J. Clin. Pharmacol. . 797–801 . Reuther LO, Vainer B, Sonne J, Larsen NE . 530045 . .
• Krynetski EY, Tai HL, Yates CR, etal . Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. . Pharmacogenetics . 6 . 4 . 279–90 . 1997 . 8873214 . 10.1097/00008571-199608000-00001 .
• Krynetski E, Evans WE . Drug methylation in cancer therapy: lessons from the TPMT polymorphism. . Oncogene . 22 . 47 . 7403–13 . 2003 . 14576848 . 10.1038/sj.onc.1206944 . 22198609 .
• Corominas H, Baiget M . Clinical utility of thiopurine S-methyltransferase genotyping. . American Journal of Pharmacogenomics . 4 . 1 . 1–8 . 2004 . 14987117 . 10.2165/00129785-200404010-00001. 1954995 .
• Krynetskiy EY, Evans WE . Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward. . Pharmacogenetics . 14 . 7 . 395–6 . 2005 . 15226671 . 10.1097/01.fpc.0000114753.08559.e9.
• Coulthard SA, Matheson EC, Hall AG, Hogarth LA . The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. . Nucleosides Nucleotides Nucleic Acids . 23 . 8–9 . 1385–91 . 2005 . 15571264 . 10.1081/NCN-200027637 . 627569 .
• Lee W, Lockhart AC, Kim RB, Rothenberg ML . Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. . Oncologist . 10 . 2 . 104–11 . 2005 . 15709212 . 10.1634/theoncologist.10-2-104 .
• Pierik M, Rutgeerts P, Vlietinck R, Vermeire S . Pharmacogenetics in inflammatory bowel disease. . World J. Gastroenterol. . 12 . 23 . 3657–67 . 2006 . 16773681 . 10.3748/wjg.v12.i23.3657. 4087457 . free .
• Krynetski EY, Schuetz JD, Galpin AJ, etal . A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. . Proc. Natl. Acad. Sci. U.S.A. . 92 . 4 . 949–53 . 1995 . 7862671 . 10.1073/pnas.92.4.949 . 42614 . 1995PNAS...92..949K . free .
• Honchel R, Aksoy IA, Szumlanski C, etal . Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. . Mol. Pharmacol. . 43 . 6 . 878–87 . 1993 . 8316220 .
• Glauser TA, Nelson AN, Zembower DE, etal . Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. . J. Pharmacol. Exp. Ther. . 266 . 1 . 23–32 . 1993 . 8392551 .
• Szumlanski C, Otterness D, Her C, etal . Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. . DNA Cell Biol. . 15 . 1 . 17–30 . 1996 . 8561894 . 10.1089/dna.1996.15.17 .
• Tai HL, Krynetski EY, Yates CR, etal . Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. . Am. J. Hum. Genet. . 58 . 4 . 694–702 . 1996 . 8644731 . 1914689 .
• Yates CR, Krynetski EY, Loennechen T, etal . Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. . Ann. Intern. Med. . 126 . 8 . 608–14 . 1997 . 9103127 . 10.7326/0003-4819-126-8-199704150-00003. 23831294 .
• Tai HL, Krynetski EY, Schuetz EG, etal . 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. . Proc. Natl. Acad. Sci. U.S.A. . 94 . 12 . 6444–9 . 1997 . 9177237 . 10.1073/pnas.94.12.6444 . 21069 . free .
• Otterness D, Szumlanski C, Lennard L, etal . Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. . Clin. Pharmacol. Ther. . 62 . 1 . 60–73 . 1997 . 9246020 . 10.1016/S0009-9236(97)90152-1 . 22016760 .
• Leipold G, Schütz E, Haas JP, Oellerich M . 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 . 1997 . 9336428 . 10.1002/art.1780401026 .
• Krynetski EY, Fessing MY, Yates CR, etal . 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 . 1998 . 9453052 . 10.1023/A:1012111325397 . 22214838 .
• Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N, etal . Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. . Hum. Mutat. . 12 . 3 . 177–85 . 1998 . 9711875 . 10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E . 11311096 . free .

External links

• City Assays page on the TPMT assay

Notes and References

1. Web site: Entrez Gene: TPMT thiopurine S-methyltransferase. 2012-07-02 . .
2. Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM . Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1 . Drug Metab. Dispos. . 23 . 3 . 398–405 . March 1995 . 7628307 .
3. Weinshilboum RM, Sladek SL . Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity . American Journal of Human Genetics . 32 . 5 . 651–662 . 1980 . 7191632 . 1686086 .
4. Fujita K, Sasaki Y . Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy . Curr. Drug Metab. . 8 . 6 . 554–62 . August 2007 . 17691917 . 10.2174/138920007781368890 . 2008-07-25 . 2013-01-12 . https://archive.today/20130112103320/http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM . dead .
5. Book: Oncea I, Duley J . Chapter 38: Pharmacogenetics of Thiopurines. Goodman & Gilman's The Pharmacological Basis of Therapeutics . McGraw-Hill's Access Medicine . 2008 . 11th .
6. Evans WE. . Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. . Ther Drug Monit. . 26 . 2 . 186–91 . 2004 . 15228163 . 10.1097/00007691-200404000-00018. 34015182 .
7. Web site: The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression. www.ebmconsult.com. 2019-03-24.
8. Web site: Human Gene TPMT (uc003ncm.1) . Genome Bioinformatics Group, Center for Biomolecular Science and Engineering . UCSC Genome Browser . University of California Santa Cruz . 2008-07-25.
9. 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 . Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy . Nat. Genet. . 41 . 12 . 1345–9 . December 2009 . 19898482 . 10.1038/ng.478 . 21293339 .
10. Web site: Cisplatin . Science & Research (Drugs) . United States Food and Drug Administration .