Thiopurine methyltransferase
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.[3][4]
Function
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.[3][5]
Clinical significance
Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. About 1/300 individual is deficient for the enzyme.[3]
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.[6][7][8]
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.[7][9]
Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[10] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[11]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- 1 2 3 "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. Retrieved 2012-07-02.
- ↑ Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM (March 1995). "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1". Drug Metab. Dispos. 23 (3): 398–405. PMID 7628307.
- ↑ Weinshilboum RM, Sladek SL (1980). "Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity". American Journal of Human Genetics. 32 (5): 651–662. PMC 1686086
. PMID 7191632. - ↑ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID 17691917.
- 1 2 Oncea I, Duley J (2008). "Pharmacogenetics of Thiopurines.". Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line) (11th ed.). Chapter 38.
- ↑ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy.". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163.
- ↑ 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.
- ↑ "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration.
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. .
- 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.
- 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.
- 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.
- 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.
- Pierik M, Rutgeerts P, Vlietinck R, Vermeire S (2006). "Pharmacogenetics in inflammatory bowel disease.". World J. Gastroenterol. 12 (23): 3657–67. PMID 16773681.
- Krynetski EY, Schuetz JD, Galpin AJ, et al. (1995). "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. doi:10.1073/pnas.92.4.949. PMC 42614. PMID 7862671.
- 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.
- Tai HL, Krynetski EY, Yates CR, et al. (1996). "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. PMC 1914689. PMID 8644731.
- Yates CR, Krynetski EY, Loennechen T, et al. (1997). "Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance.". Ann. Intern. Med. 126 (8): 608–14. doi:10.7326/0003-4819-126-8-199704150-00003. PMID 9103127.
- Tai HL, Krynetski EY, Schuetz EG, et al. (1997). "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. doi:10.1073/pnas.94.12.6444. PMC 21069. PMID 9177237.
- Otterness D, Szumlanski C, Lennard L, et al. (1997). "Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.". Clin. Pharmacol. Ther. 62 (1): 60–73. doi:10.1016/S0009-9236(97)90152-1. PMID 9246020.
- 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:10.1002/1529-0131(199710)40:10<1896::AID-ART26>3.0.CO;2-A. 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.
- Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N, et al. (1998). "Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis.". Hum. Mutat. 12 (3): 177–85. doi:10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E. PMID 9711875.
External links
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| 2bzg: CRYSTAL STRUCTURE OF THIOPURINE S-METHYLTRANSFERASE. |
| 2h11: Amino-terminal Truncated Thiopurine S-Methyltransferase Complexed with S-Adenosyl-L-Homocysteine |
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