Thiopurine S-methyltransferase

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Thiopurine S methyltransferase Low activity in about 10% of Caucasians and deficient activity in about 0.4%. High incidence of severe adverse events from azathioprine and 6-mercaptopurine in carriers of low activity. 

Thiopurine S-methyltransferase is an enzyme which inactivates the anticancer drug 6-mercaptopurine by S-methylation. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999 91[23] 2001-2008. 

Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy the thiopurine S-methyltransferase paradigm. Pharm Res 1999 16[3] 342-349. 

Thiopurine S -methyltransferase Drug metabolism SNPs in promoter region, introns and 3 UTR, but not coding region 17... 

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 1996 58 694-702. 

Spire-Vayron de la Moureyre C, De-buysere H, Mastain B et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol 1998 125 879-887. 

Tai HI, Krynetski EY, Schuetz EG, Ya-shinevski Y, Evans WE. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in human (TPMT 3A, TPMT 2) mechanism for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci USA 1997 94 6444-6449. 

Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci USA 1995 92 949-953. 

Spire-Vayron de la Moureyre C, Debuysere H, Sabbagh N, Marez D, Vinner E, Chevalier ED et al. Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat 1998 12 177— 185. 

Molecular diagnosis of thiopurine-S-methyltransferase deficiency genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997 126 608-614. 

Patients deficient in thiopurine S-methyltransferase (TPMT) are at greater risk of bone marrow suppression from azathioprine and mercaptopurine. Determination of TPMT or TPMT genotype is recommended to guide dosage. 

Evans, W.E. (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther. Drug Monk. 26, 186-191. 

Corominas, H., Domenech, M., Gonzalez, D., et al. (2000) Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. Am. J. Gastroenterol. 95, 2313-2317. 

McLeod, H.L., Siva, C. (2002) The thiopurine S-methyltransferase gene locus— implications for clinical pharmacogenomics. Pharmacogenomics. 3, 89-98. 

Yates, C.R., Krynetski, E.Y., Loennechen, T., et al. (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608-614. 

Dervieux, T., Medard, Y., Verpillat, P., et al. (2001) Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine. Leukemia. 15, 1706-1712. 

Roberts, R. L., Barclay, M. L., Gearry, R. B., and Kennedy, M. A. (2004) A multiplexed aUele-specific polymerase chain reaction assay for the detection of common thiopurine S-methyltransferase (TPMT) muta tions. Clin. Chim. Acta. 341, 49-53. 

Zelinkova, Z., Deiijks, L. J., Stokkers, P. C., et al. (2006) Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin. Gastroenterol. Hepatol. 4, 44-49. 

Schwab, M Schaffeler, E Marx, C Fischer, C., Lang, T., Behrens, C., Gregor, M., Eichelbaum, M., Zanger, U.U. and Kaskas, B.A. (2002) Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease impact of thiopurine s-methyltransferase polymorphism. Pharmacogenetics, 12, 429-438. 

Thiopurines in the Treatment of Childhood Acute Lymphoblastic Leukemia and Genetic Variants of the Thiopurine S-Methyltransferase Gene... 

Monitoring of Thiopurine Therapy Thiopurine S-Methyltransferase Conclusions and Further Perspectives References... 

Schaeffeler E, Fischer C, Brockmeier D et al. Comprehensive analysis of thiopurine S -methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004 14 407 17. 

Kroplin T, Iven H. Methylation of 6-mercaptopurine and 6-thioguanine by thiopurine S-methyltransferase a comparison of activity in red blood cell samples of 199 blood donors. Eur J Clin Pharmacol 2000 56 343-345. 

Wang L, Sullivan W, Toft D et al. Thiopurine S -methyltransferase pharmacogenetics chaperone protein association and allozyme degradation. Pharmacogenetics 2003 13 555-564. 

SchaefFeler E, Lang T, Zanger UM et al. High-throughput genotyping of thiopurine S-methyltransferase by denaturing HPLC. Clin Chem 2001 47 548-555. 

Kaskas BA, Louis E, Hindorf U et al. Safe treatment of thiopurine S -methyltransferase deficient Crohn s disease patients with azathioprine. Gut 2003 52 140-142. 

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