Abstract
Background
The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
Aim
This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.
Similar content being viewed by others
Abbreviations
- 6-dTGTP:
-
6- deoxy thioguanosine triphosphate
- 6-MeMP:
-
6-methylmercaptopurine
- 6-meTIDP:
-
6-methyl-thioinosine diphosphate
- 6-meTIMP:
-
6-methyl-thioinosine monophosphate
- 6-meTITP:
-
6-methyl-thioinosine triphosphate
- 6-MMPN:
-
6-methyl mercaptopurine nucleotides
- 6-MP:
-
6-mercaptopurine
- 6-TGDP:
-
6-thioguanine diphosphate
- 6-TGMP:
-
6-thioguanosine monophosphate
- 6-TGN:
-
6-thioguanine nucleotides
- 6-TGTP:
-
6-thioguanosine triphosphate
- 6-TIDP:
-
6-thioinosine diphosphate
- 6-TIMP:
-
6-thioinosine monophosphate
- 6-TITP:
-
6-thioinosine triphosphate
- 6-TXMP:
-
6-thioxanthine monophosphate
- ABC:
-
ATP-binding cassette
- ALL:
-
Acute lymphoblastic leukemia
- AZA:
-
Azathioprine
- DNA:
-
Deoxyribonucleic acid
- GMPS:
-
Guanosine monophosphate synthetase
- HGPRT:
-
Hypoxanthine guanine phosphoribosyltransferase
- IBD:
-
Inflammatory bowel disease
- IMPDH:
-
Inosine monophosphate dehydrogenase
- ITPA:
-
Inosine triphosphate pyrophosphatase
- MTHFR:
-
5,10-Methylenetetrahydrofolate reductase
- MRP:
-
Multidrug resistance associated protein
- NE:
-
Not explored
- Pmol:
-
Picomoles
- PRPP:
-
Phosphoribosylpyrophosphate
- RBC:
-
Red blood cells
- SAM:
-
S-adenosylmethionine
- SLC:
-
Solute carrier family
- SNPs:
-
Single nucleotide polymorphisms
- TPMT:
-
Thiopurine S-methyl transferase
- TUA:
-
Thiouric acid
- XMP:
-
Xanthosine monophosphate
- XO:
-
Xanthine oxidase
References
Schmiegelow K, Schrøder H, Gustafsson G et al (1995) Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. J Clin Oncol 13(2):345–351
Elion GB, Hitchings GH, Vanderwerff H (1951) Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem 192(2):505–518
Adam de Beaumais T, Fakhoury M, Medard Y et al (2011) Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol 71(4):575–584
McLeod HL, Krynetski EY, Relling MV, Evans WE (2000) Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14(4):567–572
Fakhoury M, de Beaumais T, Médard Y, Jacqz-Aigrain E (2010) Therapeutic drug monitoring of 6-thioguanine nucleotides in paediatric acute lymphoblastic leukaemia: interest and limits. Therapie 65(3):187–193
Bostrom B, Erdmann G (1993) Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 15(1):80–86
Swann PF, Waters TR, Moulton DC et al (1996) Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273(5278):1109–1111
Dervieux T, Blanco JG, Krynetski EY, Vanin EF, Roussel MF, Relling MV (2001) Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res 61(15):5810–5816
Karran P, Attard N (2008) Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer 8(1):24–36
Relling MV, Gardner EE, Sandborn WJ et al (2011) Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 89(3):387–391
McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE (1994) Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 55(1):15–20
Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM (1991) Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 119(6):985–989
Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM (1987) Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 41(1):18–25
Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336(8709):225–229
Loennechen T, Utsi E, Hartz I, Lysaa R, Kildalsen H, Aarbakke J (2001) Detection of one single mutation predicts thiopurine S-methyltransferase activity in a population of Saami in northern Norway. Clin Pharmacol Ther 70(2):183–188
Spire-Vayron de la Moureyre C, Debuysere H, Mastain B et al (1998) Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol 125(4):879–887
Tinel M, Berson A, Pessayre D et al (1991) Pharmacogenetics of human erythrocyte thiopurine methyltransferase activity in a French population. Br J Clin Pharmacol 32(6):729–734
De Beaumais TA, Fakhoury M, Pigneur B et al (2009) Characterization of a novel TPMT mutation associated with azathioprine-induced myelosuppression. Br J Clin Pharmacol 68(5):770–772
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
Shipkova M, Lorenz K, Oellerich M, Wieland E, von Ahsen N (2006) Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Clin Chem 52(2):240–247
von Ahsen N, Oellerich M, Armstrong VW (2008) Characterization of the inosine triphosphatase (ITPA) gene: haplotype structure, haplotype-phenotype correlation and promoter function. Ther Drug Monit 30(1):16–22
Arenas M, Duley J, Sumi S, Sanderson J, Marinaki A (2007) The ITPA c.94C > A and g.IVS2 + 21A > C sequence variants contribute to missplicing of the ITPA gene. Biochim Biophys Acta 1772(1):96–102
Sumi S, Marinaki AM, Arenas M et al (2002) Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 111(4–5):360–367
Allorge D, Hamdan R, Broly F, Libersa C, Colombel J-F (2005) ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut 54(4):565
Stocco G, Cheok MH, Crews KR et al (2009) Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 85(2):164–172
Tai HL, Fessing MY, Bonten EJ et al (1999) Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C. Pharmacogenetics 9(5):641–650
Milek M, Karas Kuzelicki N, Smid A, Mlinaric-Rascan I (2009) S-adenosylmethionine regulates thiopurine methyltransferase activity and decreases 6-mercaptopurine cytotoxicity in MOLT lymphoblasts. Biochem Pharmacol 77(12):1845–1853
Martin YN, Salavaggione OE, Eckloff BW, Wieben ED, Schaid DJ, Weinshilboum RM (2006) Human methylenetetrahydrofolate reductase pharmacogenomics: gene resequencing and functional genomics. Pharmacogenet Genomics 16(4):265–277
Arenas M, Simpson G, Lewis CM et al (2005) Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity. Clin Chem 51(12):2371–2374
Guerciolini R, Szumlanski C, Weinshilboum RM (1991) Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther 50(6):663–672
Minoshima S, Wang Y, Ichida K, Nishino T, Shimizu N (1995) Mapping of the gene for human xanthine dehydrogenase (oxidase) (XDH) to band p23 of chromosome 2. Cytogenet Cell Genet 68(1–2):52–53
Wong DR, Derijks LJJ, den Dulk MO, Gemmeke EHKM, Hooymans PM (2007) The role of xanthine oxidase in thiopurine metabolism: a case report. Ther Drug Monit 29(6):845–848
Morgan E, Honig G, Nelson DJ (1981) Acute lymphocytic leukemia in a child with congenital xanthine oxidase deficiency: implications for therapy. Am J Pediatr Hematol Oncol 3(4):439–441
Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O’Neill JP (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463(3):309–326
Kudo M, Saito Y, Sasaki T et al (2009) Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug Metab Pharmacokinet 24(6):557–564
Ding L, Zhang F-B, Liu H et al (2011) Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 18(1):63–73.
Pieters R, Huismans DR, Loonen AH et al (1992) Hypoxanthine-guanine phosphoribosyl-transferase in childhood leukemia: relation with immunophenotype, in vitro drug resistance and clinical prognosis. Int J Cancer 51(2):213–217
Haglund S, Taipalensuu J, Peterson C, Almer S (2008) IMPDH activity in thiopurine-treated patients with inflammatory bowel disease—relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol 65(1):69–77
Jain J, Almquist SJ, Ford PJ et al (2004) Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes. Biochem Pharmacol 67(4):767–776
Bowne SJ, Liu Q, Sullivan LS et al (2006) Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration? Invest Ophthalmol Vis Sci 47(9):3754–3765
Zaza G, Cheok M, Krynetskaia N et al (2010) Thiopurine pathway. Pharmacogenet Genomics 20(9):573–574
Wielinga PR, Reid G, Challa EE et al (2002) Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol 62(6):1321–1331
Reid G, Wielinga P, Zelcer N et al (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 63(5):1094–1103
Adachi M, Reid G, Schuetz JD (2002) Therapeutic and biological importance of getting nucleotides out of cells: a case for the ABC transporters, MRP4 and 5. Adv Drug Deliv Rev 54(10):1333–1342
Leeder JS, Kearns GL, Spielberg SP, van den Anker J (2010) Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol 50(12):1377–1387
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167
Ganiere-Monteil C, Medard Y, Lejus C et al (2004) Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol 60(2):89–96
McLeod HL, Krynetski EY, Wilimas JA, Evans WE (1995) Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults. Pharmacogenetics 5(5):281–286
CIGNA Health Insurance. CIGNA Health Insurance Company: Dental, Medical, Life & Disability Benefits and Coverage http://www.cigna.com/customer_care/healthcare_professional/coverage_positions/medical/mm_0016_coveragepositioncriteria_monitoring_thiopurine_levels_in_ibd.pdf
Relling MV, Hancock ML, Rivera GK et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91(23):2001–2008
Hedeland RL, Hvidt K, Nersting J et al (2010) DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol 66(3):485–491
Karas Kuzelicki N, Milek M, Jazbec J, Mlinaric-Rascan I (2009) 5,10-Methylenetetrahydrofolate reductase (MTHFR) low activity genotypes reduce the risk of relapse-related acute lymphoblastic leukemia (ALL). Leuk Res 33(10):1344–1348
Dorababu P, Nagesh N, Linga VG et al (2011) Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia. Eur J Clin Pharmacol. doi:10.1007/s00228-011-1133-1
Schmidt LE, Dalhoff K (2002) Food-drug interactions. Drugs 62(10):1481–1502
Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE (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 USA 94(12):6444–6449
Nguyen CM, Mendes MAS, Ma JD (2011) Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. PLoS Curr 3:RRN1236
Wan Rosalina WR, Teh LK, Mohamad N et al (2011) Polymorphism of ITPA 94C > A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther. Available from: doi:10.1111/j.1365-2710.2011.01272.x
Hawwa AF, Millership JS, Collier PS et al (2008) Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol 66(4):517–528
Kudo M, Moteki T, Sasaki T et al (2008) Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet Genomics 18(3):243–251
Kang SS, Wong PW, Bock HG, Horwitz A, Grix A (1991) Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet 48(3):546–551
Karas-Kuzelicki N, Jazbec J, Milek M, Mlinaric-Rascan I (2009) Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients. Leukemia 23(5):971–974
van der Put NM, Gabreëls F, Stevens EM et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051
Ogino S, Wilson RB (2003) Genotype and haplotype distributions of MTHFR677C > T and 1298A > C single nucleotide polymorphisms: a meta-analysis. J Hum Genet 48(1):1–7
Roberts RL, Gearry RB, Barclay ML, Kennedy MA (2007) IMPDH1 promoter mutations in a patient exhibiting azathioprine resistance. Pharmacogenomics J 7(5):312–317
Wang J, Zeevi A, Webber S et al (2007) A novel variant L263F in human inosine 5’-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Pharmacogenet Genomics 17(4):283–290
Grinyó J, Vanrenterghem Y, Nashan B et al (2008) Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transpl Int 21(9):879–891
Janke D, Mehralivand S, Strand D et al (2008) 6-mercaptopurine and 9-(2-phosphonyl-methoxyethyl) adenine (PMEA) transport altered by two missense mutations in the drug transporter gene ABCC4. Hum Mutat 29(5):659–669
Ban H, Andoh A, Imaeda H et al (2010) The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease. J Gastroenterol 45(10):1014–1021
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Adam de Beaumais, T., Jacqz-Aigrain, E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 68, 1233–1242 (2012). https://doi.org/10.1007/s00228-012-1251-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-012-1251-4