Review article: Recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

Alimentary Pharmacology and Therapeutics

Volumn 43, Issue 8, 2016, Pages 863-883

  Moon, W ^a,b   Loftus, E V ^a  

^a MAYO CLINIC   (United States)

^b Kosin University   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

6 METHYLMERCAPTOPURINE; 6 TIOGUANINE; ALDEHYDE OXIDASE; AZATHIOPRINE; GLUTATHIONE TRANSFERASE; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; INOSINATE DEHYDROGENASE; INOSINE TRIPHOSPHATASE; MERCAPTOPURINE; PHOSPHATASE; THIOPURINE METHYLTRANSFERASE; UNCLASSIFIED DRUG; XANTHINE OXIDASE; 6-METHYLTHIOPURINE; 6-METHYLTHIOPURINE RIBONUCLEOSIDE-5'-PHOSPHATE; MERCAPTOPURINE RIBOSIDE; METHYLTRANSFERASE; NUCLEOTIDE;

ASTHENIA; BONE MARROW TOXICITY; CLINICAL PRACTICE; CORRELATION ANALYSIS; DRUG EFFICACY; DRUG SAFETY; EAST ASIAN; ENZYME ACTIVITY; ENZYME ANALYSIS; FLU LIKE SYNDROME; GASTRIC INTOLERANCE; GASTROINTESTINAL SYMPTOM; GENETIC VARIABILITY; HEADACHE; HUMAN; INFECTION; INFLAMMATORY BOWEL DISEASE; PATIENT MONITORING; PHARMACOGENETICS; PHARMACOKINETICS; PREDICTION; PRIORITY JOURNAL; PROTEIN MOTIF; RASH; REVIEW; SIDE EFFECT; TOXIC HEPATITIS; ANALOGS AND DERIVATIVES; INFLAMMATORY BOWEL DISEASES; METABOLISM;

6-MERCAPTOPURINE; AZATHIOPRINE; HUMANS; INFLAMMATORY BOWEL DISEASES; METHYLTRANSFERASES; PHARMACOGENETICS; THIOINOSINE; THIONUCLEOTIDES;

EID: 84975682990     PISSN: 02692813     EISSN: 13652036     Source Type: Journal    
DOI: 10.1111/apt.13559     Document Type: Review

References (229)

1. Dubinsky MC,. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol 2004; 2: 731-43.
2. Fraser AG, Orchard TR, Jewell DP,. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50: 485-9.
3. Elion GB, Hitchings GH, Vanderwerff H,. Antagonists of nucleic acid derivatives. VI. Purines. J Biol Chem 1951; 192: 505-18.
4. Dignass A, Van Assche G, Lindsay JO, et al,. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: current management. J Crohns Colitis 2010; 4: 28-62.
5. Pearson DC, May GR, Fick GH, Sutherland LR,. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995; 123: 132-42.
6. Adler DJ, Korelitz BI,. The therapeutic efficacy of 6-mercaptopurine in refractory ulcerative colitis. Am J Gastroenterol 1990; 85: 717-22.
7. Hawthorne AB, Logan RF, Hawkey CJ, et al,. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305: 20-2.
8. Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP,. Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery. Gut 2005; 54: 237-41.
9. Lowenberg M, Peppelenbosch M, Hommes D,. Biological therapy in the management of recent-onset Crohn's disease: why, when and how? Drugs 2006; 66: 1431-9.
10. Hyams JS, Markowitz JF,. Can we alter the natural history of Crohn disease in children? J Pediatr Gastroenterol Nutr 2005; 40: 262-72.
11. Schwab M, Schaffeler E, Marx C, et al,. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics 2002; 12: 429-36.
12. Ansari A, Hassan C, Duley J, et al,. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16: 1743-50.
13. Marinaki AM, Ansari A, Duley JA, et al,. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004; 14: 181-7.
14. Dubinsky MC, Yang H, Hassard PV, et al,. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002; 122: 904-15.
15. Chaparro M, Ordas I, Cabre E, et al,. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis 2013; 19: 1404-10.
16. Ansari A, Arenas M, Greenfield SM, et al,. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28: 973-83.
17. Jharap B, Seinen ML, de Boer NK, et al,. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010; 16: 1541-9.
18. Seinen ML, van Asseldonk DP, Mulder CJ, de Boer NK,. Dosing 6-thioguanine in inflammatory bowel disease: expert-based guidelines for daily practice. J Gastrointest Liver Dis 2010; 19: 291-4.
19. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS,. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302: 981-7.
20. Dubinsky MC, Lamothe S, Yang HY, et al,. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118: 705-13.
21. Gisbert JP, Linares PM, McNicholl AG, Mate J, Gomollon F,. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009; 30: 126-37.
22. Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C,. Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease. Cochrane Database Syst Rev 2000; (2): CD000545.
23. Timmer A, McDonald JW, Macdonald JK,. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; (1): CD000478.
24. Pearson DC, May GR, Fick G, Sutherland LR,. Azathioprine for maintaining remission of Crohn's disease. Cochrane Database Syst Rev 2000; (2): CD000067.
25. Sandborn WJ,. 6-MP metabolite levels: a potential guide to Crohn's disease therapy. Gastroenterology 1997; 113: 690-2.
26. Sandborn WJ,. Pharmacogenomics and IBD: TPMT and thiopurines. Inflamm Bowel Dis 2004; 10 (Suppl. 1): S35-7.
27. Gisbert JP, Gomollon F, Mate J, Pajares JM,. [Individualized therapy with azathioprine or 6-mercaptopurine by monitoring thiopurine methyl-transferase (TPMT) activity]. Rev Clin Esp 2002; 202: 555-62.
28. Gisbert JP, Luna M, Mate J, Gonzalez-Guijarro L, Cara C, Pajares JM,. Choice of azathioprine or 6-mercaptopurine dose based on thiopurine methyltransferase (TPMT) activity to avoid myelosuppression. A prospective study. Hepatogastroenterology 2006; 53: 399-404.
29. Eklund BI, Moberg M, Bergquist J, Mannervik B,. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol 2006; 70: 747-54.
30. Watanabe A, Hobara N, Nagashima H,. Demonstration of enzymatic activity converting azathioprine to 6-mercaptopurine. Acta Med Okayama 1978; 32: 173-9.
31. De MP, Beacham LM 3rd, Creagh TH, Elion GB,. The metabolic fate of the methylnitroimidazole moiety of azathioprine in the rat. J Pharmacol Exp Ther 1973; 187: 588-601.
32. Kurtovic S, Grehn L, Karlsson A, Hellman U, Mannervik B,. Glutathione transferase activity with a novel substrate mimics the activation of the prodrug azathioprine. Anal Biochem 2008; 375: 339-44.
33. Bowen DG, Selby WS,. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45: 1810-3.
34. Tiede I, Fritz G, Strand S, et al,. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4 + T lymphocytes. J Clin Invest 2003; 111: 1133-45.
35. Derijks LJ, Gilissen LP, Hooymans PM, Hommes DW,. Review article: thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther 2006; 24: 715-29.
36. Al Hadithy AF, de Boer NK, Derijks LJ, Escher JC, Mulder CJ, Brouwers JR,. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 2005; 37: 282-97.
37. Sahasranaman S, Howard D, Roy S,. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64: 753-67.
38. Fairchild CR, Maybaum J, Kennedy KA,. Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol 1986; 35: 3533-41.
39. Lennard L,. TPMT in the treatment of Crohn's disease with azathioprine. Gut 2002; 51: 143-6.
40. Poppe D, Tiede I, Fritz G, et al,. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 2006; 176: 640-51.
41. Neurath MF, Kiesslich R, Teichgraber U, et al,. 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hepatol 2005; 3: 1007-14.
42. Karner S, Shi S, Fischer C, et al,. Determination of 6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes: novel targets for thiopurine therapy? Ther Drug Monit 2010; 32: 119-28.
43. Thomas CW, Myhre GM, Tschumper R, et al,. Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines. J Pharmacol Exp Ther 2005; 312: 537-45.
44. Dervieux T, Blanco JG, Krynetski EY, Vanin EF, Roussel MF, Relling MV,. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res 2001; 61: 5810-6.
45. Coulthard SA, Hogarth LA, Little M, et al,. The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs. Mol Pharmacol 2002; 62: 102-9.
46. Cara CJ, Pena AS, Sans M, et al,. Reviewing the mechanism of action of thiopurine drugs: towards a new paradigm in clinical practice. Med Sci Monit 2004; 10: RA247-54.
47. Colombel JF, Ferrari N, Debuysere H, et al,. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000; 118: 1025-30.
48. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM,. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 1987; 41: 18-25.
49. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM,. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 1990; 336: 225-9.
50. Schutz E, Gummert J, Armstrong VW, Mohr FW, Oellerich M,. Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. Eur J Clin Chem Clin Biochem 1996; 34: 199-205.
51. Hindorf U, Lindqvist M, Peterson C, et al,. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 2006; 55: 1423-31.
52. Seidman EG,. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord 2003; 3 (Suppl. 1): S30-8.
53. Cuffari C, Theoret Y, Latour S, Seidman G,. 6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. Gut 1996; 39: 401-6.
54. Gilissen LP, Derijks LJ, Bos LP, et al,. Some cases demonstrating the clinical usefulness of therapeutic drug monitoring in thiopurine-treated inflammatory bowel disease patients. Eur J Gastroenterol Hepatol 2004; 16: 705-10.
55. Nygaard U, Toft N, Schmiegelow K,. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther 2004; 75: 274-81.
56. Weinshilboum RM, Sladek SL,. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980; 32: 651-62.
57. Otterness D, Szumlanski C, Lennard L, et al,. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997; 62: 60-73.
58. Garat A, Cauffiez C, Renault N, et al,. Characterisation of novel defective thiopurine S-methyltransferase allelic variants. Biochem Pharmacol 2008; 76: 404-15.
59. Ujiie S, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M,. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT∗2-∗24). Pharmacogenet Genomics 2008; 18: 887-93.
60. Kham SK, Soh CK, Aw DC, Yeoh AE,. TPMT∗26 (208F->L), a novel mutation detected in a Chinese. Br J Clin Pharmacol 2009; 68: 120-3.
61. Appell ML, Wennerstrand P, Peterson C, Hertervig E, Martensson LG,. Characterization of a novel sequence variant, TPMT∗28, in the human thiopurine methyltransferase gene. Pharmacogenet Genomics 2010; 20: 700-7.
62. Lee CK, Loh TP, Wong ST, et al,. Detection of a novel single nucleotide polymorphism of the human thiopurine s-methyltransferase gene in a Chinese individual. Drug Metab Pharmacokinet 2012; 27: 559-61.
63. Spire-Vayron de la Moureyre C, Debuysere 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: 879-87.
64. Lindqvist M, Skoglund K, Karlgren A, et al,. Explaining TPMT genotype/phenotype discrepancy by haplotyping of TPMT∗3A and identification of a novel sequence variant, TPMT∗23. Pharmacogenet Genomics 2007; 17: 891-5.
65. Booth RA, Ansari MT, Loit E, et al,. Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med 2011; 154: 814-23, W-295-8.
66. Krynetski EY, Evans WE,. Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanisms and clinical importance. Pharmacology 2000; 61: 136-46.
67. Cheung ST, Allan RN,. Mistaken identity: misclassification of TPMT phenotype following blood transfusion. Eur J Gastroenterol Hepatol 2003; 15: 1245-7.
68. Schwab M, Schaeffeler E, Marx C, Zanger U, Aulitzky W, Eichelbaum M,. Shortcoming in the diagnosis of TPMT deficiency in a patient with Crohn's disease using phenotyping only. Gastroenterology 2001; 121: 498-9.
69. 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: 949-53.
70. 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.
71. Yates CR, Krynetski EY, Loennechen T, et al,. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126: 608-14.
72. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE,. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet 1999; 8: 371-6.
73. Vuchetich JP, Weinshilboum RM, Price RA,. Segregation analysis of human red blood cell thiopurine methyltransferase activity. Genet Epidemiol 1995; 12: 1-11.
74. Szumlanski C, Otterness D, Her C, et al,. Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. DNA Cell Biol 1996; 15: 17-30.
75. Roberts RL, Gearry RB, Bland MV, et al,. Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. Pharmacogenet Genomics 2008; 18: 434-8.
76. Yan L, Zhang S, Eiff B, et al,. Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clin Pharmacol Ther 2000; 68: 210-9.
77. Spire-Vayron de la Moureyre C, Debuysere H, Sabbagh N, et al,. Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat 1998; 12: 177-85.
78. Remy CN,. Metabolism of thiopyrimidines and thiopurines. S-Methylation with S-adenosylmethionine transmethylase and catabolism in mammalian tissues. J Biol Chem 1963; 238: 1078-84.
79. Deininger M, Szumlanski CL, Otterness DM, Van Loon J, Ferber W, Weinshilboum RM,. Purine substrates for human thiopurine methyltransferase. Biochem Pharmacol 1994; 48: 2135-8.
80. Schwahn B, Rozen R,. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics 2001; 1: 189-201.
81. Karas-Kuzelicki N, Milek M, Mlinaric-Rascan I,. MTHFR and TYMS genotypes influence TPMT activity and its differential modulation in males and females. Clin Biochem 2010; 43: 37-42.
82. Breen DP, Marinaki AM, Arenas M, Hayes PC,. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Liver Transpl 2005; 11: 826-33.
83. Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM,. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics 1992; 2: 148-59.
84. Dervieux T, Hancock ML, Pui CH, et al,. Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia. Clin Pharmacol Ther 2003; 73: 506-16.
85. Brouwer C, De Abreu RA, Keizer-Garritsen JJ, et al,. Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects. Eur J Cancer 2005; 41: 613-23.
86. Ford L, Graham V, Berg J,. Whole-blood thiopurine S-methyltransferase activity with genotype concordance: a new, simplified phenotyping assay. Ann Clin Biochem 2006; 43 (Pt 5): 354-60.
87. Winter JW, Gaffney D, Shapiro D, et al,. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2007; 25: 1069-77.
88. Relling MV, Gardner EE, Sandborn WJ, et al,. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89: 387-91.
89. Arenas M, Marinaki A, Ansari A, Sanderson J,. Typing TPMT and ITPase to detect azathioprine toxicity. Personalized Med 2006; 3: 45-59.
90. Sanderson J, Ansari A, Marinaki T, Duley J,. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004; 41 (Pt 4): 294-302.
91. Anstey AV, Wakelin S, Reynolds NJ,. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol 2004; 151: 1123-32.
92. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL,. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 1999; 8: 367-70.
93. Gurwitz D, Rodriguez-Antona C, Payne K, et al,. Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain. Eur J Hum Genet 2009; 17: 991-8.
94. Fargher EA, Tricker K, Newman W, et al,. Current use of pharmacogenetic testing: a national survey of thiopurine methyltransferase testing prior to azathioprine prescription. J Clin Pharm Ther 2007; 32: 187-95.
95. Arico M, Baruchel A, Bertrand Y, et al,. The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29-30, 2005. Leukemia 2005; 19: 1145-52.
96. Schmiegelow K, Forestier E, Kristinsson J, et al,. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 2009; 23: 557-64.
97. Relling MV, Altman RB, Goetz MP, Evans WE,. Clinical implementation of pharmacogenomics: overcoming genetic exceptionalism. Lancet Oncol 2010; 11: 507-9.
98. Burnett HF, Tanoshima R, Chandranipapongse W, Madadi P, Ito S, Ungar WJ,. Testing for thiopurine methyltransferase status for safe and effective thiopurine administration: a systematic review of clinical guidance documents. Pharmacogenomics J 2014; 14: 493-502.
99. Mosli MH, Sandborn WJ, Kim RB, Khanna R, Al-Judaibi B, Feagan BG,. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol 2014; 109: 994-1004.
100. Gisbert JP, Nino P, Rodrigo L, Cara C, Guijarro LG,. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol 2006; 101: 2769-76.
101. Gisbert JP, Gomollon F,. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol 2008; 103: 1783-800.
102. Gardiner SJ, Gearry RB, Barclay ML, Begg EJ,. Two cases of thiopurine methyltransferase (TPMT) deficiency-a lucky save and a near miss with azathioprine. Br J Clin Pharmacol 2006; 62: 473-6.
103. Zelinkova Z, Derijks LJ, Stokkers PC, et al,. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 2006; 4: 44-9.
104. Campbell S, Kingstone K, Ghosh S,. Relevance of thiopurine methyltransferase activity in inflammatory bowel disease patients maintained on low-dose azathioprine. Aliment Pharmacol Ther 2002; 16: 389-98.
105. Evans WE,. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 2004; 26: 186-91.
106. Lennard L,. Clinical implications of thiopurine methyltransferase-optimization of drug dosage and potential drug interactions. Ther Drug Monit 1998; 20: 527-31.
107. Coenen MJ, de Jong DJ, van Marrewijk CJ, et al,. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 2015; 149: 907-17.
108. Dewit O, Moreels T, Baert F, et al,. Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. Clin Biochem 2011; 44: 1062-6.
109. Collie-Duguid ES, Pritchard SC, Powrie RH, et al,. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999; 9: 37-42.
110. Engen RM, Marsh S, Van Booven DJ, McLeod HL,. Ethnic differences in pharmacogenetically relevant genes. Curr Drug Targets 2006; 7: 1641-8.
111. Higgs JE, Payne K, Roberts C, Newman WG,. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010; 11: 177-88.
112. Ford LT, Berg JD,. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol 2010; 63: 288-95.
113. Relling MV, Hancock ML, Rivera GK, et al,. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999; 91: 2001-8.
114. Stocco G, Cheok MH, Crews KR, et al,. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 2009; 85: 164-72.
115. Evans WE, Hon YY, Bomgaars L, et al,. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293-301.
116. Dubinsky MC, Reyes E, Ofman J, Chiou CF, Wade S, Sandborn WJ,. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol 2005; 100: 2239-47.
117. Ding L, Zhang FB, Liu H, et al,. 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 2012; 18: 63-73.
118. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W,. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130: 935-9.
119. Winter J, Walker A, Shapiro D, Gaffney D, Spooner RJ, Mills PR,. Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20: 593-9.
120. Lewis JD, Abramson O, Pascua M, et al,. Timing of myelosuppression during thiopurine therapy for inflammatory bowel disease: implications for monitoring recommendations. Clin Gastroenterol Hepatol 2009; 7: 1195-201; quiz 1141-2.
121. Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM,. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol 2004; 2: 410-7.
122. Kwan LY, Devlin SM, Mirocha JM, Papadakis KA,. Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease. Dig Liver Dis 2008; 40: 425-32.
123. Levesque BG, Loftus EV Jr,. Initiating azathioprine for Crohn's disease. Clin Gastroenterol Hepatol 2012; 10: 460-5.
124. Achkar JP, Stevens T, Easley K, Brzezinski A, Seidner D, Lashner B,. Indicators of clinical response to treatment with six-mercaptopurine or azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 2004; 10: 339-45.
125. Belaiche J, Desager JP, Horsmans Y, Louis E,. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol 2001; 36: 71-6.
126. Goldenberg BA, Rawsthorne P, Bernstein CN,. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol 2004; 99: 1744-8.
127. Cuffari C, Hunt S, Bayless T,. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48: 642-6.
128. Gupta P, Gokhale R, Kirschner BS,. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2001; 33: 450-4.
129. Deshpande AR, Abreu MT,. Optimizing therapy with 6-mercaptopurine and azathioprine: to measure or not to measure? Therap Adv Gastroenterol 2010; 3: 275-9.
130. Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X,. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2012; 35: 15-36.
131. Lowry PW, Franklin CL, Weaver AL, et al,. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut 2001; 49: 665-70.
132. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD,. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006; 130: 1047-53.
133. Gisbert JP, Gonzalez-Lama Y, Mate J,. [Monitoring of thiopurine methyltransferase and thiopurine metabolites to optimize azathioprine therapy in inflammatory bowel disease]. Gastroenterol Hepatol 2006; 29: 568-83.
134. Reinshagen M, Schutz E, Armstrong VW, et al,. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active crohn disease: results from a randomized, controlled, open trial. Clin Chem 2007; 53: 1306-14.
135. Dubinsky MC, Vasiliauskas EA, Singh H, et al,. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003; 125: 298-303.
136. Stoneham S, Lennard L, Coen P, Lilleyman J, Saha V,. Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 123: 100-2.
137. Hanai H, Iida T, Takeuchi K, et al,. Thiopurine maintenance therapy for ulcerative colitis: the clinical significance of monitoring 6-thioguanine nucleotide. Inflamm Bowel Dis 2010; 16: 1376-81.
138. Wright S, Sanders DS, Lobo AJ, Lennard L,. Clinical significance of azathioprine active metabolite concentrations in inflammatory bowel disease. Gut 2004; 53: 1123-8.
139. Lennard L,. Assay of 6-thioinosinic acid and 6-thioguanine nucleotides, active metabolites of 6-mercaptopurine, in human red blood cells. J Chromatogr 1987; 423: 169-78.
140. Vikingsson S, Carlsson B, Almer SH, Peterson C,. Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured? Ther Drug Monit 2009; 31: 345-50.
141. Sheffield LJ, Irving P, Gupta A, et al,. Thiopurine methyltransferase and thiopurine metabolite testing in patients with inflammatory bowel disease who are taking thiopurine drugs. Pharmacogenomics 2009; 10: 1091-9.
142. Hande S, Wilson-Rich N, Bousvaros A, et al,. 5-aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine. Inflamm Bowel Dis 2006; 12: 251-7.
143. Kopylov U, Amre D, Theoret Y, Deslandres C, Seidman EG,. Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2014; 59: 511-5.
144. Shaye OA, Yadegari M, Abreu MT, et al,. Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients. Am J Gastroenterol 2007; 102: 2488-94.
145. Rashidi MR, Beedham C, Smith JS, Davaran S,. In vitro study of 6-mercaptopurine oxidation catalysed by aldehyde oxidase and xanthine oxidase. Drug Metab Pharmacokinet 2007; 22: 299-306.
146. Derijks LJ, Wong DR,. Pharmacogenetics of thiopurines in inflammatory bowel disease. Curr Pharm Des 2010; 16: 145-54.
147. Parks DA, Granger DN,. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl 1986; 548: 87-99.
148. Huh K, Yamamoto I, Gohda E, Iwata H,. Tissue distribution and characteristics of xanthine oxidase and allopurinol oxidizing enzyme. Jpn J Pharmacol 1976; 26: 719-24.
149. Elion GB,. Significance of azathioprine metabolites. Proc R Soc Med 1972; 65: 257-60.
150. Ansari A, Aslam Z, De Sica A, et al,. Influence of xanthine oxidase on thiopurine metabolism in Crohn's disease. Aliment Pharmacol Ther 2008; 28: 749-57.
151. Krenitsky TA, Neil SM, Elion GB, Hitchings GH,. A comparison of the specificities of xanthine oxidase and aldehyde oxidase. Arch Biochem Biophys 1972; 150: 585-99.
152. Guerciolini R, Szumlanski C, Weinshilboum RM,. Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther 1991; 50: 663-72.
153. Relling MV, Lin JS, Ayers GD, Evans WE,. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther 1992; 52: 643-58.
154. Kudo M, Moteki T, Sasaki T, et al,. Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet Genomics 2008; 18: 243-51.
155. Serre-Debeauvais F, Bayle F, Amirou M, et al,. [Hematotoxicity caused by azathioprine genetically determined and aggravated by xanthine oxidase deficiency in a patient following renal transplantation]. Presse Med 1995; 24: 987-8.
156. Schwarz G,. Molybdenum cofactor biosynthesis and deficiency. Cell Mol Life Sci 2005; 62: 2792-810.
157. Smith MA, Marinaki AM, Arenas M, et al,. Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease. Aliment Pharmacol Ther 2009; 30: 375-84.
158. Per H, Gumus H, Ichida K, Caglayan O, Kumandas S,. Molybdenum cofactor deficiency: clinical features in a Turkish patient. Brain Dev 2007; 29: 365-8.
159. Peretz H, Naamati MS, Levartovsky D, et al,. Identification and characterization of the first mutation (Arg776Cys) in the C-terminal domain of the Human Molybdenum Cofactor Sulfurase (HMCS) associated with type II classical xanthinuria. Mol Genet Metab 2007; 91: 23-9.
160. Chocair P, Duley J, Simmonds HA, et al,. Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen. Lancet 1993; 342: 83-4.
161. Sparrow MP, Hande SA, Friedman S, et al,. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005; 22: 441-6.
162. Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB,. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007; 5: 209-14.
163. Ihekweazu FD, Kellermayer R,. Allopurinol: a useful adjunct to thiopurine therapy for pediatric ulcerative colitis in the biologic era. J Pediatr Gastroenterol Nutr 2014; 59: 22-4.
164. Rahhal RM, Bishop WP,. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008; 14: 1678-82.
165. Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T,. Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate. J Biochem 2007; 141: 513-24.
166. Harrison R,. Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 2002; 33: 774-97.
167. Chao J, Terkeltaub R,. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 2009; 11: 135-40.
168. Seinen ML, de Boer NK, Smid K, et al,. Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series. Nucleosides, Nucleotides Nucleic Acids 2011; 30: 1085-90.
169. Duley JA, Chocair PR, Florin TH,. Observations on the use of allopurinol in combination with azathioprine or mercaptopurine. Aliment Pharmacol Ther 2005; 22: 1161-2.
170. Blaker PA, Arenas-Hernandez M, Smith MA, et al,. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol 2013; 86: 539-47.
171. Ansari A, Patel N, Sanderson J, O'Donohue J, Duley JA, Florin TH,. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31: 640-7.
172. Hoentjen F, Seinen ML, Hanauer SB, et al,. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis 2013; 19: 363-9.
173. Ansari A, Elliott T, Baburajan B, et al,. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28: 734-41.
174. Gardiner SJ, Gearry RB, Burt MJ, et al,. Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio. J Gastroenterol Hepatol 2011; 26: 49-54.
175. Leung Y, Sparrow MP, Schwartz M, Hanauer SB,. Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. J Crohns Colitis 2009; 3: 162-7.
176. Witte TN, Ginsberg AL,. Use of allopurinol with low-dose 6-mercaptopurine in inflammatory bowel disease to achieve optimal active metabolite levels: a review of four cases and the literature. Can J Gastroenterol 2008; 22: 181-5.
177. Gerich ME, Quiros JA, Marcin JP, Tennyson L, Henthorn M, Prindiville TP,. A prospective evaluation of the impact of allopurinol in pediatric and adult IBD patients with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine. J Crohns Colitis 2010; 4: 546-52.
178. Stamp LK, Taylor WJ, Jones PB, et al,. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum 2012; 64: 2529-36.
179. Keenan RT,. Safety of urate-lowering therapies: managing the risks to gain the benefits. Rheum Dis Clin North Am 2012; 38: 663-80.
180. Lang PG Jr,. Severe hypersensitivity reactions to allopurinol. South Med J 1979; 72: 1361-8.
181. Snow JL, Gibson LE,. A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients. J Am Acad Dermatol 1995; 32: 114-6.
182. Min MX, Weinberg DI, McCabe RP,. Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use. J Clin Pharm Ther 2014; 39: 107-11.
183. Seinen ML, de Boer NK, van Hoorn ME, van Bodegraven AA, Bouma G,. Safe use of allopurinol and low-dose mercaptopurine therapy during pregnancy in an ulcerative colitis patient. Inflamm Bowel Dis 2013; 19: E37.
184. Fazal MW, Doogue MP, Leong RW, Bampton PA, Andrews JM,. Allopurinol use in pregnancy in three women with inflammatory bowel disease: safety and outcomes: a case series. BMC Gastroenterol 2013; 13: 172.
185. Sheikh M, Nelson-Piercy C, Duley J, Florin T, Ansari A,. Successful Pregnancies with Thiopurine-Allopurinol Co-Therapy for Inflammatory Bowel Disease. J Crohns Colitis 2015; 9: 680-4.
186. Choughule KV, Barnaba C, Joswig-Jones CA, Jones JP,. In vitro oxidative metabolism of 6-mercaptopurine in human liver: insights into the role of the molybdoflavoenzymes aldehyde oxidase, xanthine oxidase, and xanthine dehydrogenase. Drug Metab Dispos 2014; 42: 1334-40.
187. Kurzawski M, Dziewanowski K, Safranow K, Drozdzik M,. Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine. Ther Drug Monit 2012; 34: 266-74.
188. Galperin MY, Moroz OV, Wilson KS, Murzin AG,. House cleaning, a part of good housekeeping. Mol Microbiol 2006; 59: 5-19.
189. Holmes SL, Turner BM, Hirschhorn K,. Human inosine triphosphatase: catalytic properties and population studies. Clin Chim Acta 1979; 97: 143-53.
190. Lin S, McLennan AG, Ying K, et al,. Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene. J Biol Chem 2001; 276: 18695-701.
191. Arenas M, Duley J, Sumi S, Sanderson J, Marinaki A,. The ITPA c.94C>A and g.IVS2 + 21A>C sequence variants contribute to missplicing of the ITPA gene. Biochim Biophys Acta 2007; 1772: 96-102.
192. Sumi S, Marinaki AM, Arenas M, et al,. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002; 111: 360-7.
193. Maeda T, Sumi S, Ueta A, et al,. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population. Mol Genet Metab 2005; 85: 271-9.
194. Atanasova S, Shipkova M, Svinarov D, et al,. Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6. Ther Drug Monit 2007; 29: 6-10.
195. Shipkova M, Lorenz K, Oellerich M, Wieland E, von Ahsen N,. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Clin Chem 2006; 52: 240-7.
196. Kudo M, Saito Y, Sasaki T, et al,. Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug Metab Pharmacokinet 2009; 24: 557-64.
197. Marsh S, King CR, Ahluwalia R, McLeod HL,. Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet 2004; 49: 579-81.
198. Uchiyama K, Nakamura M, Kubota T, Yamane T, Fujise K, Tajiri H,. Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment. J Gastroenterol 2009; 44: 197-203.
199. Xiong H, Xin HW, Wu XC, Li Q, Xiong L, Yu AR,. Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients. Fundam Clin Pharmacol 2010; 24: 393-400.
200. Hawwa AF, Millership JS, Collier PS, et al,. Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine. Br J Clin Pharmacol 2008; 66: 517-28.
201. Gearry RB, Roberts RL, Barclay ML, Kennedy MA,. Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 2004; 14: 779-81.
202. Kim H, Kang HJ, Kim HJ, et al,. Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism. PLoS ONE 2012; 7: e45558.
203. Van Dieren JM, Hansen BE, Kuipers EJ, Nieuwenhuis EE, Van der Woude CJ,. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2007; 26: 643-52.
204. Shipkova M, Franz J, Abe M, Klett C, Wieland E, Andus T,. Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. Ther Drug Monit 2011; 33: 321-8.
205. Elion GB,. The purine path to chemotherapy. Science 1989; 244: 41-7.
206. Hobara N, Watanabe A,. Impaired metabolism of azathioprine in carbon tetrachloride-injured rats. Hepatogastroenterology 1981; 28: 192-4.
207. Kaplowitz N,. Enzymatic thiolysis of azathioprine in vitro. Biochem Pharmacol 1976; 25: 2421-6.
208. Kaplowitz N, Kuhlenkamp J,. Inhibition of hepatic metabolism of azathioprine in vivo. Gastroenterology 1978; 74: 90-2.
209. Zhang W, Moden O, Mannervik B,. Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine. Chem Biol Interact 2010; 186: 110-7.
210. Kraus P, Kloft HD,. The activity of glutathione-S-transferases in various organs of the rat. Enzyme 1980; 25: 158-60.
211. Rahman SH, Ibrahim K, Larvin M, Kingsnorth A, McMahon MJ,. Association of antioxidant enzyme gene polymorphisms and glutathione status with severe acute pancreatitis. Gastroenterology 2004; 126: 1312-22.
212. Stocco G, Pelin M, Franca R, et al,. Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase? World J Gastroenterol 2014; 20: 3534-41.
213. Townsend DM, Tew KD,. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 2003; 22: 7369-75.
214. Stocco G, Martelossi S, Barabino A, et al,. Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 57-64.
215. Stocco G, Cuzzoni E, De Iudicibus S, et al,. Deletion of glutathione-s-transferase m1 reduces azathioprine metabolite concentrations in young patients with inflammatory bowel disease. J Clin Gastroenterol 2014; 48: 43-51.
216. Seegmiller JE, Rosenbloom FM, Kelley WN,. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 1967; 155: 1682-4.
217. Kelley WN, Rosenbloom FM, Henderson JF, Seegmiller JE,. A specific enzyme defect in gout associated with overproduction of uric acid. Proc Natl Acad Sci USA 1967; 57: 1735-9.
218. Wu CH, Lai HM, Yang MC, et al,. Identification of a new single-nucleotide mutation on the hypoxanthine-guanine phosphoribosyltransferase gene from 983 cases with gout in Taiwan. J Rheumatol 2007; 34: 794-7.
219. Wilson JM, Young AB, Kelley WN,. Hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular basis of the clinical syndromes. N Engl J Med 1983; 309: 900-10.
220. Elion GB,. Symposium on immunosuppressive drugs. Biochemistry and pharmacology of purine analogues. Fed Proc 1967; 26: 898-904.
221. Haglund S, Taipalensuu J, Peterson C, Almer S,. IMPDH activity in thiopurine-treated patients with inflammatory bowel disease-relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol 2008; 65: 69-77.
222. Kumagai K, Hiyama K, Ishioka S, et al,. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics 2001; 11: 275-8.
223. Cao Q, Zhu Q, Shang Y, Gao M, Si J,. Thiopurine methyltransferase gene polymorphisms in Chinese patients with inflammatory bowel disease. Digestion 2009; 79: 58-63.
224. Kim JH, Cheon JH, Hong SS, et al,. Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol 2010; 44: e242-8.
225. Takatsu N, Matsui T, Murakami Y, et al,. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009; 24: 1258-64.
226. Yang SK, Hong M, Baek J, et al,. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014; 46: 1017-20.
227. Yang JJ, Landier W, Yang W, et al,. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 2015; 33: 1235-42.
228. Tanaka Y, Kato M, Hasegawa D, et al,. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol 2015; 171: 109-15.
229. Takagi Y, Setoyama D, Ito R, Kamiya H, Yamagata Y, Sekiguchi M,. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem 2012; 287: 21541-9.