Thiopurine Methyltransferase Genetic Polymorphisms and Activity and Metabolic Products of Azathioprine in Patients with Inflammatory Bowel Disease

Author(s): Paria Pashazadeh, Abdoljalal Marjani*, Jahanbakhash Asadi, Masoud Khoshnia.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. There is a correlation between thiopurine drug metabolism, response, and toxicity and genetic polymorphism of TPMT. The aim of this study is to assess TPMT genetic polymorphisms activity and metabolic products of AZA in patients with IBD.

Methods: Blood samples were obtained from 50 IBD unrelated patients from a private laboratory. We used polymerase chain reaction-restriction length polymorphism (PCR-RFLP) and allele-specific PCRbased assays to determine the TPMT gene for the different variants. A high-performance liquid chromatography system (HPLC) was carried out to determine the whole blood 6-TGN concentration. Determination of serum TMPT activity was done by ELISA kit.

Results: In IBD patients, 46/50 (92%) subjects were homozygous for the wild-type allele (TPMT*1/*1). Mutant TPMT*1/*2 and TPMT*1/*3C alleles were found in 4/46 (8%) and 3/47 (6%) of IBD patients, respectively. TPMT*1/*3B variant was not detected in any of the IBD patients. TPMT enzyme activity was higher in wild-type than that mutant variants TPMT*1/*2 and TPMT*1/*3C, suggesting that there are statistically significant differences between 6-TG levels and polymorphisms of TMPT enzyme. 6-TG levels significantly increased in IBD patients mutant variants TPMT*1/*2 and TPMT*1/*3C.

Conclusions: Our results showed that TPMT polymorphisms are associated with 6-TGN levels in patients using AZA. This study suggests that AZA dosage may be determined according to the high or low prevalence of a TPMT genotype. Moreover, the results present the determination of metabolite for assessing possible safe effective dosage of the drug.

Keywords: TPMT, gene, azathioprine, polymorphisms, IBD, Crohn’s disease, ulcerative colitis.

[1]
Sandler, R.S. Epidemiology of inflammatory bowel disease. Inflammatory Bowel Disease. From Bench to Bedside; Targan, S.R; Shanahan, F., Ed.; Williams & Wilkins: Baltimore, 1994, pp. 5-31.
[2]
Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet, 2015, 386(9995), 743-800.
[3]
Murray, C.J.; Barber, R.M.; Foreman, K.J.; Abbasoglu Ozgoren, A.; Abd-Allah, F.; Abera, S.F.; Aboyans, V.; Abraham, J.P.; Abubakar, I.; Abu-Raddad, L.J.; Abu-Rmeileh, N.M.; Achoki, T.; Ackerman, I.N.; Ademi, Z.; Adou, A.K.; Adsuar, J.C.; Afshin, A.; Agardh, E.E.; Alam, S.S.; Alasfoor, D.; Albittar, M.I.; Alegretti, M.A.; Alemu, Z.A.; Alfonso-Cristancho, R.; Alhabib, S.; Ali, R.; Alla, F.; Allebeck, P.; Almazroa, M.A.; Alsharif, U.; Alvarez, E.; Alvis-Guzman, N.; Amare, A.T.; Ameh, E.A.; Amini, H.; Ammar, W.; Anderson, H.R.; Anderson, B.O.; Antonio, C.A.; Anwari, P.; Arnlöv, J.; Arsic Arsenijevic, V.S.; Artaman, A.; Asghar, R.J.; Assadi, R.; Atkins, L.S.; Avila, M.A.; Awuah, B.; Bachman, V.F.; Badawi, A.; Bahit, M.C.; Balakrishnan, K.; Banerjee, A.; Barker-Collo, S.L.; Barquera, S.; Barregard, L.; Barrero, L.H.; Basu, A.; Basu, S.; Basulaiman, M.O.; Beardsley, J.; Bedi, N.; Beghi, E.; Bekele, T.; Bell, M.L.; Benjet, C.; Bennett, D.A.; Bensenor, I.M.; Benzian, H.; Bernabé, E.; Bertozzi-Villa, A.; Beyene, T.J.; Bhala, N.; Bhalla, A.; Bhutta, Z.A.; Bienhoff, K.; Bikbov, B.; Biryukov, S.; Blore, J.D.; Blosser, C.D.; Blyth, F.M.; Bohensky, M.A.; Bolliger, I.W.; Bora Başara, B.; Bornstein, N.M.; Bose, D.; Boufous, S.; Bourne, R.R.; Boyers, L.N.; Brainin, M.; Brayne, C.E.; Brazinova, A.; Breitborde, N.J.; Brenner, H.; Briggs, A.D.; Brooks, P.M.; Brown, J.C.; Brugha, T.S.; Buchbinder, R.; Buckle, G.C.; Budke, C.M.; Bulchis, A.; Bulloch, A.G.; Campos-Nonato, I.R.; Carabin, H.; Carapetis, J.R.; Cárdenas, R.; Carpenter, D.O.; Caso, V.; Castañeda-Orjuela, C.A.; Castro, R.E.; Catalá-López, F.; Cavalleri, F.; Çavlin, A.; Chadha, V.K.; Chang, J.C.; Charlson, F.J.; Chen, H.; Chen, W.; Chiang, P.P.; Chimed-Ochir, O.; Chowdhury, R.; Christensen, H.; Christophi, C.A.; Cirillo, M.; Coates, M.M.; Coffeng, L.E.; Coggeshall, M.S.; Colistro, V.; Colquhoun, S.M.; Cooke, G.S.; Cooper, C.; Cooper, L.T.; Coppola, L.M.; Cortinovis, M.; Criqui, M.H.; Crump, J.A.; Cuevas-Nasu, L.; Danawi, H.; Dandona, L.; Dandona, R.; Dansereau, E.; Dargan, P.I.; Davey, G.; Davis, A.; Davitoiu, D.V.; Dayama, A.; De Leo, D.; Degenhardt, L.; Del Pozo-Cruz, B.; Dellavalle, R.P.; Deribe, K.; Derrett, S.; Des Jarlais, D.C.; Dessalegn, M.; Dharmaratne, S.D.; Dherani, M.K.; Diaz-Torné, C.; Dicker, D.; Ding, E.L.; Dokova, K.; Dorsey, E.R.; Driscoll, T.R.; Duan, L.; Duber, H.C.; Ebel, B.E.; Edmond, K.M.; Elshrek, Y.M.; Endres, M.; Ermakov, S.P.; Erskine, H.E.; Eshrati, B.; Esteghamati, A.; Estep, K.; Faraon, E.J.; Farzadfar, F.; Fay, D.F.; Feigin, V.L.; Felson, D.T.; Fereshtehnejad, S.M.; Fernandes, J.G.; Ferrari, A.J.; Fitzmaurice, C.; Flaxman, A.D.; Fleming, T.D.; Foigt, N.; Forouzanfar, M.H.; Fowkes, F.G.; Paleo, U.F.; Franklin, R.C.; Fürst, T.; Gabbe, B.; Gaffikin, L.; Gankpé, F.G.; Geleijnse, J.M.; Gessner, B.D.; Gething, P.; Gibney, K.B.; Giroud, M.; Giussani, G.; Gomez Dantes, H.; Gona, P.; González-Medina, D.; Gosselin, R.A.; Gotay, C.C.; Goto, A.; Gouda, H.N.; Graetz, N.; Gugnani, H.C.; Gupta, R.; Gupta, R.; Gutiérrez, R.A.; Haagsma, J.; Hafezi-Nejad, N.; Hagan, H.; Halasa, Y.A.; Hamadeh, R.R.; Hamavid, H.; Hammami, M.; Hancock, J.; Hankey, G.J.; Hansen, G.M.; Hao, Y.; Harb, H.L.; Haro, J.M.; Havmoeller, R.; Hay, S.I.; Hay, R.J.; Heredia-Pi, I.B.; Heuton, K.R.; Heydarpour, P.; Higashi, H.; Hijar, M.; Hoek, H.W.; Hoffman, H.J.; Hosgood, H.D.; Hossain, M.; Hotez, P.J.; Hoy, D.G.; Hsairi, M.; Hu, G.; Huang, C.; Huang, J.J.; Husseini, A.; Huynh, C.; Iannarone, M.L.; Iburg, K.M.; Innos, K.; Inoue, M.; Islami, F.; Jacobsen, K.H.; Jarvis, D.L.; Jassal, S.K.; Jee, S.H.; Jeemon, P.; Jensen, P.N.; Jha, V.; Jiang, G.; Jiang, Y.; Jonas, J.B.; Juel, K.; Kan, H.; Karch, A.; Karema, C.K.; Karimkhani, C.; Karthikeyan, G.; Kassebaum, N.J.; Kaul, A.; Kawakami, N.; Kazanjan, K.; Kemp, A.H.; Kengne, A.P.; Keren, A.; Khader, Y.S.; Khalifa, S.E.; Khan, E.A.; Khan, G.; Khang, Y.H.; Kieling, C.; Kim, D.; Kim, S.; Kim, Y.; Kinfu, Y.; Kinge, J.M.; Kivipelto, M.; Knibbs, L.D.; Knudsen, A.K.; Kokubo, Y.; Kosen, S.; Krishnaswami, S. Kuate Defo, B.; Kucuk Bicer, B.; Kuipers, E.J.; Kulkarni, C.; Kulkarni, V.S.; Kumar, G.A.; Kyu, H.H.; Lai, T.; Lalloo, R.; Lallukka, T.; Lam, H.; Lan, Q.; Lansingh, V.C.; Larsson, A.; Lawrynowicz, A.E.; Leasher, J.L.; Leigh, J.; Leung, R.; Levitz, C.E.; Li, B.; Li, Y.; Li, Y.; Lim, S.S.; Lind, M.; Lipshultz, S.E.; Liu, S.; Liu, Y.; Lloyd, B.K.; Lofgren, K.T.; Logroscino, G.; Looker, K.J.; Lortet-Tieulent, J.; Lotufo, P.A.; Lozano, R.; Lucas, R.M.; Lunevicius, R.; Lyons, R.A.; Ma, S.; Macintyre, M.F.; Mackay, M.T.; Majdan, M.; Malekzadeh, R.; Marcenes, W.; Margolis, D.J.; Margono, C.; Marzan, M.B.; Masci, J.R.; Mashal, M.T.; Matzopoulos, R.; Mayosi, B.M.; Mazorodze, T.T.; Mcgill, N.W.; Mcgrath, J.J.; Mckee, M.; Mclain, A.; Meaney, P.A.; Medina, C.; Mehndiratta, M.M.; Mekonnen, W.; Melaku, Y.A.; Meltzer, M.; Memish, Z.A.; Mensah, G.A.; Meretoja, A.; Mhimbira, F.A.; Micha, R.; Miller, T.R.; Mills, E.J.; Mitchell, P.B.; Mock, C.N.; Mohamed Ibrahim, N.; Mohammad, K.A.; Mokdad, A.H.; Mola, G.L.; Monasta, L.; Montañez Hernandez, J.C.; Montico, M.; Montine, T.J.; Mooney, M.D.; Moore, A.R.; Moradi-Lakeh, M.; Moran, A.E.; Mori, R.; Moschandreas, J.; Moturi, W.N.; Moyer, M.L.; Mozaffarian, D.; Msemburi, W.T.; Mueller, U.O.; Mukaigawara, M.; Mullany, E.C.; Murdoch, M.E.; Murray, J.; Murthy, K.S.; Naghavi, M.; Naheed, A.; Naidoo, K.S.; Naldi, L.; Nand, D.; Nangia, V.; Narayan, K.M.; Nejjari, C.; Neupane, S.P.; Newton, C.R.; Ng, M.; Ngalesoni, F.N.; Nguyen, G.; Nisar, M.I.; Nolte, S.; Norheim, O.F.; Norman, R.E.; Norrving, B.; Nyakarahuka, L.; Oh, I.H.; Ohkubo, T.; Ohno, S.L.; Olusanya, B.O.; Opio, J.N.; Ortblad, K.; Ortiz, A.; Pain, A.W.; Pandian, J.D.; Panelo, C.I.; Papachristou, C.; Park, E.K.; Park, J.H.; Patten, S.B.; Patton, G.C.; Paul, V.K.; Pavlin, B.I.; Pearce, N.; Pereira, D.M.; Perez-Padilla, R.; Perez-Ruiz, F.; Perico, N.; Pervaiz, A.; Pesudovs, K.; Peterson, C.B.; Petzold, M.; Phillips, M.R.; Phillips, B.K.; Phillips, D.E.; Piel, F.B.; Plass, D.; Poenaru, D.; Polinder, S.; Pope, D.; Popova, S.; Poulton, R.G.; Pourmalek, F.; Prabhakaran, D.; Prasad, N.M.; Pullan, R.L.; Qato, D.M.; Quistberg, D.A.; Rafay, A.; Rahimi, K.; Rahman, S.U.; Raju, M.; Rana, S.M.; Razavi, H.; Reddy, K.S.; Refaat, A.; Remuzzi, G.; Resnikoff, S.; Ribeiro, A.L.; Richardson, L.; Richardus, J.H.; Roberts, D.A.; Rojas-Rueda, D.; Ronfani, L.; Roth, G.A.; Rothenbacher, D.; Rothstein, D.H.; Rowley, J.T.; Roy, N.; Ruhago, G.M.; Saeedi, M.Y.; Saha, S.; Sahraian, M.A.; Sampson, U.K.; Sanabria, J.R.; Sandar, L.; Santos, I.S.; Satpathy, M.; Sawhney, M.; Scarborough, P.; Schneider, I.J.; Schöttker, B.; Schumacher, A.E.; Schwebel, D.C.; Scott, J.G.; Seedat, S.; Sepanlou, S.G.; Serina, P.T.; Servan-Mori, E.E.; Shackelford, K.A.; Shaheen, A.; Shahraz, S.; Shamah Levy, T.; Shangguan, S.; She, J.; Sheikhbahaei, S.; Shi, P.; Shibuya, K.; Shinohara, Y.; Shiri, R.; Shishani, K.; Shiue, I.; Shrime, M.G.; Sigfusdottir, I.D.; Silberberg, D.H.; Simard, E.P.; Sindi, S.; Singh, A.; Singh, J.A.; Singh, L.; Skirbekk, V.; Slepak, E.L.; Sliwa, K.; Soneji, S.; Søreide, K.; Soshnikov, S.; Sposato, L.A.; Sreeramareddy, C.T.; Stanaway, J.D.; Stathopoulou, V.; Stein, D.J.; Stein, M.B.; Steiner, C.; Steiner, T.J.; Stevens, A.; Stewart, A.; Stovner, L.J.; Stroumpoulis, K.; Sunguya, B.F.; Swaminathan, S.; Swaroop, M.; Sykes, B.L.; Tabb, K.M.; Takahashi, K.; Tandon, N.; Tanne, D.; Tanner, M.; Tavakkoli, M.; Taylor, H.R.; Te Ao, B.J.; Tediosi, F.; Temesgen, A.M.; Templin, T.; Ten Have, M.; Tenkorang, E.Y.; Terkawi, A.S.; Thomson, B.; Thorne-Lyman, A.L.; Thrift, A.G.; Thurston, G.D.; Tillmann, T.; Tonelli, M.; Topouzis, F.; Toyoshima, H.; Traebert, J.; Tran, B.X.; Trillini, M.; Truelsen, T.; Tsilimbaris, M.; Tuzcu, E.M.; Uchendu, U.S.; Ukwaja, K.N.; Undurraga, E.A.; Uzun, S.B.; Van Brakel, W.H.; Van De Vijver, S.; van Gool, C.H.; Van Os, J.; Vasankari, T.J.; Venketasubramanian, N.; Violante, F.S.; Vlassov, V.V.; Vollset, S.E.; Wagner, G.R.; Wagner, J.; Waller, S.G.; Wan, X.; Wang, H.; Wang, J.; Wang, L.; Warouw, T.S.; Weichenthal, S.; Weiderpass, E.; Weintraub, R.G.; Wenzhi, W.; Werdecker, A.; Westerman, R.; Whiteford, H.A.; Wilkinson, J.D.; Williams, T.N.; Wolfe, C.D.; Wolock, T.M.; Woolf, A.D.; Wulf, S.; Wurtz, B.; Xu, G.; Yan, L.L.; Yano, Y.; Ye, P.; Yentür, G.K.; Yip, P.; Yonemoto, N.; Yoon, S.J.; Younis, M.Z.; Yu, C.; Zaki, M.E.; Zhao, Y.; Zheng, Y.; Zonies, D.; Zou, X.; Salomon, J.A.; Lopez, A.D.; Vos, T. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet, 2015, 386(10009), 2145-2191.
[4]
Cosnes, J.; Gower-Rousseau, C.; Seksik, P.; Cortot, A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology, 2011, 140(6), 1785-1794.
[5]
Burisch, J.; Pedersen, N.; Čuković-Čavka, S.; Brinar, M.; Kaimakliotis, I.; Duricova, D.; Shonová, O.; Vind, I.; Avnstrøm, S.; Thorsgaard, N.; Andersen, V.; Krabbe, S.; Dahlerup, J.F.; Salupere, R.; Nielsen, K.R.; Olsen, J.; Manninen, P.; Collin, P.; Tsianos, E.V.; Katsanos, K.H.; Ladefoged, K.; Lakatos, L.; Björnsson, E.; Ragnarsson, G.; Bailey, Y.; Odes, S.; Schwartz, D.; Martinato, M.; Lupinacci, G.; Milla, M.; De Padova, A.; D’Incà, R.; Beltrami, M.; Kupcinskas, L.; Kiudelis, G.; Turcan, S.; Tighineanu, O.; Mihu, I.; Magro, F.; Barros, L.F.; Goldis, A.; Lazar, D.; Belousova, E.; Nikulina, I.; Hernandez, V.; Martinez-Ares, D.; Almer, S.; Zhulina, Y.; Halfvarson, J.; Arebi, N.; Sebastian, S.; Lakatos, P.L.; Langholz, E.; Munkholm, P. East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Gut, 2014, 63(4), 588-597.
[6]
Molodecky, N.A.; Soon, I.S.; Rabi, D.M.; Ghali, W.A.; Ferris, M.; Chernoff, G.; Benchimol, E.I.; Panaccione, R.; Ghosh, S.; Barkema, H.W.; Kaplan, G.G. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology,2012, 142(1), 46-54, e42.
[7]
Leddin, D.; Tamim, H.; Levy, A.R. Decreasing incidence of inflammatory bowel disease in eastern Canada: a population database study. BMC Gastroenterol., 2014, 14, 140.
[8]
Molinié, F.; Gower-Rousseau, C.; Yzet, T.; Merle, V.; Grandbastien, B.; Marti, R.; Lerebours, E.; Dupas, J.L.; Colombel, J.F.; Salomez, J.L.; Cortot, A. Opposite evolution in incidence of Crohn’s disease and ulcerative colitis in Northern France (1988-1999). Gut, 2004, 53(6), 843-848.
[9]
Loftus, C.G.; Loftus, E.V., Jr; Harmsen, W.S.; Zinsmeister, A.R.; Tremaine, W.J.; Melton, L.J., III; Sandborn, W.J. Update on the incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. Inflamm. Bowel Dis., 2007, 13(3), 254-261.
[10]
Burisch, J. jess, T.; Martinato, M.; Lakatos, PL. The burden of inflammatory bowel disease in Europe. J. Crohn’s Colitis, 2013, 7, 322-337.
[11]
Prideaux, L.; Kamm, M.A.; De Cruz, P.P.; Chan, F.K.; Ng, S.C. Inflammatory bowel disease in Asia: a systematic review. J. Gastroenterol. Hepatol., 2012, 27(8), 1266-1280.
[12]
Ouyang, Q.; Tandon, R.; Goh, K.L.; Ooi, C.J.; Ogata, H.; Fiocchi, C. The emergence of inflammatory bowel disease in the Asian Pacific region. Curr. Opin. Gastroenterol., 2005, 21(4), 408-413.
[13]
Lakatos, P.L.; Fischer, S.; Lakatos, L. Is the epidemiology of inflammatory bowel disease changing in Eastern Europe? Scand. J. Gastroenterol., 2006, 41(7), 870-871.
[14]
Dubinsky, M.C.; Yang, H.; Hassard, P.V.; Seidman, E.G.; Kam, L.Y.; Abreu, M.T.; Targan, S.R.; Vasiliauskas, E.A. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology, 2002, 122(4), 904-915.
[15]
Fraser, A.G.; Orchard, T.R.; Jewell, D.P. The efficacy of azathioprine for the treatment of inflammatory bowel disease: A 30 year review. Gut, 2002, 50(4), 485-489.
[16]
McLeod, H.L.; Siva, C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics, 2002, 3(1), 89-98.
[17]
Pacifici, G.M.; Romiti, P.; Giuliani, L.; Rane, A. Thiopurine methyltransferase in humans: development and tissue distribution. Dev. Pharmacol. Ther., 1991, 17(1-2), 16-23.
[18]
Szumlanski, C.L.; Honchel, R.; Scott, M.C.; Weinshilboum, R.M. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics, 1992, 2(4), 148-159.
[19]
Honchel, R.; Aksoy, I.A.; Szumlanski, C.; Wood, T.C.; Otterness, D.M.; Wieben, E.D.; Weinshilboum, R.M. Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. Mol. Pharmacol., 1993, 43(6), 878-887.
[20]
Salavaggione, O.E.; Wang, L.; Wiepert, M.; Yee, V.C.; Weinshilboum, R.M. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet. Genomics, 2005, 15(11), 801-815.
[21]
Schaeffeler, E.; Zanger, U.M.; Eichelbaum, M.; Asante-Poku, S.; Shin, J.G.; Schwab, M. Highly multiplexed genotyping of thiopurine s-methyltransferase variants using MALD-TOF mass spectrometry: reliable genotyping in different ethnic groups. Clin. Chem., 2008, 54(10), 1637-1647.
[22]
McLeod, H.L.; Krynetski, E.Y.; Relling, M.V.; Evans, W.E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia, 2000, 14(4), 567-572.
[23]
Otterness, D.; Szumlanski, C.; Lennard, L.; Klemetsdal, B.; Aarbakke, J.; Park-Hah, J.O.; Iven, H.; Schmiegelow, K.; Branum, E.; O’Brien, J.; Weinshilboum, R. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin. Pharmacol. Ther., 1997, 62(1), 60-73.
[24]
Hon, Y.Y.; Fessing, M.Y.; Pui, C.H.; Relling, M.V.; Krynetski, E.Y.; Evans, W.E. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum. Mol. Genet., 1999, 8(2), 371-376.
[25]
Collie-Duguid, E.S.R.; Pritchard, S.C.; Powrie, R.H.; Sludden, J.; Collier, D.A.; Li, T.; McLeod, H.L. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics, 1999, 9(1), 37-42.
[26]
Otterness, D.; Szumlanski, C.; Lennard, L.; Klemetsdal, B.; Aarbakke, J.; Park-Hah, J.O.; Iven, H.; Schmiegelow, K.; Branum, E.; O’Brien, J.; Weinshilboum, R. Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms. Clin. Pharmacol. Ther., 1997, 62(1), 60-73.
[27]
Lennard, L.; Van Loon, J.A.; Weinshilboum, R.M. Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism. Clin. Pharmacol. Ther., 1989, 46(2), 149-154.
[28]
Krynetski, E.Y.; Krynetskaia, N.F.; Yanishevski, Y.; Evans, W.E. Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase. Mol. Pharmacol., 1995, 47(6), 1141-1147.
[29]
Lennard, L.; Van Loon, J.A.; Lilleyman, J.S.; Weinshilboum, R.M. Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin. Pharmacol. Ther., 1987, 41(1), 18-25.
[30]
Anstey, A.; Lennard, L.; Mayou, S.C.; Kirby, J.D. Pancytopenia related to azathioprine--an enzyme deficiency caused by a common genetic polymorphism: A review. J. R. Soc. Med., 1992, 85(12), 752-756.
[31]
Ansari, A.; Hassan, C.; Duley, J.; Marinaki, A.; Shobowale-Bakre, E.M.; Seed, P.; Meenan, J.; Yim, A.; Sanderson, J. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment. Pharmacol. Ther., 2002, 16(10), 1743-1750.
[32]
Benkov, K.; Lu, Y.; Patel, A.; Rahhal, R.; Russell, G.; Teitelbaum, J. Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD. J. Pediatr. Gastroenterol. Nutr., 2013, 56(3), 333-340.
[33]
Wang, L.; Pelleymounter, L.; Weinshilboum, R.; Johnson, J.A.; Hebert, J.M.; Altman, R.B.; Klein, T.E. Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenet. Genomics, 2010, 20(6), 401-405.
[34]
Miller, S.A.; Dykes, D.D.; Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 1988, 16(3), 1215.
[35]
Yates, C.R.; Krynetski, E.Y.; Loennechen, T.; Fessing, M.Y.; Tai, H.L.; Pui, C.H. Molecular diagnosis of thiopurine S-methyltransferase deficiency: Genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med., 1997, 126, 608-614.
[36]
Zhang, J.P.; Guan, Y.Y.; Wu, J.H.; Xu, A.L.; Zhou, S.; Huang, M. Phenotyping and genotyping study of thiopurine Smethyltransferase in healthy Chinese children: a comparison of Han and Yao ethnic groups. Br. J. Clin. Pharmacol., 2004, 58, 163-168.
[37]
Oender, K.; Lanschuetzer, C.M.; Laimer, M.; Klausegger, A.; Paulweber, B.; Kofler, B.; Hintner, H.; Bauer, J.W. Introducing a fast and simple PCR-RFLP analysis for the detection of mutant thiopurine S-methyltransferase alleles TPMT*3A and TPMT*3C. J. Eur. Acad. Dermatol. Venereol., 2006, 20(4), 396-400.
[38]
Teml, A.; Schaeffeler, E.; Schwab, M. Pretreatment determination of TPMT--state of the art in clinical practice. Eur. J. Clin. Pharmacol., 2009, 65(3), 219-221.
[39]
Leung, M.; Piatkov, I.; Rochester, C.; Boyages, S.C.; Leong, R.W.L. Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression. Intern. Med. J., 2009, 39(2), 121-126.
[40]
Laróvere, L.E.; de Kremer, R.D.; Lambooy, L.H.; De Abreu, R.A. Genetic polymorphism of thiopurine S-methyltransferase in Argentina. Ann. Clin. Biochem., 2003, 40(Pt 4), 388-393.
[41]
Sayitoglu, M.A.; Yildiz, I.; Hatirnaz, O.; Ozbek, U. Common cytochrome p4503A (CYP3A4 and CYP3A5) and thiopurine S-methyltransferase (TPMT) polymorphisms in Turkish population. Turk. J. Med. Sci., 2006, 36, 11-15.
[42]
Ameyaw, M.M.; Collie-Duguid, E.S.; Powrie, R.H.; Ofori-Adjei, D.; McLeod, H.L. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum. Mol. Genet., 1999, 8(2), 367-370.
[43]
Dokmanovic, L.; Urosevic, J.; Janic, D.; Jovanovic, N.; Petrucev, B.; Tosic, N.; Pavlovic, S. Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. Ther. Drug Monit., 2006, 28(6), 800-806.
[44]
Isaza, C.; Henao, J.; López, A.M.; Cacabelos, R. Allelic variants of the thiopurine methyltransferase (TPMT) gene in the Colombian population. Methods Find. Exp. Clin. Pharmacol., 2003, 25(6), 423-429.
[45]
Zhang, J.P.; Guan, Y.Y.; Wu, J.H.; Jiang, W.Q.; Huang, M. Genetic polymorphism of the thiopurine S-methyltransferase of healthy Han Chinese. Ai Zheng,, 2003, 22(4), 385-388.
[46]
Hamdy, S.I.; Hiratsuka, M.; Narahara, K.; Endo, N.; El-Enany, M.; Moursi, N.; Ahmed, M.S.; Mizugaki, M. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Br. J. Clin. Pharmacol., 2003, 55(6), 560-569.
[47]
Desatova, B.; Hlavaty, T.; Balakova, D.; Pav, I.; Celec, P.; Gregus, M.; Zakuciova, M.; Hlista, M.; Horakova, M.; Kadasi, L.; Huorka, M.; Batovsky, M. Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients. Bratisl. Lek Listy, 2013, 114(6), 330-332.
[48]
Takatsu, N.; Matsui, T.; Murakami, Y.; Ishihara, H.; Hisabe, T.; Nagahama, T.; Maki, S.; Beppu, T.; Takaki, Y.; Hirai, F.; Yao, K. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J. Gastroenterol. Hepatol., 2009, 24(7), 1258-1264.
[49]
Gearry, R.B.; Barclay, M.L. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J. Gastroenterol. Hepatol., 2005, 20(8), 1149-1157.
[50]
De Vroey, B.; Colombel, J.F. IBD in 2010: optimizing treatment and minimizing adverse events. Nat. Rev. Gastroenterol. Hepatol., 2011, 8(2), 74-76.
[51]
Lennard, L. TPMT in the treatment of Crohn’s disease with azathioprine. Gut, 2002, 51(2), 143-146.
[52]
Stocco, G.; Martelossi, S.; Barabino, A.; Fontana, M.; Lionetti, P.; Decorti, G.; Malusà, N.; Bartoli, F.; Fezzi, M.; Giraldi, T.; Ventura, A. TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease. Dig. Liver Dis., 2005, 37(12), 940-945.
[53]
Rossi, A.M.; Bianchi, M.; Guarnieri, C.; Barale, R.; Pacifici, G.M. Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects. Eur. J. Clin. Pharmacol., 2001, 57(1), 51-54.
[54]
Travis, S.P.; Stange, E.F.; Lémann, M.; Öresland, T.; Chowers, Y.; Forbes, A.; D’Haens, G.; Kitis, G.; Cortot, A.; Prantera, C.; Marteau, P.; Colombel, J.F.; Gionchetti, P.; Bouhnik, Y.; Tiret, E.; Kroesen, J.; Starlinger, M.; Mortensen, N.J. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut, 2006, 55(Suppl. 1), i16-i35.
[55]
Teml, A.; Schaeffeler, E.; Herrlinger, K.R.; Klotz, U.; Schwab, M. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin. Pharmacokinet., 2007, 46(3), 187-208.
[56]
Dignass, A.; Van Assche, G.; Lindsay, J.O.; Lémann, M.; Söderholm, J.; Colombel, J.F.; Danese, S.; D’Hoore, A.; Gassull, M.; Gomollón, F.; Hommes, D.W.; Michetti, P.; O’Morain, C.; Oresland, T.; Windsor, A.; Stange, E.F.; Travis, S.P. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Current management. J. Crohn’s Colitis, 2010, 4(1), 28-62.
[57]
Colombel, J.F.; Ferrari, N.; Debuysere, H.; Marteau, P.; Gendre, J.P.; Bonaz, B.; Soulé, J.C.; Modigliani, R.; Touze, Y.; Catala, P.; Libersa, C.; Broly, F. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology, 2000, 118(6), 1025-1030.
[58]
Evans, W.E.; Horner, M.; Chu, Y.Q.; Kalwinsky, D.; Roberts, W.M. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J. Pediatr., 1991, 119(6), 985-989.
[59]
Kaskas, B.A.; Louis, E.; Hindorf, U.; Schaeffeler, E.; Deflandre, J.; Graepler, F.; Schmiegelow, K.; Gregor, M.; Zanger, U.M.; Eichelbaum, M.; Schwab, M. Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine. Gut, 2003, 52(1), 140-142.
[60]
Gearry, R.B.; Barclay, M.L.; Burt, M.J.; Collett, J.A.; Chapman, B.A.; Roberts, R.L.; Kennedy, M.A. Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther., 2003, 18(4), 395-400.
[61]
Kubota, T.; Nishida, A.; Takeuchi, K.; Iida, T.; Yokota, H.; Higashi, K.; Nakahara, K.; Hanai, H.; Iga, T. Frequency distribution of thiopurine S-methyltransferase activity in red blood cells of a healthy Japanese population. Ther. Drug Monit., 2004, 26(3), 319-321.
[62]
Winter, J.W.; Gaffney, D.; Shapiro, D.; Spooner, R.J.; Marinaki, A.M.; Sanderson, J.D.; Mills, P.R. 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(9), 1069-1077.
[63]
Dong, X.W.; Zheng, Q.; Zhu, M.M.; Tong, J.L.; Ran, Z.H. Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease. World J. Gastroenterol., 2010, 16(25), 3187-3195.


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VOLUME: 19
ISSUE: 4
Year: 2019
Page: [541 - 547]
Pages: 7
DOI: 10.2174/1871530318666181119153522
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