Research on the relationship between thiopurine S-methyltransferase genetic polymorphisms and azathioprine adverse drug reactions in patients with kidney transplantation

Abstract

Abstract: AIM: To investigate the relationship between thiopurine S-methyltransferase (TPMT ) polymorphisms and azathioprine (AZA) adverse effects in patients with kidney transplantation.METHODS: The erythrocyte TPMT activity of 150 patients with kidney transplantation was detected by high performance liquid chromatography (HPLC).The TPMT *2, *3A, * 3B and *3C four kinds of genetype were determined by allele specific PCR and PCR-restriction fragment length polymorphism.The relationship of the activity, gene polymorphism, adverse effects induced by AZA were analyzed. RESULTS: 30 patients (20%) stopped using AZA or reduced the dose due to adverse effects, hematotoxicity (n=12) and hepatotoxicity (n=18) happened.The patients without adverse effects were as control group, their TPMT activity-range of akaryocyte was 16.63-68.25 U, the mean activityrange was (38.43±11.59) U.The akaryocyte TPMT average activity-range was (24.16±9.84) U for the 12 patients with hematotoxicity, there was significant difference to the patients with adverse effects (P=0.0003).The TPMT activity had larger straggling for the 18 patients with hepatotoxicity, compared with control group, there was no difference (P=0.145).The TPMT activity deficiency patients were not found in the research.There were 7 cases (4.7%) with TPMT *3C heterozygous alleles in the research, their TPMT activity-range was 13.04-19.21 U, the mean activity-range was (16.75±2.09) U, much lower than that in other wild types patients (P<0.0001).It was 4 cases which had taken place side effects in the 7 cases (hematotoxicity, n=2, hepatotoxicity, n=2).CONCLUSION: The TPMT activity is reduced in patients with TPMT *3C heterozygote.Hematotoxicity induced by AZA is related to the TPMT activity.The activity detection and genotyping for TPMT which are detected prior to therapy can relieve or avoid severe hematotoxicity.

Key words: azathioprine, TPMT activity, geneticpolymorphism, adverseeffect

CLC Number:

R969

WU Xiao-chun, XIONG Hui, XIONG Lei, SU Dan, XIN Hua-wen, LI Qing. Research on the relationship between thiopurine S-methyltransferase genetic polymorphisms and azathioprine adverse drug reactions in patients with kidney transplantation[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(9): 1037-1043.

References

[1] Mcleod HL, Pritchard SC, Githang'a J, et al. Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan individuals [J].Pharmcogenetics, 1999, 9(6):773-776.
[2] Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency and distribution of thiopurine methyltransferase allele in Caucasian and Asian populations [J].Pharmcogenetics, 1999, 9(1):37-42.
[3] Weinshilboum R.Thiopurine pharmacogenetics:clinical and molecular studies of thiopurine methyltransferase [J]. Drug Metab Dispos, 2001, 29(4 pt 2):601-605.
[4] Lennard L.Clinical implication of thiopurine methyltransferase optimization of drug dosage and potential drug interaction [J].Ther Drug Monit, 1998, 20(5):527-531.
[5] Schaeffeler E, Fischer C, Brockmeier D, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotypegenotype correlation in a large population of German-Caucasians and identification of novel TPMT variants [J]. Pharmacogenetics, 2004, 14(7):407-417.
[6] Xin H, Fischer C, SchwabM, et al. Effects of amino salicylates on thiopurine S-methyltransferase activity:an ex vivo study in patients with inflammatory bowel disease [J]. Aliment Pharmacol Ther, 2005, 21(9):1105-1109.
[7] 熊晖, 熊磊, 苏丹, 等.HPLC 法检测人红细胞中巯嘌呤甲基转移酶的活性 [J].中国药师, 2007, 10 (8):738-740.
[8] Kröplin T, Weyer N, Gutsche S, et al. Thiopurine Smethy ltransferase activity inhuman erythrocytes:a new HPLC method using 6-thioguanine as substrate [J].Eur J Clin Pharmacol, 1998, 54(3):265-271.
[9] Hamdan-Khalil R, Allorg D, Lo-Guidic JM, et al. In vitro characterization of four novel non-functional variants of the thiopurine S-methyltransferase [J].Biochem Biophys Res Commun, 2003, 309(4):1005-1010.
[10] Zhang JP, Zhou SF, Chen X, et al. Determination of intra-ethnic difference in the polymorphisms of thiopurine Smethyltransferase in Chinese [J].Clin Chim Acta, 2006, 365(1/2):337-341.
[11] McLeod HL, Siva C.The thiopurine S-methyltransferase gene locus implications for clinical pharmacogenomics [J]. Pharmacogenomics, 2002, 3(1):89-98.
[12] Krynetski EY, Evans WE.Genetic polymorphism of thiopurine S-methyltransferase:molecular mechanisms and clinical importance [J].Pharmacology, 2000, 61(3):136-146.
[13] Chang JG, Lee LS, Chen CM, et al. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations [J].Pharmacogenetics, 2002, 12(3): 191-195.
[14] Hon YY, Fessing MY, Pui CH, et al. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans [J].Hum Mol Genet, 1999, 8(2):371-376.
[15] Schaeffeler E, Stanulla M, Greil J, et al. A novel TPMT missense mutation associated with TPMT deficiency in a 5-year-old boy with ALL [J].Leukemia, 2003, 17(7):1422-1424.
[16] Tai HL, FessingMY, Bonten EJ, et al. 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 [J].Pharmacgenetics, 1999, 9(5):641-650.
[17] Yan L, Zhang S, Eiff B, et al. Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis [J].Clin Pharmacol Ther, 2000, 68 (2):210-219.
[18] Marinaki AM, Arenas M, Khan ZH, et al. Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians [J]. Pharmacgenetics, 2003, 13(2):97-105.
[19] SchwabM, Schaeffeler E, Marx C, et al. Shortcoming in the diagnosis of TPMT deficiency in a patient with Crohn's disease using phenotying only [J].Gastroenterology, 2001, 121(2):498-499.
[20] Evans WE, Hon YY, Bomgaars L, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine [J].J Clin Oncol, 2001, 19(8):2293-2301.
[21] Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus [J].J Nat Cancer Inst, 1999, 91(23):2001-2008.
[22] Schwab M, Schaeffeler E, Marx C, et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease:impact of thiopurine S-methyltransferase polymorphism [J].Pharmacgenetics, 2002, 12(6): 429-436.
[23] Kader HA, Wenner WJ, Telega GW, et al. Normal thiopurine methyltransferase levels do not eliminate 6-mercaptopurine or azathioprine toxicity in children with inflammatory bowel disease [J].J Clin Gastroenterol, 2000, 30(4): 409-413.
[24] Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease [J].Gastroenterology, 2000, 118(4):705-713.
[25] 辛华雯, Fischer C, Schwab M, 等.速尿、苯氧比酸、硫唑嘌呤对慢性炎症性肠病患者红细胞TPMT 活性的影响 [J].中国临床药理学与治疗学, 2005, 10 (6):655-658.
[26] 熊晖, 熊磊, 苏丹, 等.环孢素、硝苯地平等五种肾移植受者常用药物对红细胞TPMT 活性的影响 [J]. 中国临床药理学和治疗学, 2007, 12(12):1411-1414.