肾移植受者硫嘌呤甲基转移酶基因多态性与硫唑嘌呤不良反应关系的研究

摘要/Abstract

摘要： 目的:探讨硫嘌呤甲基转移酶(thiopurine Smethyltransferase,TPMT ) 表型和基因多态性与硫唑嘌呤(AZA) 所致不良反应的关系。方法:应用高效液相色谱法(HPLC) 测定150 例肾移植患者红细胞TPMT 活性, 采用等位基因特异性的PCR 和限制性片断长度多态性的方法检测TPMT *2、*3A、*3B 和*3C 四种基因型, 分析TPMT 活性和基因多态性与AZA 所致不良反应的关系。结果:30 例(20%) 患者由于发生了不良反应而停用AZA 或减少了AZA 的用量, 其中12 例患者发生了血液毒性, 另外18 例发生了肝脏毒性。将未发生不良反应的患者作为对照组, 其红细胞TPMT 活性范围为16.63～68.25 U, 平均为(38.43±11.59) U 。发生了血液毒性的患者红细胞TPMT 活性平均为(24.16±9.84) U, 明显低于未发生不良反应的患者(P=0.0003) 。另外18 例发生了肝脏毒性的患者TPMT 活性离散度较大, 与对照组比较差异无统计学意义(P=0.145) 。本研究未发现TPMT 活性缺乏者。共发现7 例(4.7%)TPMT *3C 杂合子患者, 这7 例患者均为TPMT 中等活性13.04～19.21 U, 平均为(16.75±2.09) U, 明显低于其他野生型患者(P<0.0001) 。在这7 例患者中有4 例发生了不良反应, 2 例发生了血液毒性, 另外2 例发生了肝脏毒性。结论:TPMT *3C 杂合子个体TPMT 活性下降,AZA 所致的血液毒性与TPMT 活性水平有关, 在治疗之初对患者进行TPMT 活性检测和基因分型, 可减轻或避免该药产生的严重血液毒性。

关键词: 硫唑嘌呤, 硫嘌呤甲基转移酶活性, 基因多态性, 不良反应

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

中图分类号:

R969

吴笑春, 熊晖, 熊磊, 苏丹, 辛华雯, 李罄. 肾移植受者硫嘌呤甲基转移酶基因多态性与硫唑嘌呤不良反应关系的研究[J]. 中国临床药理学与治疗学, 2008, 13(9): 1037-1043.

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.

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