肾移植患者HGPRT活性及多态性与硫唑嘌呤所致不良反应的相关性研究

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (2): 182-187.

肾移植患者HGPRT活性及多态性与硫唑嘌呤所致不良反应的相关性研究

马晓琴^1,2, 辛华雯¹, 李元启³, 黄晖³, 赵丽³, 余爱荣¹, 李维亮¹, 吴笑春¹

¹广州军区武汉总医院临床药理科,武汉 430070,湖北;
²南方医科大学,广州 510515,广东;
³湖北省药品(医疗器械)不良反应监测中心,武汉 430071,湖北

收稿日期:2013-09-12 修回日期:2014-07-07 出版日期:2015-02-26 发布日期:2015-03-20
通讯作者: 辛华雯,女,主任医师,研究方向:临床药理学。Tel: 027-68878688 E-mail: huawenxin@163.com
作者简介:马晓琴,女,硕士研究生,研究方向:临床药理学与药物代谢酶。E-mail: qingxiu1989@126.com
基金资助:
湖北省自然科学基金资助项目(2011CDC074)

Association of HGPRT activity and gene polymorphism with adverse reactions caused by azathioprine in kidney transplant recipients

MA Xiao-qin^1,2, XIN Hua-wen¹, LI Yuan-qi³, HUANG Hui³, ZHAO Li³, YU Ai-rong¹, LI Wei-liang¹, WU Xiao-chun¹

¹Department of Clinical Pharmacology,Wuhan General Hospital of Guangzhou Military, Wuhan430070,Hubei,China;
²Southern Medical University,Guangzhou 510515,Guangdong,China;
³Adverse Drug Reaction Monitoring Centre of Hubei Province, Wuhan 430071,Hubei,China

Received:2013-09-12 Revised:2014-07-07 Online:2015-02-26 Published:2015-03-20

摘要/Abstract

摘要： 目的: 本研究旨在探索次黄嘌呤鸟嘌呤磷酸核糖转移酶(HGPRT)活性及基因多态性与硫唑嘌呤(AZA)所致不良反应的相关性,为临床合理使用AZA提供理论依据。方法: 用本实验室建立的HPLC法测定入选样本的HGPRT活性,直接测序法测定HGPRT IVS6-12C>A的基因型,结合受试者不良反应发生情况,分析HGPRT活性及多态性与AZA所致不良反应的相关性。结果: 86例肾移植受者HGPRT活性范围为(44.59~262.16)U,平均为(100.17±33.50)U,健康受试者HGPRT活性范围为(28.43~153.65) U,平均为(99.30±17.21)U,均呈正态分布。两组HGPRT活性均值差异无统计学意义(P>0.05)。304例肾移植患者中发现2例HGPRT IVS6-12C>A突变体,突变频率为 2.30%。而健康受试者中未发现突变,分析发现HGPRT活性与基因型之间无明显相关性(P>0.05)。流行性感冒样症状组患者的平均HGPRT活性明显高于肾移植对照组[(147.47±101.24) U vs (100.46±29.31) U,P<0.05)],而血液毒性组、肝脏毒性组、胃肠道反应组与肾移植对照组比较,活性差异无统计学意义。AZA所致不良反应与HGPRT基因多态性之间没有明显相关性(P>0.05)。结论: 在服用AZA之前,测定患者HGPRT活性,筛选出HGPRT高活性者,减少AZA的初始剂量,有利于减少AZA所致流行性感冒样症状不良反应的发生率。

关键词: 硫唑嘌呤, 次黄嘌呤鸟嘌呤磷酸核糖转移酶, 不良反应, 酶活性, 基因多态性

Abstract: AIM: To explore the associations between HGPRT activities and genetic polymorphisms and AZA-related adverse reactions in renal transplant recipients so as to provide enough theoretic and experiment evidence for rational use of AZA.METHODS: Erythrocyte HGPRT activity were measured in 86 cases of renal transplant recipients by a modified high-performance liquid chromatography (HPLC) procedure we developed before,genotype of HGPRT IVS6-12C>A was determined by direct sequencing method.Combined with the subject occurrence of adverse reactions,the relationships between HGPRT activity and genetic polymorphisms and AZA-induced adverse reactions were systematically analyzed.RESULTS: HGPRT activity in 86 cases of renal transplant recipients ranged from 44.59 U to 262.16 U and the average activity was (100.17±33.50) U. HGPRT activity in healthy subjects ranged from 28.43 to 153.65 U and the average activity was (99.30±17.21)U. Both of them showed normal distribution.There was no statistically significant difference about HGPRT activity between the renal transplant recipients and the healthy subjects(P>0.05). In the renal transplant recipients, 2 cases of HGPRT-IVS6-12C> A mutation was found and the mutation frequency was 2.30%. No IVS6-12C> A mutation was found in the health subjects. No association was observed between HGPRT activity and genetic polymorphisms(P>0.05).The average HGPRT activity in patients with flu-like symptoms was significantly higher than that in the renal transplant recipients who had no AZA-related adverse reactions[(147.47±101.24) U vs (100.46±29.31) U,P<0.05]. The average HGPRT activities in patients with hematotoxicity, hepatotoxicity and gastrointestinal disturbance were found no significant differences compared with the patients who had no AZA-related adverse reactions (P>0.05). No association was observed between HGPRT genetic polymorphisms and AZA-related adverse reactions(P>0.05).CONCLUSION: In conclusion, before commencing AZA treatment, it is important to measure HPGRT activity in renal transplant recipients and relieve AZA-dose in order to reduce AZA-related flu-like symptoms .

Key words: azathioprine, hypoxanthine guanine phosphoribosyl transferase (HGPRT), adverse drug reaction, enzyme activity, genetic polymorphism

中图分类号:

R969

马晓琴, 辛华雯, 李元启, 黄晖, 赵丽, 余爱荣, 李维亮, 吴笑春. 肾移植患者HGPRT活性及多态性与硫唑嘌呤所致不良反应的相关性研究[J]. 中国临床药理学与治疗学, 2015, 20(2): 182-187.

MA Xiao-qin, XIN Hua-wen, LI Yuan-qi, HUANG Hui, ZHAO Li, YU Ai-rong, LI Wei-liang, WU Xiao-chun. Association of HGPRT activity and gene polymorphism with adverse reactions caused by azathioprine in kidney transplant recipients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(2): 182-187.

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