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中国肾移植患者中细胞色素P450 3A4的新突变位点
引用本文:石 磊,贺宝霞,曾晓晖,朱云松,张宏斌,保泽庆,赵树进. 中国肾移植患者中细胞色素P450 3A4的新突变位点[J]. 中国组织工程研究, 2013, 17(5): 791-796. DOI: 10.3969/j.issn.2095-4344.2013.05.005
作者姓名:石 磊  贺宝霞  曾晓晖  朱云松  张宏斌  保泽庆  赵树进
作者单位:1 解放军广州军区广州总医院,广东省广州市 5100102 河南省肿瘤医院药剂科, 河南省郑州市 450003
摘    要:背景:环孢素A在人体内主要经过细胞色素P450 3A4代谢。已有研究表明细胞色素P450 3A4基因多态性影响环孢素A的药代动力学,而且环孢素A慢性肾毒性主要是由于环孢素A在体内的长期蓄积。因此推测细胞色素P450 3A4基因多态性可能是肾移植移植后环孢素A 慢性肾毒性的主要原因之一。目的:分析细胞色素P450 3A4基因多态性与肾移植移植后环孢素A 慢性肾毒性的相关性。方法:纳入200例服用环孢素A的肾移植患者参加此项研究,其中105例经肾活检和(或)血肌酐值的变化诊断为环孢素A 慢性肾毒性,其他95例未发生肾毒性)。采集受试者外周静脉血并提取基因组DNA,采用聚合酶链式反应和直接测序法检测细胞色素P450 3A4基因外显子5,7,9和12的点突变。结果与结论:中国肾移植患者中发现3个细胞色素P450 3A4新突变位点,即336 A>G,837 G>A 和406 A>C。其中 3例肾移植患者可检测出336 A>G,8例肾移植患者可检测出837 G>A。新突变点406 A>C仅发现于3例环孢素A慢性肾毒性患者,在非肾毒性患者中未发现新突变位点,且406 A>C可导致细胞色素P450 3A4保守区136位苏氨酸(Thr)转变为苯丙氨酸(Phe)。文章未发现已报道的中国人群细胞色素P450 3A4基因在外显子5,7,9和12的多态性。结果证实,文章在中国肾移植患者中发现了3个细胞色素P450 3A4的新突变位点336 A>G,837 G>A 和406 A>C,其中406 A>C可能引起细胞色素P450 3A4酶活性的改变。

关 键 词:器官移植  肾移植  慢性肾毒性  细胞色素P450 3A4  环孢素A  新突变  省级基金  
收稿时间:2012-05-02

Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients
Shi Lei,He Bao-xia,Zeng Xiao-hui,Zhu Yun-song,Zhang Hong-bin,Bao Ze-qing,Zhao Shu-jin. Novel mutations of the cytochrome P450 3A4 gene in Chinese renal transplant recipients[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(5): 791-796. DOI: 10.3969/j.issn.2095-4344.2013.05.005
Authors:Shi Lei  He Bao-xia  Zeng Xiao-hui  Zhu Yun-song  Zhang Hong-bin  Bao Ze-qing  Zhao Shu-jin
Affiliation:1 Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, Guangdong Province, China
2 Department of Pharmacy, Henan Cancer Hospital, Zhengzhou 450003, Henan Province, China
Abstract:BACKGROUND:Cyclosporine A is metabolized mainly by cytochrome P450 3A4 (CYP3A4). Previous studies have suggested that genetic polymorphisms of CYP3A4 have an effect on the pharmacokinetics of cyclosporine A. Moreover, cyclosporine A -related chronic nephrotoxicity is caused by long-term exposure to cyclosporine A. It is conceivable that genetic polymorphisms of CYP3A4 may be responsible for the cyclosporine A-related chronic nephrotoxicity in renal transplant recipients.OBJECTIVE:To analyze the relationship between CYP3A4 gene polymorphism and cyclosporine A- related chronic nephrotoxicity.METHODS:A total of 200 patients (105 diagnosed as having cyclosporine A-related chronic renal toxicity through renal biopsy and (or) serum creatinine values change and 95 without nephrotoxicity) undergoing cyclosporine A therapy participated in this study. Peripheral venous blood samples were collected and genomic DNA was extracted. Mutations in exons 5, 7, 9, and 12 of the CYP3A4 gene were screened by PCR and direct DNA sequencing.RESULTS AND CONCLUSION:Three novel mutations of CYP3A4 gene were discovered in this study, namely 336 A>G, 837 G>A and 406 A>C. The novel mutation 336 A>G was detected in three renal transplant recipients and 837 G>A was detected in eight recipients. Importantly, the novel mutation at 406A>C was detected only in three patients with cyclosporine A nephrotoxicity, and the novel mutation 406 A>C could result in the changes from 136 Threonine in the conserved region of CYP3A4 gene to phenylalanine. However, the known polymorphisms of exons 5, 7, 9, and 12 of the CYP3A4 gene were not detected in Chinese population. Three novel mutations at 336 A>G, 837 G>A and 406 A>C were detected in CYP3A4 gene in Chinese renal transplant recipients. The novel mutation at 406 A>C was predicted to change the enzyme activity of CYP3A4 enzyme.
Keywords:organ transplantation  renal transplantation  chronic nephrotoxicity  cytochrome P450 3A4  cyclosporine A  new mutation  provincial grants-supported paper  
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