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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 336A>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 406A>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 P4503A4 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,837G>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。
Background: Cyclosporine A is mainly metabolized by cytochrome P450 3A4 in humans. It has been reported that cytochrome P450 3A4 polymorphism affects the pharmacokinetics of cyclosporine A, and chronic nephrotoxicity of cyclosporin A is mainly due to the long-term accumulation of cyclosporin A in vivo. Therefore speculate cytochrome P450 3A4 gene polymorphism may be one of the main causes of chronic nephrotoxicity of CsA after renal transplantation. Objective: To analyze the association between cytochrome P450 3A4 gene polymorphism and chronic nephrotoxicity of cyclosporin A after renal transplantation. METHODS: Two hundred and fifty renal transplant recipients of cyclosporine A were enrolled in this study. One hundred and fifty patients were diagnosed as chronic nephrotoxicity of cyclosporine A by change of renal biopsy and / or serum creatinine, while the other 95 patients without renal toxicity). Peripheral venous blood was collected from the subjects and genomic DNA was extracted. The point mutations of exon 5, 7, 9 and 12 of cytochrome P450 3A4 gene were detected by polymerase chain reaction and direct sequencing. RESULTS AND CONCLUSION: Three new cytochrome P450 3A4 mutations were found in kidney transplant recipients in China, namely 336A> G, 837G> A and 406A> C. Three of the three renal transplant recipients detected 336 A> G, and 837 G> A were detectable in 8 patients who had a kidney transplant. The new mutation point 406A> C was only found in 3 patients with chronic nephrotoxicity of cyclosporin A, no new mutation sites were found in patients with non-nephrotoxicity, and 406 A> C could lead to threonine 136 in the conserved region of cytochrome P4503A4 (Thr) to phenylalanine (Phe). No polymorphisms of cytochrome P450 3A4 gene in exons 5, 7, 9 and 12 have been reported in Chinese population. The results confirmed that three new cytochrome P450 3A4 mutation sites 336 A> G, 837G> A and 406 A> C were found in kidney transplant recipients in China, among which 406 A> C may induce cytochrome P450 3A4 activity Change.