Nair Sreeja S, Sarasamma Sreeja, Gracious Noble, George Jacob, Anish Thekkumkara Surendran Nair, Radhakrishnan Reghunathan
From the Department of Nephrology, Government Medical College, India.
Exp Clin Transplant. 2015 Apr;13 Suppl 1:197-200.
Tacrolimus is the cornerstone for immunosuppression in renal transplant and is metabolized by the cytochrome P 450 3A (CYP3A) subfamily of enzymes in the liver and small intestine. A polymorphism in intron 3 of the CYP3A5 gene affects the expression of this enzyme and tacrolimus trough blood levels. The purpose of this study was to identify the proportion of CYP3A5 gene polymorphisms in South Indian renal transplant patients and determine the effect of CYP3A5 gene polymorphisms on tacrolimus trough blood levels in patients with and without CYP3A5 expression.
We included 25 adult patients who underwent renal transplant at Government Medical College, Trivandrum. All patients received tacrolimus (dose, 0.1 mg/kg/body weight, in 2 divided doses). Tacrolimus trough blood levels were determined on postoperative day 6. The CYP3A5 genotype analysis was performed by polymerase chain reaction amplification of target and detection by restriction fragment length polymorphism analysis.
The CYP3A5*1/*1 genotype was detected in 5 recipients (20%), *1/*3 genotype in 5 recipients (20%), and *3/3 genotypes in 15 recipients (60%) of the total 25 graft recipients. Mean tacrolimus level in the CYP3A51/1 group was 5.154 ng/mL (range, 4.42 to 6.5 ng/mL), CYP3A51/3 group was 5.348 ng/mL (range, 3.1 to 9.87 ng/mL), and CYP3A53/3 group was 9.483 ng/mL (range, 4.5 to14.1 ng/mL). Acute rejection episodes were significantly more frequent for CYP3A51/1 homozygous patients (40%) than patients with CYP3A51/3 (20%) or CYP3A53/*3 (13%) genotypes.
Most patients carried the mutant allele CYP3A5*3 (A6986G). Tacrolimus drug level correlated well with presence or absence of CYP3A5 polymorphisms. Acute rejection episodes were more frequent in expressors, and they may require higher doses of tacrolimus. Similarly, tacrolimus nephrotoxicity was more frequent in non-expressors. Therefore, CYP3A5 polymorphism analysis before renal transplant may help determine the optimal dose of tacrolimus in this population and prevent acute rejection episodes or tacrolimus toxicity.
他克莫司是肾移植免疫抑制的基石，在肝脏和小肠中由细胞色素P 450 3A（CYP3A）酶亚家族代谢。CYP3A5基因内含子3中的多态性影响该酶的表达以及他克莫司血药谷浓度。本研究的目的是确定南印度肾移植患者中CYP3A5基因多态性的比例，并确定CYP3A5基因多态性对有和没有CYP3A5表达的患者他克莫司血药谷浓度的影响。
我们纳入了25例在特里凡得琅政府医学院接受肾移植的成年患者。所有患者均接受他克莫司（剂量为0.1mg/kg体重，分2次给药）。术后第6天测定他克莫司血药谷浓度。通过聚合酶链反应扩增靶标并采用限制性片段长度多态性分析进行CYP3A5基因分型分析。
在25例移植受者中，检测到5例（20%）受者为CYP3A5*1/1基因型，5例（20%）为1/3基因型，15例（60%）为3/3基因型。CYP3A51/1组他克莫司平均水平为5.154ng/mL（范围4.42至6.5ng/mL），CYP3A51/3组为5.348ng/mL（范围3.1至9.87ng/mL），CYP3A53/3组为9.483ng/mL（范围4.5至14.1ng/mL）。CYP3A51/1纯合患者（40%）急性排斥反应发作明显比CYP3A51/3（20%）或CYP3A53/*3（13%）基因型患者更频繁。
大多数患者携带突变等位基因CYP3A5*3（A6986G）。他克莫司药物水平与CYP3A5多态性的有无密切相关。表达者急性排斥反应发作更频繁，可能需要更高剂量的他克莫司。同样，非表达者他克莫司肾毒性更频繁。因此，肾移植前进行CYP3A5多态性分析可能有助于确定该人群中他克莫司的最佳剂量，并预防急性排斥反应发作或他克莫司毒性。
