Ashavaid T, Raje H, Shalia K, Shah B
Department of Lab Medicine and Research Laboratories, P. D. Hinduja National Hospital and Medical Research Center, Mumbai, India.
Indian J Nephrol. 2010 Jul;20(3):146-51. doi: 10.4103/0971-4065.70846.
The outcome of renal transplantation is improved by cyclosporine and tacrolimus. However, its success is limited by drug-induced nephrotoxicity. Therefore, monitoring their levels is important. These levels are influenced mainly by CYP3A4, CYP3A5 and MDR- 1 genes. These levels also affect target molecules of CNIs, mainly IL-2. Inter-individual differences in these levels have been attributed to SNPs in these genes and hence study of these SNPs assumes significance. So far no study has been carried out on Indian renal transplant recipients covering the SNPs of the genes involved in metabolism, efflux and drug target of CNIs, hence the data is lacking for Indian population. The aim is to study A-392G SNP of CYP3A4, A6986G SNP of CYP3A5, C3435T SNP of MDR-1 and T-330G SNP of IL-2 genes and correlate with CNI blood levels. Hundred healthy subjects and 100 consecutive renal transplant recipients; 56 on CsA and 44 on tacrolimus were genotyped by PCR followed by restriction enzyme assay for mentioned SNPs. No significant difference was observed between level/dose (L/D) ratio of CNIs and CYP3A4 and IL-2 SNPs. However, median L/D ratio for tacrolimus was significantly higher in subjects with CYP3A5*3/*3 (n = 24) (P = 0.011) and MDR- 1 3435TT (n = 18) (P = 0.0122). The findings from this study show that homozygous mutant patients for CYP3A5 and MDR-1 gene SNPs could be managed with lower tacrolimus dose to avoid nephrotoxicity.
环孢素和他克莫司可改善肾移植的结果。然而，其成功受到药物诱导的肾毒性的限制。因此，监测它们的水平很重要。这些水平主要受CYP3A4、CYP3A5和MDR-1基因的影响。这些水平也影响钙调神经磷酸酶抑制剂（CNIs）的靶分子，主要是白细胞介素-2（IL-2）。这些水平的个体差异归因于这些基因中的单核苷酸多态性（SNPs），因此对这些SNPs的研究具有重要意义。到目前为止，尚未对印度肾移植受者进行涵盖CNIs代谢、外排和药物靶点相关基因SNPs的研究，因此印度人群缺乏相关数据。目的是研究CYP3A4基因的A-392G SNP、CYP3A5基因的A6986G SNP、MDR-1基因的C3435T SNP和IL-2基因的T-330G SNP，并将其与CNIs血药浓度相关联。通过聚合酶链反应（PCR）对100名健康受试者和100名连续的肾移植受者进行基因分型，其中56名使用环孢素（CsA），44名使用他克莫司，随后对上述SNPs进行限制性酶切分析。在CNIs的水平/剂量（L/D）比与CYP3A4和IL-2 SNPs之间未观察到显著差异。然而，在携带CYP3A5*3/*3（n = 24）（P = 0.011）和MDR-1 3435TT（n = 18）（P = 0.0122）的受试者中，他克莫司的中位L/D比显著更高。这项研究的结果表明，对于CYP3A5和MDR-1基因SNPs的纯合突变患者，可以用较低剂量的他克莫司进行治疗，以避免肾毒性。
