Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation
Frequencies and roles of CYP3A5, CYP3A4 and ABCB1 single nucleotide polymorphisms in Italian teenagers after kidney transplantation
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DOI：
10.1016/s1734-1140(10)70378-9
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发表时间：
2010-11
影响因子：
4.4
通讯作者：
S. Turolo;A. Tirelli;M. Ferraresso;L. Ghio;M. Belingheri;E. Groppali;E. Torresani;A. Edefonti
中科院分区：
文献类型：
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作者：
S. Turolo;A. Tirelli;M. Ferraresso;L. Ghio;M. Belingheri;E. Groppali;E. Torresani;A. Edefonti
参与免疫抑制药物药代动力学的主要基因是编码细胞色素P450（CYP1A1）家族酶和多药耐药1（ABCB 1）的基因。在这项研究中，87名接受肾脏移植的意大利青少年（平均年龄11.6 ± 4.8岁）接受钙调磷酸酶抑制剂（CNI）的患者进行单核苷酸多态性（SNP）基因分型，CYP3A为CYP3A5 * 1/3和CYP3A4 * 1B，ABCB 1为C1236 T、G2677 T/A、C3435 T和IVS 21 + 49，并回顾性评价所筛选的SNPs对移植后不同时间CNI血液水平的影响。7%的患者存在CYP3A5 * 1等位基因，3%的患者存在CYP3A4 * 1B等位基因。ABCB 1 C1236 T、G2677 T/A和C3435 T SNPs C、G和T出现频率较高（分别为55%、53%和54%）。IVS21 + 49的T等位基因频率为86%。这两个基因中SNPs的频率与其他欧洲高加索人群中报道的频率相当，但与亚洲人或非洲裔美国人中发现的频率不同。环孢素（CsA）药代动力学参数均与CYP3A5基因多态性无关，而一些患者中存在A等位基因导致需要显著增加他克莫司（Tac）剂量以达到治疗目标水平。所有Tac药代动力学参数均与ABCB1 SNP无关，但ABCB1 SNP对CsA暴露指数和剂量需求有早期影响。总之，由于CYP3A和ABCB 1基因的SNP可能与CNI药代动力学参数和暴露指数相关，因此应考虑移植前遗传筛查，以避免免疫抑制剂相关的不良事件。
The main genes involved in the pharmacokinetics of immunosuppressive drugs are those encoding cytochrome P450 (CYP) family enzymes and multidrug resistance 1 (ABCB1). In this study, 87 Italian teenagers with transplanted kidneys (mean age 11.6±4.8 years) receiving calcineurin inhibitors (CNIs) were genotyped for the single nucleotide polymorphisms (SNPs) CYP3A5* 1/3 and CYP3A4* 1B for CYP3A, and C1236T, G2677T/A, C3435T and IVS21+ 49 for ABCB1, and retrospectively evaluated for the influence of the screened SNPs on CNI blood level at different post-transplantation times. The CYP3A5* 1 allele was present in 7% of the patients, and the CYP3A4* 1B allele was present in 3% of patients. The ABCB1 C1236T, G2677T/A and C3435T SNPs C, G and T occurred frequently (55%, 53% and 54%, respectively). The frequency of theTallele of IVS21+ 49 was 86%. The frequencyofSNPs in both genes was comparable with that reported in other European Caucasian populations but different from that found in Asians or Afro-Americans. None of the cyclosporine (CsA) pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism, whereas the presence of the A allele in some patients was responsible for the required administration of a significantly increased dose of tacrolimus (Tac) that was necessary to reach therapeutic target levels. None of the Tac pharmacokinetic parameters were associated with ABCB1 SNPs, but ABCB1 SNPs had early effects on the CsAexposure index and dose requirements. In conclusion, because SNPs of the CYP3A and ABCB1 genes may be associated with CNI pharmacokinetic parameters and exposure indices, pre-transplant genetic screening should be considered in order to avoid immunosuppressant-related adverse events.