Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Tokyo, Japan.
Clin Transplant. 2010 Nov-Dec;24(6):855-61. doi: 10.1111/j.1399-0012.2009.01181.x.
One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI-related neurotoxicity.
The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI-related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation.
Of the 63 cases, 15 cases developed CNI-related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4-51.4).
The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI-related neurotoxicity. This outcome is probably because of CYP3A5 or P-gp functions or metabolites of CNIs.
钙调磷酸酶抑制剂（CNI：如环孢素[CsA]和他克莫司[FK506]）的一种严重副作用是神经毒性。CNI 是 CYP3A5 和 P-糖蛋白（P-gp）的底物，由 ABCB1 基因编码。在本研究中，我们假设 CYP3A5 和 ABCB1 基因的遗传多态性可能与 CNI 相关的神经毒性有关。
评估了与 CNI 相关的神经毒性相关的多态性，如 CYP3A5 A6986G、ABCB1 C1236T、G2677T/A 和 C3435T 等，在 63 例造血干细胞移植患者中进行。
在 63 例患者中，有 15 例发生 CNI 相关的神经毒性。在 CsA 患者组（n=30）中，年龄（p=0.008）、高血压（p=0.017）、肾功能不全（p<0.001）、ABCB1 C1236T（p<0.001）和 G2677T/A（p=0.014）与神经毒性相关。ABCB1 C1236T 的 CC 基因型与之相关，但无统计学意义（p=0.07），经年龄、高血压和肾功能不全调整后。在 FK506 患者组（n=33）中，CYP3A5 A6986G（p<0.001）和 ABCB1 C1236T（p=0.002）与神经毒性相关。根据逻辑回归分析，CYP3A5 A6986G 至少有一个 A 等位基因（表达基因型）与之强烈相关（p=0.01；OR，8.5；95%CI，1.4-51.4）。
CYP3A5 和 ABCB1 基因的多态性与 CNI 相关的神经毒性有关。这一结果可能是由于 CYP3A5 或 P-糖蛋白的功能或 CNI 的代谢物所致。
