Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Organ Transplantation, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Pharmacotherapy. 2019 Jan;39(1):67-76. doi: 10.1002/phar.2204. Epub 2019 Jan 8.
There are limited markers that could facilitate individualized tacrolimus treatment in the early posttransplantation period. Genetic factors have been found to play critical roles in determining tacrolimus pharmacokinetics.
We aimed to examine the association of donor and recipient Toll-like receptor (TLR) polymorphisms with tacrolimus elimination and the potential mechanism for TLR gene polymorphism-mediated tacrolimus metabolism.
Two independent cohorts including 297 patients receiving liver transplantation (LT) were enrolled in this study (cohort A was composed of 200 patients; cohort B included 97 patients and served as a validation set). Toll-like receptors polymorphisms were genotyped using TaqMan single nucleotide polymorphisms (SNPs) assays. The protein expressions were detected by Western blotting. The metabolism assay was used to quantify tacrolimus elimination. The activity of nuclear factor-kB (NF-kB) was evaluated by luciferase reporter assay.
Tacrolimus dose-adjusted trough blood concentrations (C/D) ratios were significantly lower for donor TLR9 rs352139 AG/GG carriers than AA carriers at weeks 1, 2, and 3 after LT. In multivariate analysis, donor and recipient CYP3A5 rs776746 and donor TLR9 rs352139 were independent predictors of tacrolimus C/D ratios in the early period after transplantation in both cohorts. When investigating the combined effects of donor CYP3A5 rs776746 and donor TLR9 rs352139 genotypes, the C/D ratios were remarkably significant at all time points during the first month after LT within the four groups. Furthermore, CYP3A5 mRNA expression in liver tissue was significantly higher for AG/GG patients than AA carriers after LT. In addition, we demonstrated that the TLR9 rs352139 genetic variant promotes tacrolimus metabolism of liver cells via upregulation of CYP3A5, which is dependent on the repression of NF-κB/pregnane X receptor (PXR) signaling.
Donor TLR9 rs352139 genetic variant facilitated tacrolimus elimination during the early stage after LT in Chinese patients, which might be related to the upregulation of CYP3A5 enzyme via the NF-kB/PXR signaling pathway.
目前仅有少数标志物可在移植术后早期阶段帮助实现个体化他克莫司治疗。遗传因素在确定他克莫司药代动力学方面起着至关重要的作用。
我们旨在研究供体和受体 Toll 样受体（TLR）多态性与他克莫司消除的关系，以及 TLR 基因多态性介导他克莫司代谢的潜在机制。
本研究纳入了 297 例接受肝移植（LT）的患者（队列 A 由 200 例患者组成；队列 B 包括 97 例患者，作为验证集）。采用 TaqMan 单核苷酸多态性（SNP）检测 TLR 多态性。采用 Western blot 检测蛋白表达。通过代谢测定来定量他克莫司消除。采用荧光素酶报告基因测定法评估核因子-κB（NF-κB）的活性。
与 LT 后第 1、2、3 周时 TLR9 rs352139 AG/GG 携带者相比，TLR9 rs352139 AG/GG 供体的他克莫司剂量调整后谷浓度（C/D）比值显著降低。在多变量分析中，供体和受者 CYP3A5 rs776746 和供体 TLR9 rs352139 是两个队列中移植后早期他克莫司 C/D 比值的独立预测因子。在研究供体 CYP3A5 rs776746 和供体 TLR9 rs352139 基因型的联合效应时，在 LT 后第一个月的所有时间点，四组之间的 C/D 比值均有显著差异。此外，LT 后，AG/GG 患者的 CYP3A5 mRNA 表达在肝组织中明显高于 AA 携带者。此外，我们证明 TLR9 rs352139 遗传变异通过上调 CYP3A5 促进肝细胞中他克莫司的代谢，这依赖于 NF-κB/孕烷 X 受体（PXR）信号通路的抑制。
在中国患者中，供体 TLR9 rs352139 遗传变异促进 LT 后早期阶段他克莫司的消除，这可能与通过 NF-κB/PXR 信号通路上调 CYP3A5 酶有关。
