Department of General Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
PLoS One. 2013 Aug 26;8(8):e73405. doi: 10.1371/journal.pone.0073405. eCollection 2013.
Tacrolimus is the first-line immunosuppressant after organ transplantation. It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. Interleukin 6 (IL6) has been shown to cause a pan-suppression of mRNA levels of ten major CYP enzymes in human hepatocyte cultures. IL6 has been shown to provide hepatoprotection in various models of liver injury. Rs1800796 is a locus in the IL6 gene promoter region which regulates cytokine production. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation.
METHODOLOGY/PRINCIPAL FINDINGS: Ninety-six liver transplant patients receiving tacrolimus were enrolled in the study. Two single nucleotide polymorphisms (SNP), CYP3A5 rs776746 and IL6 rs1800796, were genotyped in both donors and recipients. The effects of SNPs on tacrolimus concentration/dose (C/D ratio) at four weeks after transplantation were studied, as well as the effects of donor IL6 rs1800796 polymorphisms on liver function. Both donor and recipient CYP3A5 rs776746 allele A showed association with lower C/D ratios, while donor IL6 rs1800796 allele G showed an association with higher C/D ratios. Donor CYP3A5 rs776746 allele A, IL6 rs1800796 allele C, and recipient CYP3A5 rs776746 allele A were associated with fast tacrolimus metabolism. With increasing numbers of these alleles, patients were found to have increasingly lower tacrolimus C/D ratios at time points after transplantation. Donor IL6 rs1800796 allele G carriers showed an association with higher glutamic-pyruvic transaminase (GPT) levels.
Combined analysis of donor CYP3A5 rs776746, IL6 rs1800796, and recipient CYP3A5 rs776746 polymorphisms may distinguish tacrolimus metabolism better than CYP3A5 rs776746 alone. IL6 may lead to individual differences in tacrolimus metabolism mainly by affecting liver function.
他克莫司是器官移植后的一线免疫抑制剂。它主要由细胞色素 P450，家族 3，亚家族 A（CYP3A）酶代谢，但代谢存在很大的个体差异。白细胞介素 6（IL6）已被证明可导致人肝细胞培养物中十种主要 CYP 酶的 mRNA 水平普遍抑制。IL6 已被证明在各种肝损伤模型中提供肝保护。Rs1800796 是 IL6 基因启动子区域的一个基因座，可调节细胞因子的产生。我们推测，IL6 rs1800796 多态性可能通过影响 CYP3A 酶水平和肝移植后肝功能，导致他克莫司代谢的个体差异。
方法/主要发现：本研究纳入了 96 例接受他克莫司治疗的肝移植患者。在供体和受体中均对两个单核苷酸多态性（SNP），CYP3A5 rs776746 和 IL6 rs1800796 进行了基因分型。研究了 SNP 对移植后 4 周时他克莫司浓度/剂量（C/D 比值）的影响，以及供体 IL6 rs1800796 多态性对肝功能的影响。供体 CYP3A5 rs776746 等位基因 A 与较低的 C/D 比值相关，而供体 IL6 rs1800796 等位基因 G 与较高的 C/D 比值相关。供体 CYP3A5 rs776746 等位基因 A、IL6 rs1800796 等位基因 C 和受体 CYP3A5 rs776746 等位基因 A 与他克莫司的快速代谢有关。随着这些等位基因数量的增加，发现患者在移植后的各个时间点的他克莫司 C/D 比值越来越低。供体 IL6 rs1800796 等位基因 G 携带者与谷氨酸-丙酮酸转氨酶（GPT）水平升高相关。
供体 CYP3A5 rs776746、IL6 rs1800796 和受体 CYP3A5 rs776746 多态性的综合分析可能比 CYP3A5 rs776746 单独分析更好地区分他克莫司的代谢。IL6 可能主要通过影响肝功能导致他克莫司代谢的个体差异。
