Effects of ABCB1 DNA methylation in donors on tacrolimus blood concentrations in recipients following liver transplantation

作者：Chengcheng Shi, Yan Liang, Jie Gao, Shitong Chen, Lirong Zhang · 发表于：British Journal of Clinical Pharmacology · 年份：2022 · DOI：10.1111/bcp.15376 · 被引用次数：9 · 研究领域：Organ Transplantation Techniques and Outcomes、Drug Transport and Resistance Mechanisms、Renal Transplantation Outcomes and Treatments

Aims To investigate the effects of ABCB1 DNA methylation in donors on individual differences in tacrolimus blood concentrations following liver transplantation. Methods Twenty‐three donor liver samples carrying the CYP3A5*3/*3 genotype were classified into 2 groups based on their initial tacrolimus blood concentrations (C 0 >10 μg/L or <5 μg/L) following liver transplantation. ABCB1 mRNA levels in liver tissues and HepG2 cells were determined by quantitative reverse transcriptase polymerase chain reaction. DNA methylation status in liver tissues and HepG2 cells was determined using Illumina 850 methylation chip sequencing technology and pyrosequencing. 5‐Aza‐2dC was used to reverse methylation in HepG2 cells. Intracellular tacrolimus concentrations were determined by liquid mass spectrometry. Results Genome‐wide methylation sequencing and pyrosequencing analyses showed that the methylation levels of 3 ABCB1 CpG sites (cg12501229, cg00634941 and cg05496710) were significantly different between groups with different tacrolimus concentration/dose (C 0 /D) ratios. ABCB1 mRNA expression in donor livers was found to be positively correlated with tacrolimus C 0 /D ratio ( R = .458, P < .05). After treatment with 5‐Aza‐2‐Dc, the methylation levels of the ABCB1 CpG sites in HepG2 cells significantly decreased, and this was confirmed by pyrosequencing; there was also a significant increase in ABCB1 transcription, which induced a decrease in intracellular tacrolimus concentrati...