Multiple microRNAs regulate tacrolimus metabolism through CYP3A5

Xiang-Qian Gu, Dan Tang, Ping Wan, Tian Qin, Tai-Hua Yang, Ji Wu, Hao Ji, Jin-Chuan Liu, Feng Xue, Yuan-Jia Tang, Qiang Xia

    OnderzoeksoutputAcademicpeer review

    4 Citaten (Scopus)
    91 Downloads (Pure)

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    The CYP3A5 gene polymorphism accounts for the majority of inter-individual variability in tacmlimus pharmacokinetics. We found that the basal expression of CYP3A5 in donor grafts also played a significant role in tacrolimus metabolism under the same genetic conditions after pediatric liver transplantation. Thus, we hypothesized that some potential epigenetic factors could affect CYP3A5 expression and contributed to the variability. We used a high-throughput functional screening for miRNAs to identify miRNAs that had the most abundant expression in normal human liver and could regulate tacmlimus metabolism in HepaRG cells and HepLPCs. Four of these miRNAs (miR-29a-3p, miR-99a-5p, miR-532-5p, and miR-26-5p) were selected for testing. We found that these miRNAs inhibited tacmlimus metabolism that was dependent on CYP3A5. Putative miRNAs targeting key drug-metabolizing enzymes and transporters (DMETs) were selected using an in silico prediction algorithm. Luciferase reporter assays and functional studies showed that miR-26b-5p inhibited tacrolimus metabolism by directly regulating CYP3A5, while miR-29a-5p, miR-99a-5p, and miR-532-5p targeted HNF4a, NR1I3, and NR1I2, respectively, in turn regulating the downstream expression of CYP3A5; the corresponding target gene siRNAs markedly abolished the effects caused by miRNA inhibitors. Also, the expression of miR-29a-3p, miR-99a-5p, miR-532-5p, and miR-26b-5p in donor grafts were negatively correlated with tacmlimus C/D following pediatric liver transplantation. Taken together, our findings identify these miRNAs as novel regulators of tacrolimus metabolism.

    Originele taal-2English
    Artikelnummer105382
    Aantal pagina's11
    TijdschriftPharmacological research
    Volume164
    DOI's
    StatusPublished - feb-2021

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