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Multiple microRNAs regulate tacrolimus metabolism through CYP3A5.

Xiang-Qian Gu1, Dan Tang2, Ping Wan1

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Pharmacological Research
|December 21, 2020
PubMed
Summary
This summary is machine-generated.

Epigenetic factors, specifically microRNAs (miRNAs), influence tacrolimus metabolism after liver transplants. These miRNAs, including miR-26b-5p, regulate CYP3A5 expression, impacting drug levels in pediatric patients.

Keywords:
DMSO (CID: 679)Drug metabolizing enzymesMicroRNAsPediatric liver transplantationTacrolimusTacrolimus (CID: 445643)

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Area of Science:

  • Pharmacogenomics
  • Epigenetics
  • Drug Metabolism

Background:

  • CYP3A5 gene polymorphism is a major factor in tacrolimus pharmacokinetic variability.
  • Basal CYP3A5 expression in donor grafts also significantly affects tacrolimus metabolism post-pediatric liver transplantation.
  • Epigenetic factors are hypothesized to contribute to the observed variability in tacrolimus metabolism.

Purpose of the Study:

  • To identify microRNAs (miRNAs) regulating tacrolimus metabolism.
  • To investigate the role of specific miRNAs in CYP3A5 expression and function.
  • To explore the clinical relevance of these miRNAs in pediatric liver transplant recipients.

Main Methods:

  • High-throughput functional screening of miRNAs in liver cells (HepaRG, HepLPCs).
  • In silico prediction of miRNA targets among drug-metabolizing enzymes and transporters (DMETs).
  • Luciferase reporter assays, functional studies with miRNA inhibitors and siRNAs, and correlation analysis in patient samples.

Main Results:

  • Four miRNAs (miR-29a-3p, miR-99a-5p, miR-532-5p, miR-26b-5p) were identified to inhibit tacrolimus metabolism via CYP3A5.
  • miR-26b-5p directly targets CYP3A5; miR-29a-5p, miR-99a-5p, and miR-532-5p target regulatory factors (HNF4α, NR1I3, NR1I2) affecting CYP3A5 expression.
  • Expression of these miRNAs in donor grafts negatively correlated with tacrolimus concentration/dose (C/D) in pediatric liver transplant patients.

Conclusions:

  • Specific miRNAs are novel regulators of tacrolimus metabolism.
  • These miRNAs impact tacrolimus pharmacokinetics by modulating CYP3A5 expression through direct or indirect mechanisms.
  • MiRNA expression in donor grafts may serve as a predictive biomarker for tacrolimus response in pediatric liver transplantation.