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MicroRNA regulation of CYP 1A2, CYP3A4 and CYP2E1 expression in acetaminophen toxicity

Pritmohinder Gill1,2, Sudeepa Bhattacharyya3,4, Sandra McCullough3,4

  • 1Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA. PSGill@uams.edu.

Scientific Reports
|September 28, 2017
PubMed

Insights

MicroRNAs (miRNAs) regulate acetaminophen toxicity by suppressing cytochrome P-450s. Elevated miRNAs in patients with acetaminophen overdose suggest a cellular stress response.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Acetaminophen (APAP) overdose causes liver injury.
  • Cytochrome P-450 (CYP) enzymes are critical in APAP metabolism and toxicity.
  • MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression.

Purpose of the Study:

  • To investigate the role of miRNAs in regulating CYP enzymes during APAP-induced toxicity.
  • To identify specific miRNAs involved in APAP toxicity.
  • To assess the diagnostic potential of miRNAs in APAP overdose.

Main Methods:

  • HepaRG cells were treated with APAP.
  • mRNA and protein levels of CYPs and miRNA expression were analyzed.
  • In-silico analysis identified miRNA binding sites on CYP 3'UTRs.
  • Overexpression and luciferase reporter assays confirmed miRNA-CYP interactions.
  • Serum miRNA levels were measured in children with APAP overdose.

Main Results:

  • APAP treatment increased adducts and ALT levels.
  • CYP1A2, CYP3A4, and CYP2E1 mRNA levels decreased, while specific miRNAs (miR-122-5p, miR-378a-5p, miR-27b-3p, miR-125b-5p) increased.
  • miR-122-5p and miR-378a-5p overexpression suppressed CYP protein expression.
  • miR-122 directly interacted with CYP1A2 and CYP3A4 3'UTRs.
  • Elevated serum miRNAs in APAP overdose patients showed high diagnostic accuracy (AUCs 91-100%).

Conclusions:

  • Upregulation of miR-122-5p and miR-378a-5p is associated with translational repression of CYPs in APAP toxicity.
  • Elevated circulating miRNAs in APAP overdose patients indicate a potential biomarker for toxicity.
  • MiRNA changes represent a regulatory response to cellular stress and injury during APAP toxicity.

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