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

AI Article Synopsis

  • The study looked at the role of microRNAs (miRNAs) in regulating cytochrome P-450 isoforms, which are important for understanding acetaminophen (APAP) toxicity in liver cells (HepaRG) after APAP treatment.
  • Results showed that treatment with APAP led to increased protein adducts and elevation of liver enzymes (ALT), alongside decreased mRNA levels of specific CYP enzymes and increased levels of certain miRNAs at various time points.
  • The findings suggest that elevated miRNAs, particularly miR-122-5p and miR-378a-5p, are linked to reduced translation of CYP enzymes, indicating a regulatory response to cellular damage from AP

Article Abstract

MicroRNAs (miRNAs) that regulate the cytochrome P-450 isoforms involved in acetaminophen (APAP) toxicity were examined in HepaRG cells treated with APAP (20 mM). In-vitro studies found that APAP protein adducts were increased at 1 h, followed by ALT increases at 12 and 24 h. CYP1A2, CYP3A4 and CYP2E1 mRNA levels were decreased, while miRNAs were increased for miR-122-5p, miR-378a-5p, miR-27b-3p at 6 h and miR-125b-5p at 12 h and miR-27b-3p at 24 h. Putative miRNA binding sites on the 3'UTRs of the CYPs were identified in-silico. Overexpression of miR-122-5p and miR-378a-5p in cells suppressed protein expression of CYP1A2, CYP3A4 and CYP2E1. Luciferase reporter assays confirmed the interaction between miR-122 and the 3'UTR of the CYP1A2 and CYP3A4. Thus, the in-vitro experiments showed that miR-122-5p and miR-378a-5p upregulation were associated with translational repression of CYPs. Serum samples of children with APAP overdose had significant elevation of miR-122-5p, miR-378a-5p, miR-125b-5p and miR-27b-3p, compared to healthy controls and receiver operator curves of the miRNAs had AUCs of 91 to 100%. Collectively, the data suggest that miRNA elevations in APAP toxicity represent a regulatory response to modify CYP1A2, CYP3A4 and CYP2E1 translation due to cellular stress and injury.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614957PMC
http://dx.doi.org/10.1038/s41598-017-11811-yDOI Listing

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