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Modulation of NRF2/ARE pathway- and cell death-related genes during drug-induced liver injury

B Y Ghanim1, M I Ahmad2, Q M Abdallah1,3

  • 1University of Petra Pharmaceutical Center (UPPC), University of Petra, Amman, Jordan.

Human & Experimental Toxicology
|July 5, 2021
PubMed

Insights

The NRF2 pathway

Area of Science:

  • Hepatology
  • Molecular Toxicology
  • Biomarker Discovery

Background:

  • Drug-induced liver injury (DILI) is a significant clinical issue linked to oxidative stress and cell death.
  • The Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is crucial in liver pathologies, but its efficacy in severe DILI is uncertain.
  • Understanding NRF2's role in DILI progression and its potential as a biomarker is critical.

Purpose of the Study:

  • To assess NRF2 as a biomarker for DILI severity.
  • To investigate factors influencing Nrf2 expression during DILI.
  • To explore the interplay between NRF2 signaling, oxidative stress, and cell death in acetaminophen-induced liver injury.

Main Methods:

  • Established an in vivo DILI model in C57BL/6 mice using varying acetaminophen (APAP) doses.
  • Confirmed APAP toxicity through dose-dependent liver pathology and in vitro GSH/SOD depletion in primary hepatocytes.
  • Analyzed NRF2 translocation, cytosolic content, and gene expression (ARE genes, apoptotic genes, necrosis-related genes) via molecular assays.

Main Results:

  • Mild APAP exposure (70 mg/kg) increased NRF2 transcription and translocation but downregulated key antioxidant response element (ARE) genes (Hmox1, Nqo1, Glcm) and apoptotic genes (Bcl2).
  • Necrosis inducer Parp2 was upregulated, while Hmgb1 was downregulated, indicating regulation of cell survival genes at subtoxic doses.
  • Higher APAP doses led to severe hemorrhagic necrosis and impaired transcription of NRF2 and other critical genes.

Conclusions:

  • NRF2/ARE pathway and cell death modulation are compromised with increasing chemical stress in DILI.
  • NRF2 pathway function is directly associated with the severity of drug-induced liver injury.
  • NRF2's regulatory capacity diminishes as DILI progresses, highlighting its complex role in liver protection and injury.
Keywords:
CytotoxicityNFE2L2acetaminophenapoptosisnecrosis

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