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Nrf2 protection against liver injury produced by various hepatotoxicants

Jie Liu1, Kai Connie Wu, Yuan-Fu Lu

  • 1University of Kansas Medical Center, Kansas City, KS 66160, USA.

Oxidative Medicine and Cellular Longevity
|June 15, 2013
PubMed

Insights

The transcription factor Nrf2 (Nuclear factor erythroid 2-related factor 2) protects the liver from many chemical-induced injuries. However, Nrf2 activation does not prevent all forms of drug-induced liver injury.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatotoxicity is a significant concern in drug development and environmental exposure.
  • The role of Nuclear factor erythroid 2-related factor 2 (Nrf2) in chemical-induced liver injury is not fully elucidated.
  • Understanding Nrf2's protective mechanisms is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the protective role of Nrf2 against a wide range of hepatotoxicants.
  • To establish a model of graded Nrf2 activation for comprehensive analysis.
  • To identify specific hepatotoxicants against which Nrf2 confers protection.

Main Methods:

  • Utilized Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd), and Keap1-hepatocyte knockout (Keap1-HKO) mice to create a graded Nrf2 activation model.
  • Administered 14 different hepatotoxicants to mice at appropriate doses.
  • Collected blood and liver samples at various time points (6 hours to 7 days) for analysis of liver injury markers and gene expression.

Main Results:

  • Graded Nrf2 activation provided significant protection against hepatotoxicity induced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid.
  • Moderate protection was observed against liver injury from ethanol, arsenic, bromobenzene, and allyl alcohol.
  • Nrf2 activation did not protect against D-galactosamine/endotoxin or Fas ligand antibody Jo-2 induced hepatotoxicity.
  • Nrf2 activation suppressed inflammatory, oxidative stress, ER stress, and cell death gene expression.

Conclusions:

  • Nrf2 acts as a crucial defense mechanism against a broad spectrum of chemical-induced hepatotoxicity.
  • The protective effects of Nrf2 are mediated by the induction of antioxidant genes and suppression of inflammatory and oxidative stress pathways.
  • Nrf2-mediated protection is not universal, as certain hepatotoxicants remain effective despite Nrf2 activation.

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