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Nilotinib interferes with the signalling pathways implicated in acetaminophen hepatotoxicity

Mohamed E Shaker1

  • 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Basic & Clinical Pharmacology & Toxicology
|October 15, 2013
PubMed

Insights

Nilotinib at a low dose protected against acetaminophen-induced liver injury by boosting glutathione. However, higher nilotinib doses worsened acetaminophen toxicity, increasing mortality.

Area of Science:

  • Pharmacology
  • Hepatology
  • Toxicology

Background:

  • Nilotinib is a tyrosine kinase inhibitor approved for chronic myeloid leukemia.
  • Acetaminophen (APAP) overdose is a common cause of acute liver injury.
  • Understanding drug interactions is crucial for patient safety.

Purpose of the Study:

  • To investigate the effects of nilotinib on APAP-induced hepatotoxicity in a mouse model.
  • To determine the dose-dependent effects of nilotinib in mitigating or exacerbating liver injury.

Main Methods:

  • Mice were administered APAP followed by nilotinib (25 or 50 mg/kg).
  • Liver injury, necro-inflammation, oxidative stress, and protein expression were assessed.
  • Survival rates were analyzed following APAP and nilotinib co-administration.

Main Results:

  • Nilotinib (25 mg/kg) abolished APAP-induced liver injury, increased hepatic glutathione (GSH), and reduced oxidative stress.
  • Higher nilotinib doses (50 mg/kg) depleted hepatic GSH and exacerbated APAP toxicity, increasing mortality.
  • Nilotinib modulated proteins involved in cell survival and proliferation (bcl-2, cyclin-D1, c-Kit).

Conclusions:

  • Nilotinib can counteract APAP-induced hepatotoxicity at lower doses.
  • Higher nilotinib doses pose a risk of increased mortality due to GSH depletion and c-Kit inhibition.
  • Clinical co-administration of nilotinib and APAP requires careful dose consideration.

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