A NO-releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway

Br J Pharmacol. 2002 Feb;135(3):589-99. doi: 10.1038/sj.bjp.0704500.

Abstract

NCX-701 is a nitric oxide (NO)-releasing acetaminophen (APAP) derivative. In the present study we demonstrated that NCX-701 is as effective as APAP in controlling body temperature in a rat model of endotoxin-induced fever. Liver toxicity is a major complication of APAP overdosing. To investigate whether NCX-701 is hepatotoxic, BALB/C mice were injected with 100 - 500 mg kg(-1) APAP or NCX-701 alone or in combination (i.e. 500 mg kg(-1) of both compounds). Our results demonstrated that although APAP caused a dose-dependent liver injury, NCX-701 was completely devoid of liver toxicity. At the dose of 500 mg kg(-1) APAP caused an approximately 40 fold increase of AST plasma levels and extensive centrilobular necrosis. APAP and NCX-701 share the same metabolic pathway as demonstrated by the time-course of APAP-glucuronide concentrations in plasma and liver. NCX-701 was safe in mice with pre-existing chronic liver disease. Indeed, while C57BL6 transgenic mice expressing the hepatitis B virus (HBV) at the age of 8 months were significantly more susceptible to liver damage induced by APAP (500 mg kg(-1)) than their congenic littermates, treating HBV-transgenic mice with NCX-701, 500 mg kg(-1), caused no damage. Co-administration of NCX-701 at the dose 500 mg kg(-1) to mice treated with APAP, 500 mg kg(-1), completely protected against liver damage induced by APAP. APAP, but not NCX-701, upregulated liver Fas and Fas Ligand mRNA expression in vivo. Incubating mouse hepatocytes with APAP, but not with NCX-701, increased cell surface Fas expression and sensitized hepatocytes to death induced by challenge with a Fas-agonistic antibody. Collectively, these observations suggest that APAP toxicity is Fas mediated and that NCX-701 spares the liver by acting at several checkpoints in the Fas pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Acetaminophen / analogs & derivatives*
  • Acetaminophen / blood
  • Acetaminophen / pharmacology*
  • Animals
  • Body Temperature / drug effects
  • Cytokines / biosynthesis
  • Dose-Response Relationship, Drug
  • Fas Ligand Protein
  • Liver / drug effects*
  • Liver / pathology
  • Male
  • Membrane Glycoproteins / biosynthesis*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / blood
  • Nitric Oxide Donors / chemistry
  • Nitric Oxide Donors / pharmacology
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar

Substances

  • Cytokines
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Faslg protein, rat
  • Membrane Glycoproteins
  • Nitric Oxide Donors
  • RNA, Messenger
  • Nitric Oxide
  • Acetaminophen