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

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.

• Authors: Stefano Fiorucci, Elisabetta Antonelli, Andrea Mencarelli, Barbara Palazzetti, Lorena Alvarez-Miller, Marcelo Muscara, Piero del Soldato, Laura Sanpaolo, John L Wallace, Antonio Morelli
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 135 Issue 3 Pg. 589-99 (Feb 2002) ISSN: 0007-1188 [Print] England
• PMID: 11834606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

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

Topics

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