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

• Published in: British journal of pharmacology 2002-02, Vol.135 (3), p.589-599
• Main Authors: FIORUCCI, Stefano, ANTONELLI, Elisabetta, MENCARELLI, Andrea, PALAZZETTI, Barbara, ALVAREZ-MILLER, Lorena, MUSCARA, Marcelo, DEL SOLDATO, Piero, SANPAOLO, Laura, WALLACE, John L, MORELLI, Antonio
• Format: Article
• Language: English
• Subjects: Acetaminophen - analogs & derivatives; Acetaminophen - blood; Acetaminophen - pharmacology; Analgesics; Animals; Biological and medical sciences; Body Temperature - drug effects; Cytokines - biosynthesis; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Fas antigen; Fas Ligand Protein; Liver - drug effects; Liver - pathology; Male; Medical sciences; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neuropharmacology; Nitric Oxide - secretion; Nitric Oxide Donors - blood; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; RNA, Messenger - biosynthesis; Toxicity: digestive system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704500

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.