A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway THIS ARTICLE HAS BEEN RETRACTED
S Fiorucci, E Antonelli, A Mencarelli… - British journal of …, 2002 - Wiley Online Library
S Fiorucci, E Antonelli, A Mencarelli, B Palazzetti, L Alvarez‐Miller, M Muscara…
British journal of pharmacology, 2002•Wiley Online LibraryNCX‐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 (ie 500 mg kg−
1 of both compounds). Our results demonstrated that although APAP caused a dose …
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 (ie 500 mg kg−
1 of both compounds). Our results demonstrated that although APAP caused a dose …
- 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 ∼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.
British Journal of Pharmacology (2002) 135, 589–599; doi:10.1038/sj.bjp.0704500
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