A NO‐releasing derivative of acetaminophen spares the liver by acting at several checkpoints in the Fas pathway THIS ARTICLE HAS BEEN RETRACTED
2002
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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