title: 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.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Italy. fiorucci@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Antonelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Palazzetti
authors.forename: Lorena
authors.initials: L
authors.lastname: Alvarez-Miller
authors.forename: Marcelo
authors.initials: M
authors.lastname: Muscara
authors.forename: Piero
authors.initials: P
authors.lastname: del Soldato
authors.forename: Laura
authors.initials: L
authors.lastname: Sanpaolo
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D009569:Nitric Oxide; D000082:Acetaminophen