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RETRACTED ARTICLE

Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice.
Br J Pharmacol. 2004 Sep; 143(1):33-42.BJ

Abstract

1. NCX-1000, (3alpha, 5beta, 7beta)-3,7-dihydroxycholan-24oic acid[2-methoxy-4-[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ester, is a nitric oxide (NO)-derivative of ursodeoxyxholic acid (UDCA) that selectively release NO in the liver. 2. Here, we demonstrated that administering mice with 40 micromol kg(-1) NCX-1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 micromol kg(-1) APAP from 60 to 25% (P<0.01). Administration of NCX-1000, in a therapeutic manner, that is, 2 h after acetaminophen (APAP) intoxication reduced mortality, improved liver histopathology and prevented liver IFN-gamma, TNF-alpha, Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP. 3. In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 mm, resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Deltapsi(m)) hyperpolarization followed by depolarization and cytochrome c translocation from mitochondria to cytosol. APAP-induced apoptosis associated with procaspase-3 and -9 cleavage, appearance of truncated Bid and activation of poly(ADP-ribose) polymerase (PARP). 4. Treating primary culture of hepatocytes with 5 microm cyclosporine and 10 microm trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Deltapsim was mechanistically involved in apoptosis induced by APAP in vitro. 5. NCX-1000, but not UDCA, concentration-dependently (ED(50)=16 microm) protected against Deltapsi(m) depolarization and reduced transition from apoptosis to necrosis caused by 6.6 mm APAP. 6. Treating primary cultures of hepatocytes with the NO-donor DETA-NO, 100 microm, reduced apoptosis induced by APAP and prevented caspase activation. 7. In conclusion, NCX-1000 is effective in protecting against APAP-induced hepatotoxicity when administered in a therapeutic manner. This protection may involve the inhibition of apoptosis and the maintenance of mitochondrial integrity.

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Authors+Show Affiliations

Fiorucci S
Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Italy. fiorucci@unipg.it
Antonelli E
No affiliation info available
Distrutti E
No affiliation info available
Mencarelli A
No affiliation info available
Farneti S
No affiliation info available
Del Soldato P
No affiliation info available
Morelli A
No affiliation info available

MeSH

AcetaminophenAnalgesics, Non-NarcoticAnimalsApoptosisCaspasesCell SeparationCells, CulturedChromatography, High Pressure LiquidCulture MediaCytosolHepatocytesLiverLiver FailureMembrane PotentialsMiceMitochondria, LiverNitratesNitric OxideNitric Oxide DonorsOxidative StressSulfhydryl CompoundsUrsodeoxycholic Acid

Pub Type(s)

Journal Article
Retracted Publication

Language

eng

PubMed ID

15345658

Citation

Fiorucci, Stefano, et al. "Liver Delivery of NO By NCX-1000 Protects Against Acute Liver Failure and Mitochondrial Dysfunction Induced By APAP in Mice." British Journal of Pharmacology, vol. 143, no. 1, 2004, pp. 33-42.
Fiorucci S, Antonelli E, Distrutti E, et al. Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice. Br J Pharmacol. 2004;143(1):33-42.
Fiorucci, S., Antonelli, E., Distrutti, E., Mencarelli, A., Farneti, S., Del Soldato, P., & Morelli, A. (2004). Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice. British Journal of Pharmacology, 143(1), 33-42.
Fiorucci S, et al. Liver Delivery of NO By NCX-1000 Protects Against Acute Liver Failure and Mitochondrial Dysfunction Induced By APAP in Mice. Br J Pharmacol. 2004;143(1):33-42. PubMed PMID: 15345658.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice. AU - Fiorucci,Stefano, AU - Antonelli,Elisabetta, AU - Distrutti,Eleonora, AU - Mencarelli,Andrea, AU - Farneti,Silvana, AU - Del Soldato,Piero, AU - Morelli,Antonio, PY - 2004/9/4/pubmed PY - 2005/2/11/medline PY - 2004/9/4/entrez SP - 33 EP - 42 JF - British journal of pharmacology JO - Br J Pharmacol VL - 143 IS - 1 N2 - 1. NCX-1000, (3alpha, 5beta, 7beta)-3,7-dihydroxycholan-24oic acid[2-methoxy-4-[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ester, is a nitric oxide (NO)-derivative of ursodeoxyxholic acid (UDCA) that selectively release NO in the liver. 2. Here, we demonstrated that administering mice with 40 micromol kg(-1) NCX-1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 micromol kg(-1) APAP from 60 to 25% (P<0.01). Administration of NCX-1000, in a therapeutic manner, that is, 2 h after acetaminophen (APAP) intoxication reduced mortality, improved liver histopathology and prevented liver IFN-gamma, TNF-alpha, Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP. 3. In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 mm, resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Deltapsi(m)) hyperpolarization followed by depolarization and cytochrome c translocation from mitochondria to cytosol. APAP-induced apoptosis associated with procaspase-3 and -9 cleavage, appearance of truncated Bid and activation of poly(ADP-ribose) polymerase (PARP). 4. Treating primary culture of hepatocytes with 5 microm cyclosporine and 10 microm trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Deltapsim was mechanistically involved in apoptosis induced by APAP in vitro. 5. NCX-1000, but not UDCA, concentration-dependently (ED(50)=16 microm) protected against Deltapsi(m) depolarization and reduced transition from apoptosis to necrosis caused by 6.6 mm APAP. 6. Treating primary cultures of hepatocytes with the NO-donor DETA-NO, 100 microm, reduced apoptosis induced by APAP and prevented caspase activation. 7. In conclusion, NCX-1000 is effective in protecting against APAP-induced hepatotoxicity when administered in a therapeutic manner. This protection may involve the inhibition of apoptosis and the maintenance of mitochondrial integrity. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/15345658/Liver_delivery_of_NO_by_NCX_1000_protects_against_acute_liver_failure_and_mitochondrial_dysfunction_induced_by_APAP_in_mice_ DB - PRIME DP - Unbound Medicine ER -