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Liver delivery of NO by NCX‐1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice
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Author(s) -
Fiorucci Stefano,
Antonelli Elisabetta,
Distrutti Eleonora,
Mencarelli Andrea,
Farneti Silvana,
Soldato Piero Del,
Morelli Antonio
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705780
Subject(s) - apoptosis , acetaminophen , hepatocyte , pharmacology , necrosis , nitric oxide , centrilobular necrosis , nitric oxide synthase , liver injury , mitochondrial permeability transition pore , programmed cell death , cytochrome c , viability assay , chemistry , endocrinology , biology , medicine , biochemistry , in vitro
NCX‐1000, (3 α , 5 β , 7 β )‐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. Here, we demonstrated that administering mice with 40 μ mol kg −1 NCX‐1000, but not UDCA, improves liver histopathology and reduces mortality caused by 330 μ mol 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‐ γ , TNF‐ α , Fas/Fas ligand and inducible nitric oxide synthase (iNOS) mRNA accumulation caused by APAP.In vitro exposure of primary cultures of mouse hepatocytes to APAP, 6.6 m M , resulted in apoptosis followed by necrosis. Loss of cell viability correlates with early mitochondrial membrane potential (Δ ψ 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). Treating primary culture of hepatocytes with 5 μ M cyclosporine and 10 μ M trifluoperazine for eight resulted in significant reduction of apoptosis induced by APAP suggesting that loss of Δ ψ m was mechanistically involved in apoptosis induced by APAP in vitro . NCX‐1000, but not UDCA, concentration‐dependently (ED 50 =16 μ M ) protected against Δ ψ m depolarization and reduced transition from apoptosis to necrosis caused by 6.6 m M APAP. Treating primary cultures of hepatocytes with the NO‐donor DETA‐NO, 100 μ M , reduced apoptosis induced by APAP and prevented caspase activation. 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.British Journal of Pharmacology (2004) 143 , 33–42. doi: 10.1038/sj.bjp.0705780