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Ethanol Plus the Jo2 Fas Agonistic Antibody‐Induced Liver Injury is Attenuated in Mice with Partial Ablation of Argininosuccinate Synthase
Author(s) -
Lu Yongke,
Ward Stephen C.,
Nieto Natalia
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12309
Subject(s) - liver injury , argininosuccinate synthase , chemistry , nitric oxide synthase , citrulline , argininosuccinate lyase , nitric oxide , urea cycle , arginase , tbars , pharmacology , biochemistry , glutathione , medicine , arginine , endocrinology , enzyme , amino acid , organic chemistry
Background Argininosuccinate synthase ( ASS ) is an enzyme shared by the urea cycle and the l ‐citrulline/nitric oxide ( NO ·) cycle. ASS is the rate‐limiting enzyme in the urea cycle and along with nitric oxide synthase 2 ( NOS 2), it endows cells with the l ‐citrulline/ NO · salvage pathway to continuously supply l ‐arginine from l ‐citrulline for sustained NO · generation. Thus, ASS conditions NO · synthesis by NOS 2. Because of the relevance of NOS 2 activation for liver injury, we examined the contribution of ASS to NO · generation and how it impacts liver injury. Methods Wild‐type ( WT ) mice and Ass +/− mice ( Ass −/− mice are lethal) were intraperitoneally injected with ethanol ( EtOH ) at a dose of 2.5 g/kg of body weight twice a day for 3 days. Two hours after the last dose of EtOH , mice were administered the agonistic J o2 anti‐mouse F as monoclonal antibody (Ab) at a dose of 0.2 μg/g of body weight. Mice were sacrificed 8 hours after the J o2 A b injection. Markers of nitrosative and oxidative stress as well as liver damage were analyzed. Results EtOH plus Jo2 injection induced liver injury as shown by serum alanine aminotransferase and aspartate aminotransferase activity, liver pathology, TUNEL , and cleaved caspase‐3 were lower in Ass +/− mice compared with WT mice, suggesting that ASS contributes to EtOH plus J o2‐mediated liver injury. CYP 2 E 1 induction, glutathione depletion, and elevated thiobarbituric acid reactive substances were comparable in both groups of mice, suggesting that CYP 2 E 1‐mediated oxidative stress is not linked to ASS ‐induced liver injury. In contrast, NOS 2 induction, 3‐nitrotyrosine adducts formation and elevated nitrites, nitrates, and S ‐nitrosothiols were higher in livers from WT mice than from Ass +/− mice. Conclusion Decreased nitrosative stress causes lower EtOH plus J o2‐induced liver injury in Ass +/− mice.