{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:18:28Z","timestamp":1774916308900,"version":"3.50.1"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":6393,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,3]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Acetaminophen is a mild analgesic and antipyretic agent known to cause centrilobular hepatic necrosis at toxic doses. Although this may be due to a direct interaction of reactive acetaminophen metabolites with hepatocyte proteins, recent studies have suggested that cytotoxic mediators produced by parenchymal and nonparenchymal cells also contribute to the pathophysiological process. Nitric oxide is a highly reactive oxidant produced in the liver in response to inflammatory mediators. In the present studies we evaluated the role of nitric oxide in the pathophysiology of acetaminophen-induced liver injury. Treatment of male Long Evans Hooded rats with acetaminophen (1 g\/kg) resulted in damage to centrilobular regions of the liver and increases in serum transaminase levels, which were evident within 6 hours of treatment of the animals and reached a maximum at 24 hours. This was correlated with expression of inducible nitric oxide synthase (iNOS) protein in these regions. Hepatocytes isolated from both control and acetaminophen-treated rats were found to readily synthesize nitric oxide in response to inflammatory stimuli. Cells isolated from acetaminophen-treated rats produced more nitric oxide than cells from control animals. Production of nitric oxide by cells from both control and acetaminophen-treated rats was blocked by aminoguanidine, a relatively specific inhibitor of iNOS. Arginine uptake and metabolism studies revealed that the inhibitory effects of aminoguanidine were due predominantly to inhibition of iNOS enzyme activity. Pretreatment of rats with aminoguanidine was found to prevent acetaminophen-induced hepatic necrosis and increases in serum transaminase levels. This was associated with reduced nitric oxide production by hepatocytes. Inhibition of toxicity was not due to alterations in acetaminophen metabolism since aminoguanidine had no effect on hepatocyte cytochrome P4502E1 protein expression or <jats:italic toggle=\"yes\">N<\/jats:italic>-acetyl-<jats:italic toggle=\"yes\">p<\/jats:italic>-benzoquinone-imine formation. Taken together, these data demonstrate that nitric oxide is an important mediator of acetaminophen-induced hepatotoxicity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510270316","type":"journal-article","created":{"date-parts":[[2004,7,27]],"date-time":"2004-07-27T23:44:28Z","timestamp":1090971868000},"page":"748-754","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":198,"title":["Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat"],"prefix":"10.1097","volume":"27","author":[{"given":"Carol R.","family":"Gardner","sequence":"first","affiliation":[]},{"given":"Diane E.","family":"Heck","sequence":"additional","affiliation":[]},{"given":"Chung S.","family":"Yang","sequence":"additional","affiliation":[]},{"given":"Paul E.","family":"Thomas","sequence":"additional","affiliation":[]},{"given":"Xu-Jie","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"George L.","family":"DeGeorge","sequence":"additional","affiliation":[]},{"given":"Jeffrey D.","family":"Laskin","sequence":"additional","affiliation":[]},{"given":"Debra L.","family":"Laskin","sequence":"additional","affiliation":[]}],"member":"276","reference":[{"key":"BIB1","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1056\/NEJM199312303292706","volume":"329","author":"Moncada","year":"1993","journal-title":"N Engl J Med"},{"key":"BIB2","first-page":"223","volume":"22","author":"Laskin","year":"1995","journal-title":"Hepatology"},{"key":"BIB3","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/jlb.56.6.751","volume":"56","author":"Laskin","year":"1994","journal-title":"J Leukoc Biol"},{"key":"BIB4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/jlb.55.4.507","volume":"55","author":"Feder","year":"1994","journal-title":"J Leukoc Biol"},{"key":"BIB5","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1002\/hep.1840200621","volume":"20","author":"Helyar","year":"1994","journal-title":"Hepatology"},{"key":"BIB6","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1006\/bbrc.1993.1896","volume":"194","author":"Nussler","year":"1993","journal-title":"Biochem Biophys Res Commun"},{"key":"BIB7","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1084\/jem.170.5.1769","volume":"170","author":"Curran","year":"1989","journal-title":"J Exp Med"},{"key":"BIB8","first-page":"267","volume-title":"The molecular basis of oxidative damage by leukocytes","author":"Gardner","year":"1992","unstructured":"Differential regulation of reactive oxygen and nitrogen intermediate production by hepatic macrophages and endothelial cells. 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