{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:46:36Z","timestamp":1790253996031,"version":"4.1.0"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":6362,"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":[[1998,4]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Recent evidence suggests that macrophages and\/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-\u03b1 (LT-\u03b1). Male TNF\/LT-\u03b1 knockout mice and C57BL\/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg\/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF\/LT-\u03b1-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL\/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-\u03b1 were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-\u03b1, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.510270418","type":"journal-article","created":{"date-parts":[[2004,7,27]],"date-time":"2004-07-27T23:51:48Z","timestamp":1090972308000},"page":"1021-1029","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":95,"title":["Acetaminophen hepatotoxicity in tumor necrosis factor\/lymphotoxin-\u03b1 gene knockout 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