Bilirubin release induced by tumor necrosis factor in combination with galactosamine is toxic to mice

Application of tumor necrosis factor (TNF) in combination with galactosamine (GaIN) in mice causes severe apoptosis of hepatocytes, resulting in complete destruction of the liver. Administration of high levels of unconjugated bilirubin and abnormally high production of unconjugated bilirubin have been reported to cause liver damage and are associated with several human pathologies. Serum alanine aminotransferase as well as total and direct bilirubin levels in mice were determined. Bilirubin levels are shown to significantly increase after a challenge with TNF/GaIN in mice. Pretreatment with a heme oxygenase-1 inhibitor significantly prevents this release in bilirubin and offers significant protection against TNF/GaIN-induced lethality. A correlation between the release of unconjugated bilirubin and the toxicity accompanied with this release is provided. (C) 2003 Elsevier Ltd. All rights reserved.