title: Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat.
abstract: OBJECTIVE
  Hydrophobic bile acids have been implicated in the pathogenesis of cholestatic liver injury. The hypothesis that hydrophobic bile acid toxicity is mediated by oxidant stress in an in vivo rat model was tested in this study.
  
  
  METHODS
  A dose-response study of bolus intravenous (i.v.) taurochenodeoxycholic acid (TCDC) in rats was conducted. Rats were then pretreated with parenteral alpha-tocopherol, and its effect on i.v. TCDC toxicity was evaluated by liver blood tests and by assessing mitochondrial lipid peroxidation.
  
  
  RESULTS
  Four hours after an i.v. bolus of TCDC (10 mumol/100 g weight), serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels peaked, hepatic mitochondria showed evidence of increased lipid peroxidation, and serum bile acid analysis was consistent with a cholestatic injury. Liver histology at 4 hours showed hepatocellular necrosis and swelling and mild portal tract inflammation. Treatment with parenteral alpha-tocopherol was associated with a 60%-70% reduction in AST and ALT levels, improved histology, and a 60% reduction in mitochondrial lipid peroxidation in rats receiving TCDC.
  
  
  CONCLUSIONS
  These data show that hepatocyte injury and oxidant damage to mitochondria caused by i.v. TCDC can be significantly reduced by pretreatment with the antioxidant vitamin E. These in vivo findings support the role for oxidant stress in the pathogenesis of bile acid hepatic toxicity.
authors.affiliation: Pediatric Liver Center, Children's Hospital, Denver, Colorado, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Sokol
authors.forename: J M
authors.initials: JM
authors.lastname: McKim
authors.forename: M C
authors.initials: MC
authors.lastname: Goff
authors.forename: S Z
authors.initials: SZ
authors.lastname: Ruyle
authors.forename: M W
authors.initials: MW
authors.lastname: Devereaux
authors.forename: D
authors.initials: D
authors.lastname: Han
authors.forename: L
authors.initials: L
authors.lastname: Packer
authors.forename: G
authors.initials: G
authors.lastname: Everson
mesh_terms: D000818:Animals; D002756:Cholagogues and Choleretics / Q000633:toxicity*; D004336:Drug Antagonism; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000633:toxicity*; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D002756:Cholagogues and Choleretics; D014810:Vitamin E; D013655:Taurochenodeoxycholic Acid