title: Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis.
abstract: OBJECTIVE
  Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron-deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis.
  
  
  METHODS
  Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation.
  
  
  RESULTS
  The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis.
  
  
  CONCLUSIONS
  These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Murase
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kado
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Okamoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shohei
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagashima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.forename: Kohichi
authors.initials: K
authors.lastname: Takada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iyama
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
authors.forename: Rishu
authors.initials: R
authors.lastname: Takimoto
authors.forename: Junji
authors.initials: J
authors.lastname: Kato