title: Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation.
abstract: OBJECTIVE
  To investigated the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation.
  
  
  METHODS
  Livers of male Lewis rats were transplanted after 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting. During a 2-h reperfusion period either saline (controls, n=8) or GSH (50 or 100 micromol/(h/kg), n=5 each) was continuously administered via the jugular vein.
  
  
  RESULTS
  Two hours after starting reperfusion plasma ALT increased to 1457+/-281 U/L (mean+/-SE) in controls but to only 908+/-187 U/L (P<0.05) in animals treated with 100 microGSH/(h/kg). No protection was conveyed by 50 micromol GSH(h/kg). Cytoprotection was confirmed by morphological findings on electron microscopy: GSH treatment prevented detachment of sinusoidal endothelial cells (SEC) as well as loss of microvilli and mitochondrial swelling of hepatocytes. Accordingly, postischemic bile flow increased 2-fold. Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Following infusion of 50 micromol and 100 micromol GSH/(h/kg), plasma GSH increased to 65+/-7 mol/L and 97+/-18 mol/L, but to only 20+/-3 mol/L in untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased to 7.5+/-1.0 mol/L in animals treated with 100 micro(h/kg) GSH but did not raise levels of untreated controls (1.8+/-0.5 mol/L) following infusion of 50 microGSH/(h/kg) (2.2+/-0.2 mol/L).
  
  
  CONCLUSIONS
  Plasma GSH levels above a critical level may act as a "sink" for ROS produced in the hepatic vasculature during reperfusion of liver grafts. Therefore, GSH can be considered a candidate antioxidant for the prevention of reperfusion injury after liver transplantation, in particular since it has a low toxicity in humans.
authors.affiliation: Surgical Department, University Hospital Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. schauer@gch.med.uni-muenchen.de
authors.forename: Rolf J
authors.initials: RJ
authors.lastname: Schauer
authors.forename: Sinan
authors.initials: S
authors.lastname: Kalmuk
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Leiderer
authors.forename: Herbert
authors.initials: H
authors.lastname: Meissner
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Schildberg
authors.forename: Konrad
authors.initials: K
authors.lastname: Messmer
authors.forename: Manfred
authors.initials: M
authors.lastname: Bilzer
mesh_terms: D000818:Animals; D005978:Glutathione / Q000008:administration & dosage*; D022781:Hepatocytes / Q000187:drug effects*; D007262:Infusions, Intravenous; D008102:Liver Circulation; D016031:Liver Transplantation; D008297:Male; D011184:Postoperative Period; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D005978:Glutathione