Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation.
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.
Schauer
Rolf J
RJ
Surgical Department, University Hospital Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. schauer@gch.med.uni-muenchen.de
Kalmuk
Sinan
S
Gerbes
Alexander L
AL
Leiderer
Rosemarie
R
Meissner
Herbert
H
Schildberg
Friedrich W
FW
Messmer
Konrad
K
Bilzer
Manfred
M
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*
D005978:Glutathione