Beneficial effects of extracellular glutathione against endotoxin-induced liver injury during ischemia and reperfusion.
The potential beneficial effect of hepatocellular glutathione against inflammatory liver damage was investigated in a model of endotoxin-enhanced ischemia-reperfusion injury. Animals were subjected to 20 min of hepatic ischemia, followed by 4 hr of reperfusion. The injection of 0.5 mg/kg Salmonella enteritidis endotoxin potentiated liver injury and the postischemic oxidant stress, as indicated by increased plasma levels of glutathione disulfide. Depletion of hepatic glutathione levels by > 90% with phorone and inhibition of glutathione synthesis with buthionine sulfoximine further increased liver injury in this model, as indicated by enhancement of plasma alanine aminotransferase activities from 2,234 +/- 122 U/L to 4,024 +/- 282 U/L. Continuous infusion of a glutathione (GSH) solution in GSH-depleted animals (22 mumol/kg/hr) attenuated reperfusion injury by 55%. In vitro experiments demonstrated the capability of GSH to react rapidly with reactive oxygen species, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). Only H2O2 oxidized GSH quantitatively to its disulfide; HOCl oxidized GSH to higher oxidation states. These data support the hypothesis that the enhanced release of hepatocellular GSH functions as a defense mechanism against reactive oxygen species generated by inflammatory cells during endotoxemia and reperfusion. This internal defense system of the liver may be of general importance in preventing, or at least limiting, liver damage by reactive oxygen generated in particular by Kupffer cells during their physiological function to remove gut-derived endotoxin and bacteria.
Liu
P
P
Drug Metabolism Research, Upjohn Company, Kalamazoo, Michigan 49001.
Fisher
M A
MA
Farhood
A
A
Smith
C W
CW
Jaeschke
H
H
D000818:Animals; D001427:Bacterial Toxins; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004731:Endotoxins; D005978:Glutathione / Q000008:administration & dosage* / Q000378:metabolism; D007262:Infusions, Intravenous; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D001427:Bacterial Toxins; D004731:Endotoxins; C027952:salmonella toxin; D005978:Glutathione