Susceptibility to lipopolysaccharide of cholestatic rat liver produced with bile duct ligation: assessments of the mitochondrial glutathione pool and the effects of N-acetylcysteine.

We investigated whether rats with obstructive jaundice produced with bile duct ligation for 2 weeks are more susceptible to the additional stress of lipopolysaccharide (LPS) administration than sham-operated rats and also examined the effects of N-acetylcysteine (NAC) on LPS stimulation in rats with bile duct ligation. The effects of LPS on the mitochondrial glutathione pool and on oxidative stress of polymorphonuclear leukocytes were investigated in cholestatic rats. Serum concentrations of alpha-glutathione S-transferase showed that lipopolysaccharide stimulation caused more severe hepatocellular injury in cholestatic rats than in sham-operated rats. In addition, concentrations of mitochondrial reduced and oxidized glutathione and hepatic adenosine triphosphate showed that LPS stimulation decreased mitochondrial function more in cholestatic rats than in sham-operated rats. Intraperitoneal administration of NAC for 2 weeks significantly improved mitochondrial function and decreased hepatocellular injury. However, the oxidative stress of polymorphonuclear leukocytes that had infiltrated hepatic tissue was increased by NAC. The present results indicate that the cholestatic liver is susceptible to the additional stress of LPS, that NAC suppresses the adverse effects of LPS in cholestatic livers, and that the oxidative stress of polymorphonuclear leukocytes is not significantly involved in mitochondrial dysfunction or hepatocellular injury in this model. Copyright 2000 S. Karger AG, Basel