Glutathione depletion enhances the formation of superoxide anion released into hepatic sinusoids after lipopolysaccharide challenge

Background: We examined the effects of glutathione depletion on the level o f superoxide anion released into hepatic sinusoids after lipopolysaccharide challenge. Methods: Rats were given 1 mg/kg of maleic acid diethyl ester to deplete gl utathione in vivo and then 0.5 mg/kg body weight of lipopolysaccharide. Results: This treatment significantly depleted serum reduced glutathione (3 2.7 +/- 1.7 vs. 23.0 +/- 3.2 mM, p = 0.002). However, it did not affect the serum oxidized glutathione concentration (2.88 +/- 0.56 vs. 3.10 +/- 0.78 mM, not significant). The lipopolysaccharide challenge caused significant s uperoxide anion formation as compared with controls (0.12 +/- 0.04 vs. 0.22 +/- 0.05 o.d., p < 0.001), and it was enhanced significantly by glutathion e depletion (0.28 +/- 0.04 o.d., p < 0.05). There were no significant diffe rences in levels of lipopolysaccharide (2142 +/- 452 vs. 2503 +/- 612 pg/ml ) and tumor necrosis factor alpha (277 +/- 186 vs. 252 +/- 88 pg/ml) after the lipopolysaccharide challenge between the glutathione-depleted and nonde pleted rats. Moreover, the purine nucleoside phosphorylase/glutamic-pyruvic transaminase ratio in liver perfusates, a marker of damage to endothelial cells in hepatic sinusoids, was significantly higher in the glutathione-dep leted rats than in the nondepleted rats. Conclusions: The reduced form of glutathione can decrease levels of the sup eroxide anion released into hepatic sinusoids and can decrease subsequent d amage to endothelial cells in these sinusoids caused by lipopolysaccharide; that is, it can reduce lipopolysaccharide-induced liver injury.