IN-VIVO ENDOTOXIN ENHANCES BILIARY ETHANOL-DEPENDENT FREE-RADICAL GENERATION

Endotoxemia is associated with alcoholic liver diseases; however, the effect of endotoxin on the oxidation of ethanol is not known. We teste d the hypothesis that endotoxin treatment enhances hepatic ethanol rad ical production. The generation of free radicals by the liver was stud ied with spin-trapping technique utilizing the primary trap ethanol (0 .8 g/kg) and the secondary trap alpha-(4-pyridyl-1-oxide)-N-t-butylnit rone (4-POBN; 500 mg/kg). Electron paramagnetic resonance (EPR) spectr a of bile showed six-line signals, which were dependent on ethanol, in dicating the trapping of ethanol-dependent radicals. Intravenous injec tions of Escherichia coli lipopolysaccharide (0.5 mg/kg) 0.5 h before 4-POBN plus ethanol treatment caused threefold increases of biliary ra dical adducts. EPR analyses of bile from [1-C-13]ethanol-treated endot oxic rats showed the presence of species attributable to a-hydroxyethy l adduct, carbon-centered adducts, and ascorbate radical. The generati on of endotoxin-induced increases of ethanol-dependent radicals was su ppressed by 50% on GdCl3 (20 mg/kg iv) or desferrioxamine mesylate (1 g/kg ip) treatment. Our data show that in vivo endotoxin increases bil iary ethanol-dependent free radical formation and that these processes are modulated by Kupffer cell activation and catalytic metals.