ACETAMINOPHEN-INDUCED LIVER OXIDATIVE STRESS AND HEPATOTOXICITY - INFLUENCE OF KUPFFER CELL-ACTIVITY ASSESSED IN THE ISOLATED-PERFUSED RAT-LIVER

The influence of acetaminophen (APAP) treatment (400 mg/kg) on Kupffer cell function was studied in the isolated perfused liver by colloidal carbon infusion, concomitantly with parameters related to oxidative s tress (thiobarbituric acid reactants (TEARS) formation and glutathione (GSH) content) and tissue injury (sinusoidal efflux of lactate dehydr ogenase (LDH)). APAP led to increased rates of hepatic TEARS formation , GSH depletion, and higher sinusoidal LDH efflux compared to control values, without changes in the basal rate of O-2 consumption. In addit ion, APAP significantly enhanced the rate of carbon uptake by perfused livers and the associated carbon-induced O-2 consumption, with carbon -induced LDH effluxes being increased by 411% over control values or b y 124% compared to basal LDH release in APAP-treated rats. APAP-induce d changes in liver TEARS formation and GSH levels were attenuated by g adolinium chloride (GdCl3) pretreatment, whereas those in carbon uptak e, carbon-induced respiration, and LDH efflux were abolished. GdCl3 pr etreatment decreased liver O-2 consumption irrespectively of APAP trea tment, an effect that seems to be due to depression of mitochondrial r espiration. It is concluded that APAP intoxication enhances Kupffer ce ll function as assessed in the intact liver, which may represent an im portant source of reactive O-2 species and chemical mediators conditio ning the increased oxidative stress status and the tissue injury which developed.