SINUSOIDAL ENDOTHELIAL-CELLS AS A TARGET FOR ACETAMINOPHEN TOXICITY -DIRECT ACTION VERSUS REQUIREMENT FOR HEPATOCYTE ACTIVATION IN DIFFERENT MOUSE STRAINS

Hepatic congestion occurs early in acetaminophen poisoning. This study examines whether acetaminophen is toxic to sinusoidal endothelial cel ls (SEC), which might lead to microcirculatory disruption. Acetaminoph en toxicity was examined in vivo and in vitro in SEC and hepatocytes f rom C3H-HEN and Swiss Webster mice. In both strains, there was signifi cantly more toxicity to SEC than to hepatocytes; in SEC from C3H-HEN m ice, acetaminophen was directly toxic, but the presence of hepatocytes was required for toxicity to Swiss SEC. Acetaminophen, 750 mg/kg, by gavage caused toxicity with variability within and between strains, bu t all animals died between 3.5 and 6 hr with zone 3 hemorrhagic necros is. Pretreatment of C3H-HEN SEC with aminobenzotriazole, a suicide inh ibitor of P450, abolished toxicity. Baseline glutathione (GSH) levels were comparable, but a 12-hr incubation with acetaminophen decreased G SH by 60 and 8%, respectively, in C3H-HEN and Swiss SEC in single cell type culture. in co culture, under conditions where Swiss SEC Viabili ty declined by 73%, hepatocyte viability and GSH only decreased by 21 and 20%, respectively. In conclusion, acetaminophen was toxic to SEC. It was directly toxic to SEC in one mouse strain and required hepatocy te activation in another strain. The lack of direct toxicity to Swiss SEC may be due to the lack of an activating P450 isozyme. Zone 3 hemor rhagic necrosis in vivo was comparable in both strains, despite differ ences in the pathways leading to SEC toxicity in vitro. We propose tha t toxicity to SEC may contribute to hepatic congestion in acetaminophe n intoxication. (C) 1997 Elsevier Science Inc.