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Potential Role of Activated Nonparenchymal Cells in Acetaminophen-Induced Potentiation of Hepatotoxicity

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Uniformed Services University Of The Health Sciences Bethesda United States

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A role for macrophages in the manifestations of acute chemically-induced hepatic necrosis has been hypothesized, but evidence to prove this has been limited. Acetaminophen has been shown at both necrogenic and non-necrogenic doses to stimulate an inflammatory cell infiltration into the liver Dixon et al. 1971, 1975 Walker et al. 1980, 1983 and Laskin and Pilaro, 1986. It was the goal of this project to determine if the presence of these activated inflammatory cells in the liver after non-necrogenic doses of acetaminophen alters the hepatotoxicity of prototype hepatotoxicants. The studies presented here show that pretreatment of rats with non-necrogenic doses of acetaminophen increased the susceptibility of rats to hepatic injury induced by allyl alcohol, bromobenzene, carbon tetrachloride, 1,1-dichloroethylene, and thioacetamide. Acetaminophen-pretreatment also increased the lethality induced by allyl alcohol and 1,1-dichloroethylene. In vivo, hepatic glutathione levels were decreased twenty-four hours after acetaminophen administration. Yet, acetaminophen-induced glutathione depletion cannot fully explain acetaminophen-induced potentiation of hepatotoxicity in these studies. Administration of dextran sulfate and gadolinium chloride, compounds which suppressed the function of the reticuloendothelial system, protected animals from acetaminophen-induced potentiation of allyl alcohol toxicity. In vitro, nonparenchymal cells from control or acetaminophen-pretreated rats cocultured with hepatocytes did not mimic the in vivo observations. These cocultures were resistant to allyl alcohol at doses which were cytotoxic to hepatocytes cultured alone. Hepatocytes cultured in media conditioned by nonparenchymal cells from acetaminophen-pretreated rats were more sensitive to allyl alcohol than hepatocytes cultured in media from control pretreated rats.

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