Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen.
Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophen-mercapturic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Laskin
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DL
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08855-0789, USA.
Gardner
C R
CR
Price
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VF
Jollow
D J
DJ
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016264:Dextran Sulfate / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats
D008070:Lipopolysaccharides; D000082:Acetaminophen; D016264:Dextran Sulfate; D005682:Gadolinium; C038958:gadolinium chloride