The prevention of acetaminophen-induced hepatotoxicity by the interferon inducer poly(rI·rC)

When mice were pretreated with the interferon inducer poly(rI·rC) for 24 hr, the mortality caused by acetaminophen was significantly reduced. Acetaminophen doses up to 600 mg/kg which killed 100% of the saline-treated control mice caused no deaths in poly(rI·rC)-treated animals. Even doses as high as 900 mg/kg acetaminophen killed only 38% of the animals. Histological examination of the livers demonstrated that acetaminophen-induced necrosis was decreased in poly(rI·rC)-treated animals compared to controls. Significant protection against necrosis was observed even with doses as high as 900 mg/kg acetaminophe. Following a dose of 300 mg acetaminophen, 0.67 ± 0.5 nmol/mg protein were covalently bound to liver protein in control mice compared to 0.33 ± 0.02 nmol/mg protein bound in poly(rI·rC)-treated mice. This protective effect of poly(rI·rC) did not result from an increase in hepatic glutathione content; in fact, the glutathione level was depressed in animals treated with poly(rI·rC). Since cytochrome P-450 levels were depressed in these experiments, it is concluded that poly(rI·rC) depresses the cytochrome P-450 species responsible for the formation of the toxic metabolite and less reactive species are available for binding to cell macromolecules. It is likely that the toxicity of acetaminophen will be decreased considerably during viral infections which promote the formation of interferon.