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
acetaminophen. 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.