MODULATION OF MACROPHAGE FUNCTIONING ABROGATES THE ACUTE HEPATOTOXICITY OF ACETAMINOPHEN

Acetaminophen is a mild analgesic and antipyretic agent that is safe a nd 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 g enerally thought to be caused by direct interaction of its reactive me tabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirec tly through the release of cytotoxic mediators. We analyzed the potent ial role of hepatic macrophages in acetaminophen hepatotoxicity by exa mining 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 necrosi s, 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 tiss ue injury induced by acetaminophen. To exclude the possibility that th e effects of gadolinium chloride, dextran sulfate; or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of th ese agents on various pharmacokinetic properties of this analgesic. De xtran sulfate and gadolinium chloride had no effect on the half-life o f a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of ace taminophen-mercapturic acid. LPS treatment of rats caused a general de pression of acetaminophen metabolism involving all of the known pathwa ys of metabolic clearance, resulting in a decrease in the blood half-l ife of the drug. However, the fraction of the dose converted to the to xic metabolite (NAPQI) was not different from that observed in rats gi ven acetaminophen alone. Collectively, these data indicate that the pr otection afforded the animals by pretreatment with macrophage modulato rs was not due to suppression of the formation of NAPQI and hence supp ort the hypothesis that macrophages may contribute directly to acetami nophen hepatotoxicity by an independent mechanism.