ROLE OF MACROPHAGES IN ACETAMINOPHEN (PARACETAMOL)-INDUCED HEPATOTOXICITY

Research into the pathogenesis of acetaminophen (paracetamol)-induced hepatotoxicity has concentrated on the generation of toxic metabolites by the hepatocytes, It has, however, recently been shown that human m acrophages cultured with acetaminophen secrete increased quantities of tumour necrosis factor (TNF). This study examines whether macrophages have a direct role in acetaminophen toxicity, using a mouse model in which it is possible to eliminate more that 99 per cent of hepatic mac rophages by previously injecting liposomes containing dichloromethylen e disphosphonate (DMDP), Acetaminophen-induced liver damage was assess ed biochemically and histologically, It was shown that the liver damag e occurring 0.5, 1, and 2 h after an intraperitoneal injection of acet aminophen was significantly less in mice previously injected with lipo somes containing DMDP than in previously untreated mice, or mice previ ously injected with empty liposomes. By 4 h there was no difference be tween the groups. We conclude that macrophages play an early and proba bly a direct role in mediating the liver damage due to acetaminophen, This is consistent with the role that macrophages have been shown to p lay in the pathogenesis of alcohol-induced liver damage.