title: Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity.
abstract: 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 macrophages 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 macrophages by previously injecting liposomes containing dichloromethylene disphosphonate (DMDP). Acetaminophen-induced liver damage was assessed biochemically and histologically. It was shown that the liver damage occurring 0.5, 1, and 2 h after an intraperitoneal injection of acetaminophen was significantly less in mice previously injected with liposomes containing DMDP than in previously untreated mice, or mice previously injected with empty liposomes. By 4 h there was no difference between the groups. We conclude that macrophages play an early and probably a direct role in mediating the liver damage due to acetaminophen. This is consistent with the role that macrophages have been shown to play in the pathogenesis of alcohol-induced liver damage.
authors.affiliation: Division of Pathology Sciences, St Mary's Hospital Medical School, London, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Goldin
authors.forename: I D
authors.initials: ID
authors.lastname: Ratnayaka
authors.forename: C S
authors.initials: CS
authors.lastname: Breach
authors.forename: I N
authors.initials: IN
authors.lastname: Brown
authors.forename: S N
authors.initials: SN
authors.lastname: Wickramasinghe
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004002:Clodronic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D006224:Cricetinae; D004337:Drug Carriers; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008081:Liposomes; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018712:Analgesics, Non-Narcotic; D004337:Drug Carriers; D008081:Liposomes; D004002:Clodronic Acid; D000082:Acetaminophen; D000410:Alanine Transaminase