title: Enhancement of allyl alcohol hepatotoxicity by endotoxin requires extrahepatic factors.
abstract: Noninjurious doses of bacterial endotoxin (lipopolysaccharide; LPS) enhance allyl alcohol-induced liver damage in rats in a Kupffer cell (KC)-dependent fashion. To investigate the mechanism by which KCs contribute to liver injury in this model, isolated KCs and hepatocytes (HCs) were cocultured. Addition of LPS to the cocultured cells did not enhance allyl alcohol-induced cytotoxicity. In addition, recirculating perfusion of isolated livers from naïve rats with LPS for 2 h did not significantly enhance allyl alcohol-induced toxicity as measured by release of alanine aminotransferase (ALT). These results suggest an extrahepatic factor is required for LPS potentiation of allyl alcohol hepatotoxicity. To examine whether the coagulation cascade contributes to injury in this model, rats were given either warfarin at 42 and 18 h before LPS, or heparin at 1 h before LPS, and were treated with allyl alcohol 2 h after LPS. Warfarin and heparin each significantly blocked the decrease in plasma fibrinogen levels and attenuated the increase in plasma ALT activity in rats treated with LPS and allyl alcohol. To assess the role of thrombin in this injury, isolated livers from rats pretreated with LPS were perfused with thrombin or vehicle and allyl alcohol. Though LPS pretreatment enhanced the toxicity of allyl alcohol compared with livers from naïve rats, perfusion with thrombin did not increase sensitivity to allyl alcohol. In summary, LPS augments the hepatotoxicity of allyl alcohol through a mechanism involving extrahepatic factors, one of which may be a component of the coagulation cascade.
authors.affiliation: Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, 214 Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Kinser
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002469:Cell Separation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D004731:Endotoxins / Q000633:toxicity*; D005340:Fibrinogen / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D007728:Kupffer Cells / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008111:Liver Function Tests; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D010477:Perfusion; D020005:Propanols / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000502:physiology
chemical_list: D000925:Anticoagulants; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004731:Endotoxins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D020005:Propanols; D012333:RNA, Messenger; C006463:allyl alcohol; D005340:Fibrinogen; D006493:Heparin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013917:Thrombin