Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat.
Monocrotaline (MCT) is a pyrrolizidine alkaloid plant toxin that produces hepatotoxicity in humans and animals. Human exposure to MCT occurs through consumption of contaminated grains and herbal medicines. Administration of MCT to rats stimulates activation of the coagulation system and fibrin deposition in the liver. Fibrin deposition occurs simultaneously with endothelial cell damage and prior to hepatic parenchymal cell injury. Accordingly, the hypothesis that activation of the coagulation system is required for MCT-induced liver injury was tested. Treatment of rats with either heparin or warfarin significantly reduced MCT-induced activation of the coagulation system and the increase in alanine aminotransferase activity in the plasma, a biomarker of hepatic parenchymal cell injury. Histopathological examination of liver sections revealed that heparin decreased parenchymal cell necrosis but did not affect central venular endothelial cell damage, congestion and dilation of the sinusoids, or hemorrhage in the liver. Morphometric analysis revealed that 28% of the area of livers from MCT-treated rats contained regions of coagulative necrosis, whereas less than 5% of the area of livers from rats treated with MCT and heparin contained these regions. By contrast, neither heparin nor warfarin prevented MCT-induced damage to endothelial cells in the liver as estimated by increased plasma hyaluronic acid concentration. These results suggest that activation of the coagulation system is required for MCT-induced parenchymal cell injury but not endothelial cell injury in the liver.
Copple
Bryan L
BL
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
Woolley
Brook
B
Banes
Amy
A
Ganey
Patricia E
PE
Roth
Robert A
RA
D000704:Analysis of Variance; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004727:Endothelium / Q000187:drug effects*; D005337:Fibrin / Q000378:metabolism*; D006493:Heparin / Q000627:therapeutic use*; D008297:Male; D016686:Monocrotaline / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; D016686:Monocrotaline; D005337:Fibrin; D006493:Heparin