Document Detail


Modes of cell death in rat liver after monocrotaline exposure.
MedLine Citation:
PMID:  14600277     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Monocrotaline (MCT) is a pyrrolizidine alkaloid (PA) plant toxin that produces sinusoidal endothelial cell (SEC) injury, hemorrhage, fibrin deposition, and coagulative hepatic parenchymal cell (HPC) oncosis in centrilobular regions of rat livers. Cells with apoptotic morphology have been observed in the livers of animals exposed to other PAs. Whether apoptosis occurs in the livers of MCT-treated animals and whether it is required for full manifestation of pathological changes is not known. To determine this, rats were treated with 300 mg MCT/kg, and apoptosis was detected by transmission electron microscopy and the TUNEL (TdT-mediated dUTP nick end labeling) assay. MCT produced significant apoptosis in the liver by 4 h after treatment. To determine if MCT kills cultured HPCs by apoptosis, HPCs were isolated from the livers of rats and exposed to MCT. MCT caused a concentration-dependent release of alanine aminotransferase (ALT), a marker of HPC injury. Furthermore, caspase 3 was activated and TUNEL staining increased in MCT-treated HPCs. MCT-induced TUNEL staining and release of ALT into the medium were completely prevented by the pancaspase inhibitors z-VAD.fmk and IDN-7314, suggesting that MCT kills cultured HPCs by apoptosis. To determine if caspase inhibition prevents MCT-induced apoptosis in the liver, rats were cotreated with MCT and IDN-7314. IDN-7314 reduced MCT-induced TUNEL staining in the liver and release of ALT into the plasma. Morphometric analysis confirmed that IDN-7314 reduced HPC oncosis in the liver by approximately 50%. Inasmuch as HPC hypoxia occurred in the livers of MCT-treated animals, upregulation of the hypoxia-regulated cell-death factor, BNIP3 (Bcl2/adenovirus EIB 19kD-interacting protein 3), was examined. BNIP3 was increased in the livers of mice treated 24 h earlier with MCT. Results from these studies show that MCT kills cultured HPCs by apoptosis but causes both oncosis and apoptosis in the liver in vivo. Furthermore, caspase inhibition reduces both apoptosis and HPC oncosis in the liver after MCT exposure.
Authors:
Bryan L Copple; Catherine M Rondelli; Jane F Maddox; Niel C Hoglen; Patricia E Ganey; Robert A Roth
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2003-11-04
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  77     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-05     Completed Date:  2004-08-31     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  172-82     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824, USA.
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MeSH Terms
Descriptor/Qualifier:
Alanine Transaminase / metabolism
Animals
Apoptosis / drug effects*
Caspase 3
Caspases / antagonists & inhibitors,  metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Hepatocytes / drug effects*,  enzymology,  ultrastructure
In Situ Nick-End Labeling
Kupffer Cells / drug effects*,  enzymology,  ultrastructure
Liver / drug effects*,  enzymology,  pathology
Male
Mice
Mice, Inbred C57BL
Microscopy, Electron
Monocrotaline / administration & dosage,  metabolism,  toxicity*
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
DK50728/DK/NIDDK NIH HHS; ES04139/ES/NIEHS NIH HHS; ES05866/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 315-22-0/Monocrotaline; EC 2.6.1.2/Alanine Transaminase; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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