Document Detail


Arjunolic acid, a triterpenoid saponin, prevents acetaminophen (APAP)-induced liver and hepatocyte injury via the inhibition of APAP bioactivation and JNK-mediated mitochondrial protection.
MedLine Citation:
PMID:  19969075     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug and is safe at therapeutic doses but its overdose frequently causes liver injury. In earlier studies, we demonstrated that arjunolic acid (AA) has a protective effect against chemically induced hepatotoxicity. The purpose of this study was to explore whether AA plays any protective role against APAP-induced acute hepatotoxicity and, if so, what molecular pathways it utilizes for the mechanism of its protective action. Exposure of rats to a hepatotoxic dose of acetaminophen (700 mg/kg, ip) altered a number of biomarkers (related to hepatic oxidative stress), increased reactive oxygen species production, reduced cellular adenosine triphosphate level, and induced necrotic cell death. Arjunolic acid pretreatment (80 mg/kg, orally), on the other hand, afforded significant protection against liver injury. Arjunolic acid also prevented acetaminophen-induced hepatic glutathione depletion and APAP metabolite formation although arjunolic acid itself did not affect hepatic glutathione levels. The results suggest that this preventive action of arjunolic acid is due to the metabolic inhibition of specific forms of cytochrome P450 that activate acetaminophen to N-acetyl-p-benzoquinone imine. In addition, administration of arjunolic acid 4 h after acetaminophen intoxication reduced acetaminophen-induced JNK and downstream Bcl-2 and Bcl-xL phosphorylation, thus protecting against mitochondrial permeabilization, loss of mitochondrial membrane potential, and cytochrome c release. In conclusion, the data suggest that arjunolic acid affords protection against acetaminophen-induced hepatotoxicity through inhibition of P450-mediated APAP bioactivation and inhibition of JNK-mediated activation of mitochondrial permeabilization.
Authors:
Jyotirmoy Ghosh; Joydeep Das; Prasenjit Manna; Parames C Sil
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Publication Detail:
Type:  Journal Article     Date:  2009-12-04
Journal Detail:
Title:  Free radical biology & medicine     Volume:  48     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-03     Completed Date:  2010-06-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  535-53     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Inc. All rights reserved.
Affiliation:
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
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MeSH Terms
Descriptor/Qualifier:
Acetaminophen / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cytochrome P-450 Enzyme System / metabolism
Glutathione / metabolism
Hepatocytes / drug effects*
Hydroxyl Radical
Liver / drug effects*
MAP Kinase Kinase 4 / metabolism*
Male
Mitochondria / drug effects,  metabolism*
Oxidative Stress
Rats
Reactive Oxygen Species
Saponins / chemistry*
Superoxides / metabolism
Triterpenes / pharmacology*
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Reactive Oxygen Species; 0/Saponins; 0/Triterpenes; 103-90-2/Acetaminophen; 11062-77-4/Superoxides; 3352-57-6/Hydroxyl Radical; 465-00-9/arjunolic acid; 70-18-8/Glutathione; 9035-51-2/Cytochrome P-450 Enzyme System; EC 2.7.12.2/MAP Kinase Kinase 4

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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