Document Detail


The relationship between diphenylamine structure and NSAIDs-induced hepatocytes injury.
MedLine Citation:
PMID:  19429231     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Many nonsteroidal anti-inflammatory drugs (NSAIDs) with diphenylamine structure induce severe hepatotoxicities. We evaluated the role of diphenylamine structure in liver injuries induced by these NSAIDs. METHODS: Effects of diphenylamine, diclofenac and tolfenamic acid on mitochondrial permeability transition (MPT) and efflux of calcium in isolated liver mitochondria as well as on cellular ATP content and mitochondrial membrane depolarization in rat primary hepatocyte cultures were examined. RESULTS: Diclofenac and tolfenamic acid induced cyclosporine A (CsA)-sensitive mitochondrial swelling and membrane depolarization in isolated liver mitochondria. Only diclofenac caused the release of calcium in isolated liver mitochondria. Diphenylamine had no effects on isolated liver mitochondria. All three compounds decreased ATP content and induced mitochondrial membrane depolarization. CsA attenuated these effects, suggesting MPT might be involved in the hepatotoxicities caused by diphenylamine, diclofenac and tolfenamic acid. SKF-525A, a general inhibitor of CYP450, markedly inhibited the injury induced by diphenylamine, but not diclofenac or tolfenamic acid. CONCLUSION: The hepatotoxicities caused by diclofenac and tolfenamic acid may be attributed to the mitochondrial dysfunction induced by these drugs instead of the diphenylamine structure per se.
Authors:
Yan Li; Xin-Ming Qi; Xiang Xue; Xiong-Fei Wu; Yuan-Feng Wu; Min Chen; Guo-Zhen Xing; Yang Luan; Jin Ren
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-01-16
Journal Detail:
Title:  Toxicology letters     Volume:  186     ISSN:  0378-4274     ISO Abbreviation:  Toxicol. Lett.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-05-11     Completed Date:  2009-05-29     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  111-4     Citation Subset:  IM    
Affiliation:
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Anthranilic Acids / toxicity
Anti-Inflammatory Agents, Non-Steroidal / chemistry*,  toxicity*
Cell Survival / drug effects
Cells, Cultured
Diclofenac / toxicity
Diphenylamine / analogs & derivatives*,  chemistry,  toxicity*
Drug-Induced Liver Injury / pathology*
Enzyme Inhibitors / pharmacology
Hepatocytes / drug effects*,  pathology*
Male
Membrane Potentials / drug effects
Mitochondria, Liver / drug effects
Mitochondrial Swelling / drug effects
Proadifen / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Anthranilic Acids; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Enzyme Inhibitors; 122-39-4/Diphenylamine; 13710-19-5/tolfenamic acid; 15307-86-5/Diclofenac; 302-33-0/Proadifen; 56-65-5/Adenosine Triphosphate

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


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