Document Detail


Toxicity of uricosuric diuretics in rat hepatocyte culture.
MedLine Citation:
PMID:  2706015     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of the uricosuric properties of some of them. This study was designed to test the utility of the hepatocyte monolayer culture as a model for studying these compounds. In addition, an attempt was made to define the structural components that are common to hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid and A-49816, an investigational compound, were found to be toxic in hepatocyte cultures; thus, with the exception of indacrinone, paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chemical structure. A-56234, an investigational uricosuric, was also found to be toxic in cultures but has not been demonstrated to be hepatotoxic in humans in limited clinical experience. It does not possess the ketodichlorophenoxyacetic acid structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the ketodichlorophenoxyacetic acid structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is ketodichlorophenoxyacetic acid or a closely related compound. The hepatocyte monolayer system appears to be a good model for demonstrating toxicity and, perhaps, for predicting toxicity of new compounds under development.
Authors:
K G Tolman; P D Gray; S el Masry; R R Luther; R S Janicki
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  38     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1989 Apr 
Date Detail:
Created Date:  1989-05-12     Completed Date:  1989-05-12     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1181-4     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Diuretics / toxicity*
Drug Evaluation, Preclinical / methods
Ethacrynic Acid / toxicity
Glycolates / toxicity
Indans / toxicity
Liver / drug effects*
Male
Models, Biological
Rats
Rats, Inbred Strains
Ticrynafen / toxicity
Uricosuric Agents / toxicity*
Chemical
Reg. No./Substance:
0/Diuretics; 0/Glycolates; 0/Indans; 0/Uricosuric Agents; 40180-04-9/Ticrynafen; 56049-88-8/indanone; 58-54-8/Ethacrynic Acid; 78235-72-0/A 49816

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


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