Document Detail


Myeloperoxidase-mediated bioactivation of 5-hydroxythiabendazole: A possible mechanism of thiabendazole toxicity.
MedLine Citation:
PMID:  21513789     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Thiabendazole (TBZ), an antihelminthic and antifungal agent, is associated with a host of adverse effects including nephrotoxicity, hepatotoxicity, and teratogenicity. Bioactivation of the primary metabolite of TBZ, 5-hydroxythiabendazole, has been proposed to yield a reactive intermediate. Here we show that this reactive intermediate can be catalyzed by myeloperoxidase (MPO), a neutrophil-bourne peroxidase. Using a cell viability endpoint, we examined the toxicity of TBZ, 5OH-TBZ, and MPO-generated metabolites in cell-based models including primary rat proximal tubule epithelial cells, NRK-52E rat proximal tubule cells, and H9C2 rat myocardial cells. Timecourse experiments with MPO showed complete turnover of 5OH-TBZ within 15min and a dramatic leftward shift in dose-response curves after 12h. After a 24h exposure in vitro, the LC(50) of this reactive intermediate was 23.3±0.2μM reduced from greater than 200μM from 5OH-TBZ alone, an approximately 10-fold decrease. LC(50) values were equal in all cell types used. Comparison of lactate dehydrogenase leakage and caspase 3/7 activity revealed that cell death caused by the reactive intermediate is primarily associated with necrosis rather than apoptosis. This toxicity can be completely rescued via incubation with rutin, an inhibitor of MPO. These results suggest that MPO-mediated biotransformation of 5OH-TBZ yields a reactive intermediate which may play a role in TBZ-induced toxicity.
Authors:
Joseph D Jamieson; Evan B Smith; Deepak K Dalvie; Gregory J Stevens; Gina M Yanochko
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-12
Journal Detail:
Title:  Toxicology in vitro : an international journal published in association with BIBRA     Volume:  -     ISSN:  1879-3177     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8712158     Medline TA:  Toxicol In Vitro     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Ltd.
Affiliation:
Pfizer Global Research and Development, 10646 Science Center Drive, San Diego, CA 92121, USA.
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