Document Detail


Activation of the Nrf2 pathway, but decreased gamma-glutamylcysteine synthetase heavy subunit chain levels and caspase-3-dependent apoptosis during exposure of primary mouse hepatocytes to diphenylarsinic acid.
MedLine Citation:
PMID:  17628625     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Diphenylarsinic acid (DPAsV) is a degradation product of chemical warfare agents, over which there has been a public outcry in the Kamisu Area of Ibaraki Prefecture in Japan. In this study, we investigated the cytotoxicity of and cellular response to DPAsV in primary mouse hepatocytes. Exposure of the hepatocytes to DPAsV resulted in cell damage accompanied by cellular accumulation of DPAsV in a time-dependent manner. The cell death caused by DPAsV was attributable to apoptosis. DPAsV activated a basic leucine-zipper transcription factor Nrf2 as determined by the nuclear translocation of Nrf2, anti-oxidant response element (ARE)-dependent luciferase activity, and upregulation of downstream gene products. However, gamma-glutamylcysteine synthetase heavy subunit chain (gamma-GCS(H)), which is regulated by Nrf2, underwent cleavage by activated caspase-3 to a 17 kDa fragment, leading to a minimal level of constitutive gamma-GCS(H) expression 72 h following the exposure (25 microM). Experiments with cycloheximide revealed that the DPAsV-mediated reduction in gamma-GCS(H) was due to a post-translational modification. The results suggest that DPAsV causes caspase-3-dependent cleavage of gamma-GCS(H) regardless of Nrf2 activation in primary mouse hepatocytes.
Authors:
Daigo Sumi; Aiko Manji; Yasuhiro Shinkai; Takashi Toyama; Yoshito Kumagai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-06-18
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  223     ISSN:  0041-008X     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-09-10     Completed Date:  2007-10-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  218-24     Citation Subset:  IM    
Affiliation:
Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Arsenicals / chemistry,  pharmacology*
Blotting, Western
Caspase 3 / metabolism*
Cell Survival / drug effects
Cells, Cultured
Chemical Warfare Agents / chemistry,  toxicity*
Down-Regulation
Glutamate-Cysteine Ligase / biosynthesis*
Hepatocytes / drug effects*,  enzymology,  metabolism,  pathology
Mice
Molecular Structure
NF-E2-Related Factor 2 / metabolism*
Chemical
Reg. No./Substance:
0/Arsenicals; 0/Chemical Warfare Agents; 0/NF-E2-Related Factor 2; 0/diphenylarsinic acid; EC 3.4.22.-/Caspase 3; EC 6.3.2.2/Glutamate-Cysteine Ligase

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