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Citation
Tags
HERO ID
627874
Reference Type
Journal Article
Title
Toxicity of a trivalent organic arsenic compound, dimethylarsinous glutathione in a rat liver cell line (TRl 1215)
Author(s)
Sakurai, T; Kojima, C; Kobayashi, Y; Hirano, S; Sakurai, MH; Waalkes, MP; Himeno, S
Year
2006
Is Peer Reviewed?
Yes
Journal
British Journal of Pharmacology
ISSN:
0007-1188
EISSN:
1476-5381
Volume
149
Issue
7
Page Numbers
888-897
Language
English
PMID
17043674
DOI
10.1038/sj.bjp.0706899
Web of Science Id
WOS:000242742600009
Abstract
BACKGROUND AND PURPOSE: Although inorganic arsenite (As(III)) is toxic in humans, it has recently emerged as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). In humans and most animals, As(III) is enzymatically methylated in the liver to weakly toxic dimethylarsinic acid (DMAs(V)) that is a major pentavalent methylarsenic metabolite. Recent reports have indicated that trivalent methylarsenicals are produced through methylation of As(III) and participate in arsenic poisoning. Trivalent methylarsenicals may be generated as arsenical-glutathione conjugates, such as dimethylarsinous glutathione (DMAs(III)G), during the methylation process. However, less information is available on the cytotoxicity of DMAs(III)G. EXPERIMENTAL APPROACH: We synthesized and purified DMAs(III)G using high performance TLC (HPTLC) methods and measured its cytotoxicity in rat liver cell line (TRL 1215 cells). KEY RESULTS: DMAs(III)G was highly cytotoxic in TRL 1215 cells with a LC(50) of 160 nM. We also found that DMAs(III)G molecule itself was not transported efficiently into the cells and was not cytotoxic; however it readily became strongly cytotoxic by dissociating into trivalent dimethylarsenicals and glutathione (GSH). The addition of GSH in micromolar physiological concentrations prevented the breakdown of DMAs(III)G, and the DMAs(III)G-induced cytotoxicity. Physiological concentrations of normal human serum (HS), human serum albumin (HSA), and human red blood cells (HRBC) also reduced both the cytotoxicity and cellular arsenic uptake induced by exposure to DMAs(III)G. CONCLUSIONS AND IMPLICATIONS: These findings suggest that the significant cytotoxicity induced by DMAs(III)G may not be seen in healthy humans, even if DMAs(III)G is formed in the body from As(III).
Keywords
arsenic; arsenite; dimethylarsenic; dimethylarsinous glutathione; dimethylarsinic acid; trivalent methylarsenic; trivalent dimethylarsenic; GSH; methylation; acute promyelocytic leukemia
Tags
IRIS
•
Arsenic (Inorganic)
1. Literature
PubMed
Toxline, TSCATS, & DART
Web of Science
Identified during manual review of authoritative sources
3. Hazard ID Screening
Other potentially supporting studies
4. Adverse Outcome Pathways/Networks Screening
Relevant
5. Susceptibility Screening
Excluded/Not relevant
•
Arsenic MOA
4. Adverse Outcome Pathways
Cell viability, cell proliferation, cell cycle changes (unrelated to regenerative proliferation)
5. Health Effect
Liver Effects
1. MOA Literature Screening
MOA Cluster
Susceptibility Screening
•
Arsenic Susceptibility
5. Health Effect
Not Relevant
1. Susceptibility Literature Screening
Supplemental Search
2. Excluded
MOA/Mechanistic
3. References Identified During Review
•
Inorganic Arsenic (7440-38-2) [Final 2025]
1. Initial Lit Search
PubMed
WOS
ToxNet
4. Considered through Oct 2015
6. Cluster Filter through Oct 2015
7. Other Studies through Oct 2015
MOA
iAs MOA Literature Categorization
Cytotoxicity and Regenerative Proliferation
Endocrine Signaling
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