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627874 
Journal Article 
Toxicity of a trivalent organic arsenic compound, dimethylarsinous glutathione in a rat liver cell line (TRl 1215) 
Sakurai, T; Kojima, C; Kobayashi, Y; Hirano, S; Sakurai, MH; Waalkes, MP; Himeno, S 
2006 
Yes 
British Journal of Pharmacology
ISSN: 0007-1188
EISSN: 1476-5381 
149 
888-897 
English 
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). 
arsenic; arsenite; dimethylarsenic; dimethylarsinous glutathione; dimethylarsinic acid; trivalent methylarsenic; trivalent dimethylarsenic; GSH; methylation; acute promyelocytic leukemia 
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