Toxicity of a trivalent organic arsenic compound, dimethylarsinous glutathione in a rat liver cell line (TRL 1215)

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 . British Journal of Pharmacology (2006) 149 , 888–897. doi: 10.1038/sj.bjp.0706899