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


METHODS
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).


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
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).
Sakurai
T
T
Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan. teruaki@ph.bunri-u.ac.jp
Kojima
C
C
Kobayashi
Y
Y
Hirano
S
S
Sakurai
M H
MH
Waalkes
M P
MP
Himeno
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism; D020261:Arsenic Poisoning / Q000378:metabolism; D001152:Arsenicals / Q000138:chemical synthesis / Q000378:metabolism; D018053:Arsenites / Q000009:adverse effects / Q000378:metabolism; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002855:Chromatography, Thin Layer / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008745:Methylation; D051381:Rats; D011916:Rats, Inbred F344; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D001152:Arsenicals; D018053:Arsenites; D012709:Serum Albumin; C472511:dimethylarsinous acid; C515055:darinaparsin; D002101:Cacodylic Acid; D005978:Glutathione