Cytotoxic effects of S-(dimethylarsino)-glutathione: A putative intermediate metabolite of inorganic arsenicals

Glutathione (GSH) plays an important role in the metabolism of arsenite and arsenate by generating arsenic-glutathione complexes. Although dimethylarsinic acid (DMAV) is the major metabolite of inorganic arsenicals (iAs) in urine, it is not clear how DMAV is produced from iAs. In the present study we report that S-(dimethylarsino)-glutathione (DMAIII(SG)), a putative precursor of dimethylarsinic acid DMAV, was unstable in the culture medium without excess GSH and generated volatile substances which were highly cytotoxic for both rat heart microvascular endothelial cells and HL60, a human leukemia cell line. Cytotoxicity of DMAIII(SG) was higher than that of iAs and its LC50 value was calculated to be 7.8 μM in the endothelial cells. To our surprise DMAIII(SG) effectively killed cells in the neighbor wells of the same multi-well dish, indicating that volatile toxic compounds generated from DMAIII(SG) in the culture medium. High performance lipid chromatography–inductively coupled plasma mass spectrometry (HPLC–ICPMS) analyses suggested that the freshly generated volatile compounds dissolved into aqueous solution and formed an unstable arsenic compound and the unstable compound was further converted to DMAV. These results suggested that DMAIII(SG) exerts its cytotoxicity by generating volatile arsenicals and is implicated in the metabolic conversion of inorganic arsenicals into DMAV, a major final metabolite of inorganic arsenicals in most mammals.