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J.Health Sci., 49(3), 171-178, 2003
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Biomethylation of Arsenic is Essentially Detoxicating Event
Teruaki Sakurai*
Laboratory of Environmental Chemistry, School of Life Science, Tokyo University of Pharmacy and Life Science, Horinouchi 1432-1, Hachioji, Tokyo 192-0392, Japan
Inorganic arsenic is clearly a toxicant and carcinogen in humans. In mammals, including humans, inorganic arsenic often undergo methylation, forming compounds such as pentavalent dimethyarsinic acid (DMAsV). Recent evidence indicates that DMAsV is a complete carcinogen in rodents while evidence for inorganic arsenic as a carcinogen in rodents remains unclear. Thus, we studied the molecular mechanisms of the in vitro cytolethality of DMAsV compared to that of the trivalent inorganic arsenic, sodium arsenite, using rat liver TRL 1215 cells. Arsenite was very cytotoxic in these cells; its lethal concentration in vitro in 50% of a population (LC50) was 20 mu M after a 48-hr exposure. With arsenite, most dead cells showed histological and biochemical evidence of necrosis. The arsenite cytolethality markedly increased when cellular reduced glutathione (GSH) was depleted with the glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). In contrast, DMAsV was nearly three orders of magnitude less cytotoxic (LC50 = 1.5 mM) although evidence showed the predominating form of death was apoptosis. Surprisingly, GSH depletion actually decreased the DMAsV-induced apoptosis. It is suggested that DMAsV requires intracellular GSH to induce apoptosis. Ethacrynic acid (EA), an inhibitor of glutathione S-transferase that catalyzes GSH-substrate conjugation, and aminooxyacetic acid (AOAA), an inhibitor of beta-lyase which catalyzes the final breakdown of GSH-substrate conjugates, were also effective in suppressing the DMAsV-induced apoptosis. These findings indicate that DMAsV was likely conjugated in some form with cellular GSH, and this conjugate induced apoptosis during subsequent metabolic reactions. Because apoptosis is a process by which organisms eliminate abnormal cells, the arsenic biomethylation in the human body may essentially a detoxicating event.
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