Biomethylation of Arsenic is Essentially Detoxicating Event

抄録

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 (DMAs^V). Recent evidence indicates that DMAs^V 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 DMAs^V 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 μM 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, DMAs^V 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 DMAs^V-induced apoptosis. It is suggested that DMAs^V 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 β-lyase which catalyzes the final breakdown of GSH-substrate conjugates, were also effective in suppressing the DMAs^V-induced apoptosis. These findings indicate that DMAs^V 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.