Biomethylation of Arsenic is Essentially Detoxicating Event

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概要

• 論文の詳細を見る

• 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 (LC_<50>) was 20μM 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 (LC_<50>=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 break-down 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.

• 公益社団法人日本薬学会の論文
• 2003-06-01

著者

• Sakurai Teruaki

  Laboratory Of Environmental Chemistry School Of Life Science Tokyo University Of Pharmacy And Life S

関連論文

• Mechanisms of Cadmium Transport in Mammalian Cells (特集1:若手が拓く微量元素研究の最前線)
• Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds(Biochemistry)
• Clinical Pharmacokinetic Study of Arsenic Trioxide in an Acute Promyelocytic Leukemia (APL) Patient : Speciation of Arsenic Metabolites in Serum and Urine(Pharmacology)
• Evaluation of Immunotoxic Effects of Arsenic and Other Trace Elements on Human Peripheral Blood Monocytes
• Biomethylation of Arsenic is Essentially Detoxicating Event
• 研究学術賞受賞論文「浜理薬品賞」 Chemical and Biological Studies for the Molecular Mechanisms of Human Trivalent Dimethylarsenic Metabolite-Induced Cytolethality; Chemical Biology of Arsenicals (特集:骨と微量元素)

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