Release of Apoptotic Cytochrome c From Mitochondria by Dimethylarsinous Acid Occurs Through Interaction With Voltage- Dependent Anion Channel In Vitro

Arsenic is known to be a human carcinogen as well as one of the most effective drugs for treatment of patients with acute promye-locytic leukemia. The intermediate metabolites of arsenic, mono-methylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), are formed by methylation reactions, and they are more reactive and toxic than the inorganic precursor arsenite (iAsIII); however, the detailed mechanism of toxicity is poorly understood. Here, we studied the effects of three arsenic compounds (i.e., iAsIII, MMAIII, and DMAIII) on mitochondrial permeability transition pore (mPTP) and release of apoptotic cytochrome c (Cyt c) after incubating with rat liver mitochondria. Inorganic iAsIII had no effect on mitochon-drial swelling even at higher concentrations ranging up to 100μM, but swelling was significantly induced in the presence of Ca2+. Add-itionally, mitochondrial swelling was strongly induced by exposure to the methylated forms of MMAIII and DMAIII in a dose-dependen