alexa Release of apoptotic cytochrome C from mitochondria by dimethylarsinous acid occurs through interaction with voltage-dependent anion channel in vitro
Pharmaceutical Sciences

Pharmaceutical Sciences

Pharmaceutical Regulatory Affairs: Open Access

Author(s): Hua Naranmandura, Mariko Tanaka, Zhe Chen

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Arsenic is known to be a human carcinogen as well as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia. The intermediate metabolites of arsenic, monomethylarsonous 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 mitochondrial swelling even at higher concentrations ranging up to 100μM, but swelling was significantly induced in the presence of Ca2+. Additionally, mitochondrial swelling was strongly induced by exposure to the methylated forms of MMAIII and DMAIII in a dose-dependent manner in the absence of Ca2+, suggesting that the methylated forms may have potent effects on cellular mitochondria. Although mitochondrial swelling was completely inhibited in the presence of cyclosporin-A (an inhibitor of mitochondrial permeability transition) or ruthenium red (an inhibitor of Ca2+ uniporter) following exposure to methylated arsenicals, the release of apoptotic Cyt c from mitochondria was not inhibited, indicating that release of Cyt c is probably not dependent on mPTP opening. In addition, inhibitors of Bax (e.g., Bax-inhibiting peptide) did not reduce the release of Cyt c from the mitochondria by formation of Bax-voltage-dependent anion channel (VDAC) complex, whereas the recombinant Bcl-xL proteins significantly reduced the release of Cyt c after exposure to DMAIII, suggesting that dimethylated DMAIII directly interacted with the VDAC in mitochondria and caused the release of Cyt c from mitochondria.

This article was published in Toxicol Sci and referenced in Pharmaceutical Regulatory Affairs: Open Access

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