title: Release of apoptotic cytochrome C from mitochondria by dimethylarsinous acid occurs through interaction with voltage-dependent anion channel in vitro.
abstract: 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 (MMA(III)) and dimethylarsinous acid (DMA(III)), are formed by methylation reactions, and they are more reactive and toxic than the inorganic precursor arsenite (iAs(III)); however, the detailed mechanism of toxicity is poorly understood. Here, we studied the effects of three arsenic compounds (i.e., iAs(III), MMA(III), and DMA(III)) on mitochondrial permeability transition pore (mPTP) and release of apoptotic cytochrome c (Cyt c) after incubating with rat liver mitochondria. Inorganic iAs(III) had no effect on mitochondrial swelling even at higher concentrations ranging up to 100 μM, but swelling was significantly induced in the presence of Ca(2+). Additionally, mitochondrial swelling was strongly induced by exposure to the methylated forms of MMA(III) and DMA(III) in a dose-dependent manner in the absence of Ca(2+), 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 Ca(2+) 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-x(L )proteins significantly reduced the release of Cyt c after exposure to DMA(III), suggesting that dimethylated DMA(III) directly interacted with the VDAC in mitochondria and caused the release of Cyt c from mitochondria.
authors.affiliation: Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. narenman@zju.edu.cn
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
authors.forename: Xuan
authors.initials: X
authors.lastname: Chen
authors.forename: Mariko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Wen Wen
authors.initials: WW
authors.lastname: Wang
authors.forename: Kanwal
authors.initials: K
authors.lastname: Rehman
authors.forename: Shi
authors.initials: S
authors.lastname: Xu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.forename: Shu Qing
authors.initials: SQ
authors.lastname: Chen
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats
chemical_list: D007473:Ion Channels; C472511:dimethylarsinous acid; D045304:Cytochromes c; D002101:Cacodylic Acid