title: Mitochondria are the main target organelle for trivalent monomethylarsonous acid (MMA(III))-induced cytotoxicity.
abstract: Excessive generation of reactive oxygen species (ROS) is considered to play an important role in arsenic-induced carcinogenicity in the liver, lungs, and urinary bladder. However, little is known about the mechanism of ROS-based carcinogenicity, including where the ROS are generated, and which arsenic species are the most effective ROS inducers. In order to better understand the mechanism of arsenic toxicity, rat liver RLC-16 cells were exposed to arsenite (iAs(III)) and its intermediate metabolites [i.e., monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III))]. MMA(III) (IC(50) = 1 μM) was found to be the most toxic form, followed by DMA(III) (IC(50) = 2 μM) and iAs(III) (IC(50) = 18 μM). Following exposure to MMA(III), ROS were found to be generated primarily in the mitochondria. DMA(III) exposure resulted in ROS generation in other organelles, while no ROS generation was seen following exposures to low levels of iAs(III). This suggests the mechanisms of induction of ROS are different among the three arsenicals. The effects of iAs(III), MMA(III), and DMA(III) on activities of complexes I-IV in the electron transport chain (ETC) of rat liver submitochondrial particles and on the stimulation of ROS production in intact mitochondria were also studied. Activities of complexes II and IV were significantly inhibited by MMA(III), but only the activity of complexes II was inhibited by DMA(III). Incubation with iAs(III) had no inhibitory effects on any of the four complexes. Generation of ROS in intact mitochondria was significantly increased following incubation with MMA(III), while low levels of ROS generation were observed following incubation with DMA(III). ROS was not produced in mitochondria following exposure to iAs(III). The mechanism underlying cell death is different among As(III), MMA(III), and DMA(III), with mitochondria being one of the primary target organelles for MMA(III)-induced cytotoxicity.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. narenman@zju.edu.cn
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
authors.forename: Shi
authors.initials: S
authors.lastname: Xu
authors.forename: Takashi
authors.initials: T
authors.lastname: Sawata
authors.forename: Wen Hui
authors.initials: WH
authors.lastname: Hao
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.forename: Na
authors.initials: N
authors.lastname: Bu
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Ogra
authors.forename: Yi Jia
authors.initials: YJ
authors.lastname: Lou
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D017209:Apoptosis; D018053:Arsenites / Q000633:toxicity; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D018053:Arsenites; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; D002101:Cacodylic Acid; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; C015001:arsenite