Mitochondria are the main target organelle for trivalent monomethylarsonous acid (MMA(III))-induced cytotoxicity
- PMID: 21648415
- DOI: 10.1021/tx200156k
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.
© 2011 American Chemical Society
Similar articles
-
Comparative toxicity of arsenic metabolites in human bladder cancer EJ-1 cells.Chem Res Toxicol. 2011 Sep 19;24(9):1586-96. doi: 10.1021/tx200291p. Epub 2011 Aug 16. Chem Res Toxicol. 2011. PMID: 21815631
-
Trivalent methylated arsenical-induced phosphatidylserine exposure and apoptosis in platelets may lead to increased thrombus formation.Toxicol Appl Pharmacol. 2009 Sep 1;239(2):144-53. doi: 10.1016/j.taap.2008.12.020. Epub 2009 Jan 6. Toxicol Appl Pharmacol. 2009. PMID: 19167414
-
Arsenite and its mono- and dimethylated trivalent metabolites enhance the formation of benzo[a]pyrene diol epoxide-DNA adducts in Xeroderma pigmentosum complementation group A cells.Chem Res Toxicol. 2009 Feb;22(2):382-90. doi: 10.1021/tx800335p. Chem Res Toxicol. 2009. PMID: 19146383
-
The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds.Toxicol Appl Pharmacol. 2004 Aug 1;198(3):458-67. doi: 10.1016/j.taap.2003.10.023. Toxicol Appl Pharmacol. 2004. PMID: 15276427 Review.
-
Arsenic-induced bladder cancer in an animal model.Toxicol Appl Pharmacol. 2007 Aug 1;222(3):258-63. doi: 10.1016/j.taap.2006.10.010. Epub 2006 Oct 17. Toxicol Appl Pharmacol. 2007. PMID: 17109909 Review.
Cited by
-
A Computational Model of Endogenous Hydrogen Peroxide Metabolism in Hepatocytes, Featuring a Critical Role for GSH.Comput Toxicol. 2024 Mar;29:100299. doi: 10.1016/j.comtox.2024.100299. Epub 2024 Jan 23. Comput Toxicol. 2024. PMID: 38682127
-
Update of the risk assessment of inorganic arsenic in food.EFSA J. 2024 Jan 18;22(1):e8488. doi: 10.2903/j.efsa.2024.8488. eCollection 2024 Jan. EFSA J. 2024. PMID: 38239496 Free PMC article.
-
Mechanisms Associated with Cognitive and Behavioral Impairment Induced by Arsenic Exposure.Cells. 2023 Oct 28;12(21):2537. doi: 10.3390/cells12212537. Cells. 2023. PMID: 37947615 Free PMC article. Review.
-
Expanding the Chemical Space of Arsenicin A-C Related Polyarsenicals and Evaluation of Some Analogs as Inhibitors of Glioblastoma Stem Cell Growth.Mar Drugs. 2023 Mar 17;21(3):186. doi: 10.3390/md21030186. Mar Drugs. 2023. PMID: 36976235 Free PMC article.
-
Arsenic and cancer: Evidence and mechanisms.Adv Pharmacol. 2023;96:151-202. doi: 10.1016/bs.apha.2022.08.001. Epub 2022 Sep 27. Adv Pharmacol. 2023. PMID: 36858772 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials