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Radical model of arsenic(III) toxicity: theoretical and EPR spin trapping studies



Radical model of arsenic(III) toxicity: theoretical and EPR spin trapping studies



Chemical Research in Toxicology 27(5): 765-774



Arsenic is one of the most environmentally significant pollutants and a great global health concern. Although a growing body of evidence suggests that reactive oxygen species (ROS) mediate the mechanism of arsenic toxicity, the exact mechanism remains elusive. In this study, we examine the capacity of trivalent arsenic species arsenous acid (iAs(III)), monomethylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)) to generate ROS through a theoretical analysis of their structures, redox properties, and their reactivities to various ROS using a density functional theory (DFT) approach at the B3LYP/6-31+G**//B3LYP/6-31G* level of theory and by employing electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap. Results show that the oxidized forms (As(IV)) are structurally more stable compared to the reduced forms (As(II)) that impart elongated As-O bonds leading to the formation of As(III) and hydroxide anion. Enthalpies of one-electron reduction and oxidation indicate that increasing the degree of methylation makes it harder for As(III) to be reduced but easier to be oxidized. The order of increasing favorability for arsenical activation by ROS is O2 < O2(•-) < HO(•), and the oxidation of DMA(III) to DMA(V) is highly exoergic in multiple redox pathways with concomitant generation of radicals. This is followed by MMA(III) and by iAs(III) being the least favorable. Spin trapping studies showed a higher propensity for methylated arsenicals to generate radicals than iAs(III) upon treatment with H2O2. However, in the presence of Fe(II,III), all showed radical generation where MMA(III) gave predominantly C-centered adducts, while acidified iAs (III) and DMA(III) gave primarily HO-adducts, and their formation was affected in the presence of SOD suggesting a As(III)-OO/OOH radical intermediate. Therefore, our results suggest a basis for the increased redox activity of methylated arsenicals that can be applied to the observed trends in arsenic methylation and toxicity in biological systems.

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Accession: 055345908

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PMID: 24754521

DOI: 10.1021/tx4004227


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