Radical Model of Arsenic(III) Toxicity: Theoretical and EPR Spin Trapping Studies

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• 作者：Pedro L. Zamora ; Antal Rockenbauer ; Frederick A. Villamena
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：May 19, 2014
• 年：2014
• 卷：27
• 期：5
• 页码：765-774
• 全文大小：561K
• 年卷期：v.27,no.5(May 19, 2014)
• ISSN：1520-5010

文摘

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鈥揙 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^{鈥⑩€?/sup> < HO鈥?/sup>, and the oxidation of DMAIII to DMAV is highly exoergic in multiple redox pathways with concomitant generation of radicals. This is followed by MMAIII and by iAsIII being the least favorable. Spin trapping studies showed a higher propensity for methylated arsenicals to generate radicals than iAsIII upon treatment with H₂O₂. However, in the presence of FeII,III, all showed radical generation where MMAIII gave predominantly C-centered adducts, while acidified iAs III and DMAIII gave primarily HO-adducts, and their formation was affected in the presence of SOD suggesting a AsIII鈥揙O/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.}