+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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.

(PDF emailed within 0-6 h: $19.90)

Accession: 055345908

Download citation: RISBibTeXText

PMID: 24754521

DOI: 10.1021/tx4004227

Related references

Time resolved esr studies on carbohydrate radical spin trapping by 2 methyl 2 nitrosopropane hydroxyalkyl radical trapping kinetics. Abstracts of Papers American Chemical Society 199(1-2): CARB 89, 1990

Theoretical and experimental studies of the spin trapping of inorganic radicals by 5,5-dimethyl-1-pyrroline N-oxide (DMPO). 2. Carbonate radical anion. Journal of Physical Chemistry. A 111(2): 384-391, 2007

Theoretical and experimental studies of the spin trapping of inorganic radicals by 5,5-dimethyl-1-pyrroline N-oxide (DMPO). 1. Carbon dioxide radical anion. Journal of Physical Chemistry. A 110(49): 13253-8, 2006

Theoretical and experimental studies of the spin trapping of inorganic radicals by 5,5-dimethyl-1-pyrroline N-oxide (DMPO). 3. Sulfur dioxide, sulfite, and sulfate radical anions. Journal of Physical Chemistry. A 116(26): 7210-7218, 2012

Intramolecular electron transfer between tyrosyl radical and cysteine residue inhibits tyrosine nitration and induces thiyl radical formation in model peptides treated with myeloperoxidase, H2O2, and NO2-: EPR SPIN trapping studies. Journal of Biological Chemistry 280(49): 40684-40698, 2005

Superoxide anion radical production as a cadmium-mediated mechanism of toxicity in avian thyroid: An electron spin resonance study by spin trapping. Comparative Biochemistry and Physiology C Pharmacology Toxicology and Endocrinology 118(1): 89-95, 1997

Effect of the phosphoryl substituent in the linear nitrone on the spin trapping of superoxide radical and the stability of the superoxide adduct: combined experimental and theoretical studies. Journal of Organic Chemistry 71(20): 7753-7762, 2006

Amyloid beta-peptide spin trapping. I: Peptide enzyme toxicity is related to free radical spin trap reactivity. Neuroreport 6(3): 489-492, 1995

Intramolecular Electron Transfer between Tyrosyl Radical and Cysteine Residue Inhibits Tyrosine Nitration and Induces Thiyl Radical Formation in Model Peptides Treated with Myeloperoxidase, H subscript 2O subscript 2, and NO subscript 2 superscript -: EPR SPIN TRAPPING STUDIES. Journal of biological chemistry9 280(49): 40684-40698, 2005

New insights into the detection of sulfur trioxide anion radical by spin trapping: radical trapping versus nucleophilic addition. Free Radical Biology & Medicine 47(2): 128-134, 2009

Theoretical study of the spin trapping of hydroxyl radical by cyclic nitrones: a density functional theory approach. Journal of the American Chemical Society 126(6): 1816-1829, 2004

Theoretical study of low-spin, high-spin, and intermediate-spin states of [Fe(III)(pap)2](+) (pap = N-2-pyridylmethylidene-2-hydroxyphenylaminato). Mechanism of light-induced excited spin state trapping. Journal of Physical Chemistry. A 111(25): 5515-5522, 2007

Study of reproducibility of spin trapping results in the use of C-phenyl-N-tert-butyl nitrone (PBN) for trichloromethyl radical detection in CCl4 metabolism by rat liver microsomal dispersions. Biological spin trapping I. Journal of Biochemical and Biophysical Methods 29(3-4): 189-205, 1994

Spin trapping and spin labeling studies of oxygen toxicity. Canadian Federation of Biological Societies Proceedings (21): 105, 1978