Faculty Collaboration Database

An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions. Free Radic Biol Med 2019 Jan;130:1-7

Date

10/24/2018

Pubmed ID

30352302

DOI

10.1016/j.freeradbiomed.2018.10.425

Scopus ID

2-s2.0-85055679458 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.

Author List

Xie LN, Shao J, Huang CH, Li F, Xu D, Kalyanaraman B, Zhu BZ

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antidotes
Carcinogens
Chemical Warfare Agents
Chloranil
Electron Spin Resonance Spectroscopy
Free Radicals
Halogenation
Humans
Models, Theoretical
Nerve Agents
Organic Chemistry Phenomena
Oximes
Pralidoxime Compounds
Pyridinium Compounds