Free radical production from the interaction of 2-chloroethyl vesicants (mustard gas) with pyridine nucleotide-driven flavoprotein electron transport systems

The biochemical sequelae to chloroethyl mustard exposure correspond very well to toxic processes initiated by free radicals. Additionally, mustard solutions contain spontaneously formed cyclic onium ions which produce carbon free radicals when reduced electrochemically. Therefore, we hypothesized th...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2009-01, Vol.234 (1), p.128-134
Main Authors: Brimfield, A.A., Mancebo, A.M., Mason, R.P., Jiang, J.J., Siraki, A.G., Novak, M.J.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
Biological and medical sciences
BRAIN
Brain - metabolism
BRASSICA
Chemical and industrial products toxicology. Toxic occupational diseases
Chemical warfare
Chemical Warfare Agents - toxicity
Chloroethyl mustards
Cytochromes c - metabolism
ELECTROCHEMISTRY
ELECTRON SPIN RESONANCE
Electron Spin Resonance Spectroscopy
Electron transport
Enzymatic reduction
EPITHELIUM
EPR
EPR SPECTROMETERS
EYES
Flavoenzyme
Free radical
Free Radicals - metabolism
Gas, fumes
HEAT
Humans
LIVER
Liver - metabolism
Medical sciences
METABOLIC ACTIVATION
Mustard Gas - toxicity
NADP - metabolism
NADPH-Ferrihemoprotein Reductase - metabolism
NITRIC OXIDE
Nitric Oxide Synthase - metabolism
NITROGEN MUSTARD
Nitrogen Mustard Compounds - toxicity
NUCLEOTIDES
Onium ion
OXIDOREDUCTASES
PYRIDINE
Pyridines
RATS
SKIN
Spin Trapping
SULFUR
Swine
Thioredoxin-Disulfide Reductase - metabolism
TOXICITY
Toxicology
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Summary:The biochemical sequelae to chloroethyl mustard exposure correspond very well to toxic processes initiated by free radicals. Additionally, mustard solutions contain spontaneously formed cyclic onium ions which produce carbon free radicals when reduced electrochemically. Therefore, we hypothesized that the onium ions of sulfur or nitrogen mustards might produce carbon free radicals upon being reduced enzymatically, and that these radicals might constitute a metabolic activation. We set out to document radical production using an in vitro metabolic system and electron paramagnetic resonance (EPR). Our system consisted of NADPH, one of several pyridine nucleotide-driven flavoprotein reductases, cytochrome c as a terminal electron acceptor, various sulfur or nitrogen mustards and the spin trap α-[4-pyridyl-1-oxide]- N- tert-butylnitrone in buffer. Reactions were started by adding the reductase to the other materials, vortexing and immediately transferring the mixture to a 10 mm EPR flat cell. Repeated scans on a Bruker ESP 300E EPR spectrometer produced a triplet of doublets with hyperfine splitting constants of a N = 15.483 G and a H = 2.512 G. The outcome supported our hypothesis that carbon-centered free radicals are produced when mustard-related onium ions are enzymatically reduced. The EPR results varied little with the chloroethyl compound used or with porcine or human cytochrome P450 reductase, the reductase domain of rat brain neuronal nitric oxide synthase or rat liver thioredoxin reductase. Our results offer new insight into the basis for mustard-induced vesication and the outcome of exposure to different mustards. The free radical model provides an explanation for similarities in the lesions arising from mustard exposure and energy-based lesions such as those from heat, ultraviolet and nuclear radiation as well as damage across tissue types such as skin, eyes or airway epithelium.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2008.10.002