MODULATION OF SULFUR MUSTARD TOXICITY BY ARGININE ANALOGUES AND RELATED NITRIC OXIDE SYNTHASE INHIBITORS IN VITRO

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Authors
  1. Sawyer, T.W.
Corporate Authors
Defence Research Establishment Suffield, Ralston ALTA (CAN)
Abstract
The modulating effects of a series of arginine analogues and related nitric oxide synthease inhibitors against the toxicity of sulfur mustard (HD) in parimary cultures of chick embryo forebrain neurons were examined. In addition to the previously identified protective compounds, D- and L-nitroarginine methyl est, eight additional arginine analogues were shown to have significant, concentration-dependent protective characteristics against HD toxicity. Of these, L-nitroarginine was the most potent, increasing the LC50 of vehicle-pretreated HD-treated control cultures by approximately 350%. In addition to these protective agents, five compounds related to arginine were also identified that potentiated the toxicity of HD in the neuron cultures in a concentration-dependent manner. This action occurred at concentrations where these chemicals alone exhibited no toxicity. Characterization of the active compounds in this study showed that it was likely that the protective agents, as well as those compounds that potentiated HD toxicity, were exerting their effects at the same biochemical target, but not through the inhibition of nitric oxide synthase. Although the identity of this target site is as yet unknown, these studies demonstrate that subtle alterations to the arginine structure can yield compounds that differentially modulate the toxicity of HD through their activity at a common target site.
Keywords
Molecular analogues;Nitic Oxide Synthase Inhibitors;Modulation;Arginine analogues
Report Number
DRES-OL-96-025 — Reprint
Date of publication
06 Jul 1998
Number of Pages
14
Reprinted from
Toxicological Sciences, vol 46, 1998, p 112-123
DSTKIM No
99-00366
CANDIS No
510254
Format(s):
Hardcopy;Document Image stored on Optical Disk

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