Cholinesterase Activity in Guinea Pigs Following Intravenous Exposure to the Optically Pure Enantiomers of VX
Technical Report,01 Jan 2016,30 Sep 2016
Combat Capabilities Development Command Chemical Biological Center APG United States
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The center phosphorus atom of VX O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate rotates linearly polarized light both clockwise P-isomer and anticlockwise P-isomer so that its synthesis results in equal amounts of two enantiomers with the same chemical and physical properties. The toxicological properties of the two enantiomers, however, are anticipated to be different because they exert their effects in a chiral, biologic environment. We recently estimated median lethal doses 24 h LD50 for intravenous exposure to the optically pure enantiomers of VX in adult, male guinea pigs the P-isomer of VX was 60 less toxic than the P-isomer. Serial blood samples were collected from a subset of these guinea pigs to characterize the toxicodynamic profile of each enantiomer. Acetylcholinesterase AChE activity was inhibited more slowly with the P-isomer of VX than with the P-isomer. In addition, the P-isomer of VX inhibited nearly 95 of the butyrylcholinesterase BuChE activity compared to only 40 with the P-isomer. The stereoselectivity differences between AChE and BuChE inhibition may explain why the P-isomer of VX was less toxic than the P-isomer in the guinea pig model.