Chromatographic resolution, characterisation and quantification of VX enantiomers in hemolysed swine blood samples

Reiter, Georg; Mikler, John; Hill, Ira; Weatherby, Kendal; Thiermann, Horst; Worek, Franz

doi:10.1016/j.jchromb.2008.08.001

Cited by 51 publications

(35 citation statements)

References 29 publications

(33 reference statements)

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“…Thus, VX S -(Ϫ) is only 5.4-fold more potent than VX R -(ϩ), in good agreement with literature data (12,13).…”

Section: Inhibition Rate Constants For Optically Pure Vx Enantiomers-supporting

confidence: 91%

“…This explains why no aging was observed during mass spectrometry analysis of the VR-BChE conjugate or kinetics experiments (9). By extrapolation from VX, the P S adducts results likely from the in-line attack by VR R and CVX R , whereas we expect a strong selectivity of human AChE for VR S and CVX S , knowing that VX S -(Ϫ) is at least already 100-fold more reactive than VX R -(ϩ) (12,13).…”

Section: Discussionmentioning

confidence: 88%

“…However, measurements of the inhibition rate of separated VX isomers by independent laboratory showed that VX S -(Ϫ) inhibits BChE a few-fold faster than VX R -(ϩ), whereas the difference in rate is more than 2 orders of magnitude for hAChE (12,13). This in turn leads to the conclusion that both cholinesterases share the same stereoselectivity for VX S -(Ϫ) but that AChE is much more stereoselective than BChE.…”

mentioning

confidence: 99%

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Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Wandhammer

Carletti²,

Schans

et al. 2011

Journal of Biological Chemistry

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Nerve agents are chiral organophosphate compounds (OPs) that exert their acute toxicity by phosphorylating the catalytic serine of acetylcholinesterase (AChE). The inhibited cholinesterases can be reactivated using oximes, but a spontaneous timedependent process called aging alters the adduct, leading to resistance toward oxime reactivation. Human butyrylcholinesterase (BChE) functions as a bioscavenger, protecting the cholinergic system against OPs. The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhibited in solution or in cristallo with racemic V-agents (VX, Russian VX, and Chinese VX) systematically show the formation of the P S adduct. In this configuration, no catalysis of aging seems possible as confirmed by the three-dimensional structures of the three conjugates incubated over a period exceeding a week. Crystals of BChE soaked in optically pure VX R -(؉) and VX S -(؊) solutions lead to the formation of the P S and P R adduct, respectively. These structural data support an in-line phosphonylation mechanism. Additionally, they show that BChE reacts with VX R -(؉) in the presence of racemic mixture of V-agents, at odds with earlier kinetic results showing a moderate higher inhibition rate for VX S -(؊). These combined results suggest that the simultaneous presence of both enantiomers alters the enzyme stereoselectivity. In summary, the three-dimensional data show that BChE reacts preferentially with P R enantiomer of V-agents and does not age, in complete contrast to AChE, which is selectively inhibited by the P S enantiomer and ages.

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“…Thus, VX S -(Ϫ) is only 5.4-fold more potent than VX R -(ϩ), in good agreement with literature data (12,13).…”

Section: Inhibition Rate Constants For Optically Pure Vx Enantiomers-supporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

See 1 more Smart Citation

Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Wandhammer

Carletti²,

Schans

et al. 2011

Journal of Biological Chemistry

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show abstract

“…In that article, he focused on the separation and detection of VX to study the stereoselective degradation of VX in plasma. Reiter et al (2008) published the chiral separation of VX isomers with gas chromatography using a HYDRODEX-β-TBDAc column. The same authors reported the chiral separation of VX isomers using LC-MS with Chiral AGP column.…”

Section: Vxmentioning

confidence: 99%

Laboratory Analysis of Chemical Warfare Agents, Adducts, and Metabolites in Biomedical Samples

Schans¹

2015

Handbook of Toxicology of Chemical Warfare Agents

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“…Determination of toxicological and toxicokinetic parameters of nerve agents for the development of antidotal therapies demands consideration of different biochemical and physiological characteristics of its stereoisomers. Hence, in order to assess toxicokinetic and toxicodynamic properties, reliable analytical methods are required for the specific and selective determination of individual isomers of OP in blood and plasma [1,2].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a sensitive gas chromatography–ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species

Tenberken

Worek

Thiermann

et al. 2010

Journal of Chromatography B

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Chromatographic resolution, characterisation and quantification of VX enantiomers in hemolysed swine blood samples

Cited by 51 publications

References 29 publications

Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Laboratory Analysis of Chemical Warfare Agents, Adducts, and Metabolites in Biomedical Samples

Development and validation of a sensitive gas chromatography–ammonia chemical ionization mass spectrometry method for the determination of tabun enantiomers in hemolysed blood and plasma of different species

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