Suitability of human butyrylcholinesterase as therapeutic marker and pseudo catalytic scavenger in organophosphate poisoning: A kinetic analysis

Aurbek, Nadine; Thiermann, Horst; Eyer, Florian; Eyer, Peter; Worek, Franz

doi:10.1016/j.tox.2009.02.014

Cited by 64 publications

(50 citation statements)

References 38 publications

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“…3 The absence of aging with VX R -(ϩ) is in agreement with the structural and mass spectrometry data. Noteworthy, very slow aging has been recently reported for BChE inhibited by racemic VX, t1 ⁄ 2 ϭ 77 h (9). This half-time value seems to be intermediate between those of the VX R -(ϩ) and the VX S -(Ϫ) conjugates.…”

Section: Discussionmentioning

confidence: 82%

“…Here, the x-ray structures of VR-and CVX-BChE confirm that the long n-butyloxy of CVX or the bulky isobutyloxy of VR do fit as well. 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: 84%

“…This may be favored by the high concentrations of VX required for x-ray crystallography and mass spectrometry. Aging kinetic of BChE inhibited by racemic VX could provide some clues regarding this hypothesis, but the exact concentration of inhibitor was not reported (9). Although unexplained electron density is visible in the active site gorge of the conjugate, next to Trp-82, it does not correspond to a second molecule of V-agents in which P and S atoms large electron density is easily recognizable.…”

Section: Discussionmentioning

confidence: 97%

“…Accordingly, no aging will occur if the alkoxy substituent of V-agents is not pointing toward this pocket. A marginal aging rate is reported for VX-inhibited BChE (t1 ⁄ 2 ϭ 77 h), and no aging could be detected for VR-inhibited BChE (9). Furthermore, mass spectrometry analysis shows that no aged adduct was detectable for BChE treated with an excess solution of racemic VX or VR (10).…”

mentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 94%

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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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“…However, packed RBCs transfusion has advantages over whole blood transfusion, since the total volume administrated into patients is less that could avoid risks of overloading and fever or allergy by substances in serum. Some studies tried to use human ChE substitute's administration [15], however, due to the high costs and large quantity needed, these substitutes could not be used in human now.…”

Section: Discussionmentioning

confidence: 99%

Fresh Red Blood Transfusion as a Successful Erythrocyte Cholinesterase Supplement in Organophosphate Poisoning

Wang¹,

Huang²,

Chen³

et al. 2016

J Clinic Toxicol

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Despite improvements to standard treatments (atropine, oxime) and intensive care management, the mortality associated with organophosphate (OP) poisoning has not substantially decreased. In this study, we evaluated the role of packed red blood cells (RBCs) transfusion in acute OP poisoning. Patients diagnosed with OP poisoning were included in this prospective study, and then were transfused with packed RBCs stored less than 10 days or 10 to 35 days. Cholinesterase (ChE) level in blood, atropine usage and durations were recorded. We found both shorter-and longer-storage RBCs (200~400 ml) significantly increased AChE level in blood, improved ChE recovery, and reduced the usage and shortened the duration of atropine and followed clinical recovery. Shorter-storage RBCs had better effect than longer-storage (longer storage) ones. Due to erythrocyte cholinesterase supplement, packed RBCs might be used as an alternative approach in patients with OP poisoning, especially at the early stages.

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Role of the Laboratory in Detecting Other Poisoning, Including Pesticides, Ethylene Glycol, and Methanol

Dasgupta

2012

Resolving Erroneous Reports in Toxicology and Therapeutic Drug Monitoring

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Suitability of human butyrylcholinesterase as therapeutic marker and pseudo catalytic scavenger in organophosphate poisoning: A kinetic analysis

Cited by 64 publications

References 38 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

Fresh Red Blood Transfusion as a Successful Erythrocyte Cholinesterase Supplement in Organophosphate Poisoning

Role of the Laboratory in Detecting Other Poisoning, Including Pesticides, Ethylene Glycol, and Methanol

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