Prophylaxis against Soman Inhalation Toxicity in Guinea Pigs by Pretreatment Alone with Human Serum Butyrylcholinesterase,

Allon, Nahum

doi:10.1006/toxs.1998.2463

Cited by 19 publications

(10 citation statements)

References 30 publications

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“…Human BChE is also known to be a good scavenger of organophosphorus (OP) pesticides and chemical warfare nerve agents [5]. For example, injections of purified BChE as pretreatment against nerve agent poisoning in mice, rats and guinea pigs increased their survival with a higher efficiency than the classical pretreatment with pyridostigmine [6–8]. Similar observations have been reported for monkeys [9,10].…”

mentioning

confidence: 81%

Engineering of a monomeric and low‐glycosylated form of human butyrylcholinesterase

Nachon

Nicolet

Viguié

et al. 2002

European Journal of Biochemistry

128

113

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Human butyrylcholinesterase (BChE; EC 3.1.1.8) is of particular interest because it hydrolyzes or scavenges a wide range of toxic compounds including cocaine, organophosphorus pesticides and nerve agents. The relative contribution of each N-linked glycan for the solubility, the stability and the secretion of the enzyme was investigated. A recombinant monomeric BChE lacking four out of nine N-glycosylation sites and the C-terminal oligomerization domain was stably expressed as a monomer in CHO cells. The puri®ed recombinant BChE showed catalytic properties similar to those of the native enzyme. Tetragonal crystals suitable for X-ray crystallography studies were obtained; they were improved by recrystallization and found to diract to 2.0 A Ê resolution using synchrotron radiation. The crystals belong to the tetragonal space group I422 with unit cell dimensions a b 154.7 A Ê , c 124.9 A Ê , giving a V m of 2.73 A Ê 3 per Da (estimated 60% solvent) for a single molecule of recombinant BChE in the asymmetric unit. The crystal structure of butyrylcholinesterase will help elucidate unsolved issues concerning cholinesterase mechanisms in general.

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mentioning

confidence: 81%

Engineering of a monomeric and low‐glycosylated form of human butyrylcholinesterase

Nachon

Nicolet

Viguié

et al. 2002

European Journal of Biochemistry

128

113

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“…The treatment of OP poisoning is based mainly on therapeutic combination of anti‐cholinergic drugs such as atropine together with quaternary oxime reactivators of inhibited acetylcholinesterase such as 2‐pyridinealdoximemethiodide and toxogonin [2–4]. The potential use of acetylcholinesterase and butyrylcholinesterase for stoichiometric scavenging of toxic OPs and various OP hydrolases (OPHs) as catalytic scavengers has been studied extensively [5–8]. OPHs could also be used for noncorrosive decontamination of sensitive surfaces including human skin [9].…”

mentioning

confidence: 99%

Enhanced stereoselective hydrolysis of toxic organophosphates by directly evolved variants of mammalian serum paraoxonase

et al. 2006

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We addressed the ability of various organophosphorus (OP) hydrolases to catalytically scavenge toxic OP nerve agents. Mammalian paraoxonase (PON1) was found to be more active than Pseudomonas diminuta OP hydrolase (OPH) and squid O,O-di-isopropyl fluorophosphatase (DFPase) in detoxifying cyclosarin (O-cyclohexyl methylphosphonofluoridate) and soman (O-pinacolyl methylphosphonofluoridate). Subsequently, nine directly evolved PON1 variants, selected for increased hydrolytic rates with a fluorogenic diethylphosphate ester, were tested for detoxification of cyclosarin, soman, O-isopropyl-O-(p-nitrophenyl) methyl phosphonate (IMP-pNP), DFP, and chlorpyrifos-oxon (ChPo). Detoxification rates were determined by temporal acetylcholinesterase inhibition by residual nonhydrolyzed OP. As stereoisomers of cyclosarin and soman differ significantly in their acetylcholinesterase-inhibiting potency, we actually measured the hydrolysis of the more toxic stereoisomers. Cyclosarin detoxification was $ 10-fold faster with PON1 mutants V346A and L69V. V346A also exhibited fourfold and sevenfold faster hydrolysis of DFP and ChPo, respectively, compared with wild-type, and ninefold higher activity towards soman. L69V exhibited 100-fold faster hydrolysis of DFP than the wildtype. The active-site mutant H115W exhibited 270-380-fold enhancement toward hydrolysis of the P-S bond in parathiol, a phosphorothiolate analog of parathion. This study identifies three key positions in PON1 that affect OP hydrolysis, Leu69, Val346 and His115, and several amino-acid replacements that significantly enhance the hydrolysis of toxic OPs. GC ⁄ pulsed flame photometer detector analysis, compared with assay of residual acetylcholinesterase inhibition, displayed stereoselective hydrolysis of cyclosarin, soman, and IMP-pNP, indicating that PON1 is less active toward the more toxic optical isomers.

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“…Administration of exogenous cholinesterases can provide protection against nerve agents, as was demonstrated in a variety of rodent models (Allon et al, 1998;Ashani et al, 1991;Brandeis et al, 1993;Genovese and Doctor, 1995;Maxwell et al, 1993) and in primates (Maxwell et al, 1992;Raveh et al, 1997). The considerable success with plasma-purified butyrylcholinesterase (BChE) as an OP bioscavenger (Ashani, 2000;Doctor and Saxena, 2005) brings to the foreground, nonetheless, the question of the practicality of this therapeutic approach as it depends on the availability of large amounts of these human enzymes, which are required in stoichiometric rather than catalytic quantities.…”

Section: A Stoichiometric Bioscavengersmentioning

confidence: 99%

Organophosphate Intoxication

Geyer

Evron

Soreq

et al. 2009

Handbook of Toxicology of Chemical Warfare Agents

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Prophylaxis against Soman Inhalation Toxicity in Guinea Pigs by Pretreatment Alone with Human Serum Butyrylcholinesterase,

Cited by 19 publications

References 30 publications

Engineering of a monomeric and low‐glycosylated form of human butyrylcholinesterase

Engineering of a monomeric and low‐glycosylated form of human butyrylcholinesterase

Enhanced stereoselective hydrolysis of toxic organophosphates by directly evolved variants of mammalian serum paraoxonase

Organophosphate Intoxication

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