Isolation, anticholinesterase properties, and acute toxicity in mice of the four stereoisomers of the nerve agent soman

Benschop, H. P.; Konings, Cornelis A. G.; Genderen, J.L. van; Jong, L.P.A. de

doi:10.1016/0041-008x(84)90249-7

Cited by 143 publications

(69 citation statements)

References 21 publications

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“…The most probable cause for the lower protective efficacy of BChE against soman intoxication observed in mice (see above) is its lower stereoselectivity toward OP agents, compared with AChE. The limited stereoselectivity of BChE toward the different stereoisomers of soman was manifested for both rHuBChE and equine serum BChE and contrasts the marked stereoselectivity of the human or native bovine AChEs (Table 4) (Benschop et al, 1984;Benschop and de Jong, 1988;De Bisschop et al, 1991;Millard et al, 1998;Ordentlich et al, 1999Ordentlich et al, , 2004. Thus, unlike AChE, which is highly stereoselective toward the toxic P Sdiastereomer, BChE displays considerable reactivity toward both the toxic P S -and the nontoxic P R -diastereomers of soman.…”

Section: Comparison Of the Ability Of Ache And Bche To Neutralize Op mentioning

confidence: 99%

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Comparison of Polyethylene Glycol-Conjugated Recombinant Human Acetylcholinesterase and Serum Human Butyrylcholinesterase as Bioscavengers of Organophosphate Compounds

Cohen

Kronman²,

Raveh³

et al. 2006

Mol Pharmacol

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Comparative protection studies in mice demonstrate that on a molar basis, recombinant human acetylcholinesterase (rHuAChE) confers higher levels of protection than native human butyrylcholinesterase (HuBChE) against organophosphate (OP) compound intoxication. For example, mice challenged with 2.5 LD 50 of O-isopropyl methylphosphonofluoridate (sarin), pinacolylmethyl phosphonofluoridate (soman), and O-ethyl-S-(2-isopropylaminoethyl) methylphosphonothiolate (VX) after treatment with equimolar amounts of the two cholinesterases displayed 80, 100, and 100% survival, respectively, when pretreatment was carried out with rHuAChE and 0, 20, and 60% survival, respectively, when pretreatment was carried out with HuBChE. Kinetic studies and active site titration analyses of the tested OP compounds with acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs) from different mammalian species demonstrate that the superior in vivo efficacy of acetylcholinesterases is in accordance with the higher stereoselectivity of AChE versus BChE toward the toxic enantiomers comprising the racemic mixtures of the various OP agents. In addition, we show that polyethylene glycol-conjugated (PEGylated) rHuAChE, which is characterized by a significantly extended circulatory residence both in mice and monkeys (Biochem J 357:795-802, 2001; Biochem J 378:117-128, 2004), retains full reactivity toward OP compounds both in vitro and in vivo and provides a higher level of protection to mice against OP poisoning, compared with native serum-derived HuBChE. Indeed, PEGylated rHuAChE also confers superior prophylactic protection when administered intravenously or intramuscularly over 20 h before exposure of mice to a lethal dose of VX (1.3-1.5 LD 50 ). These findings together with the observations that the PEGylated rHuAChE exhibits unaltered biodistribution and high bioavailability present a case for using PEGylated rHuAChE as a very efficacious bioscavenger of OP agents.

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Section: Comparison Of the Ability Of Ache And Bche To Neutralize Op mentioning

confidence: 99%

“…Bimolecular rate constants for HuAChE with VX and soman are based on Ordentlich et al (1999Ordentlich et al ( , 2004. Bimolecular rate constants for BoAChE with VX, sarin, and soman are based on Benschop et al (1984) and Benschop and de Jong (1988). Bimolecular rate constants for HuBChE with sarin and VX were determined in the present study.…”

Section: Tablementioning

confidence: 99%

Comparison of Polyethylene Glycol-Conjugated Recombinant Human Acetylcholinesterase and Serum Human Butyrylcholinesterase as Bioscavengers of Organophosphate Compounds

Cohen

Kronman²,

Raveh³

et al. 2006

Mol Pharmacol

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“…In aqueous solutions soman exists in the form of four stereoisomers, P(+)C(+) to P(-)C(-), the pair of P(-) isomers being about 100 times more toxic than the P(+) ones. This is caused by their higher affinity to cholinesterases, which may be inhibited almost completely (Benschop et al 1984;Johnson et al 1985).…”

Section: Introductionmentioning

confidence: 97%

Detoxification of soman in the perfused rat liver: Quantitative uptake and stereoisomer metabolism

Wahlländer

Szinicz

1990

Arch Toxicol

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The detoxification of soman (1,2,2-dimethyl-propyl methylphosphonofluoridate) was measured in rat livers, using hemoglobin-free, non-recirculating perfusion in situ. Since the detoxification processes may differ in perivenous and periportal zones of liver parenchyma, soman uptake, stereoselective metabolism and inhibition of esterases were compared in antegrade and retrograde perfusion experiments. At low concentrations of soman (up to about 10 mumol l-1 for 5 min) soman was taken up by the liver nearly quantitatively. About 5% recovery rate in the perfusate corresponded well to the intrahepatic shunt flow. Infusions of higher amounts yielded increasing recovery rates. The racemic infusion medium contained the four isomers of soman, C(-)P(-) to C(+)P(+), in nearly identical amounts, whereas in the effluent perfusate only P(-) isomers were found. Even small amounts of soman (5-120 nmol g-1 liver wet weight) caused significant inhibition of hepatic aliesterase activity. Doses higher than 200 nmol g-1 suppressed esterase activity by more than 90%. No essential differences in soman uptake, stereoselective metabolism or inhibition of esterases were found between antegrade and retrograde perfusion experiments.

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“…First, reactivation occurs more readily with the conjugated S p -than the R penantiomers.The S p -phosphonates have been shown previously to be the more inhibitory or faster reacting enantiomer (9)(10)(11)17,18). If we assume an orientation, where the leaving group directed out of the gorge and where the phosphonyl oxygen directed towards the oxyanion hole, facilitates the acylation reaction (9-11), then the S p -enantiomers will have the phosphonyl methyl 'linkage to /-serine for the diastereomer directed to the space-confining acyl pocket and the more bulky alkoxyl group will be directed to the choline subsite ( fig.…”

Section: Conclusion and Directions Of The Oxime Studiesmentioning

confidence: 99%

Cholinesterase Structure: Identification of Residues and Domains Affecting Organophosphate Inhibition and Catalysis

Taylor¹

1998

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Isolation, anticholinesterase properties, and acute toxicity in mice of the four stereoisomers of the nerve agent soman

Cited by 143 publications

References 21 publications

Comparison of Polyethylene Glycol-Conjugated Recombinant Human Acetylcholinesterase and Serum Human Butyrylcholinesterase as Bioscavengers of Organophosphate Compounds

Comparison of Polyethylene Glycol-Conjugated Recombinant Human Acetylcholinesterase and Serum Human Butyrylcholinesterase as Bioscavengers of Organophosphate Compounds

Detoxification of soman in the perfused rat liver: Quantitative uptake and stereoisomer metabolism

Cholinesterase Structure: Identification of Residues and Domains Affecting Organophosphate Inhibition and Catalysis

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