QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.026179v1 70/3/1121    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cohen, O. Articles by Shafferman, A. Search for Related Content PubMed PubMed Citation Articles by Cohen, O. Articles by Shafferman, A.

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

Departments of Biochemistry and Molecular Genetics (O.C., C.K., O.M., A.O., A.S.) and Pharmacology (L.R.), Israel Institute for Biological Research, Ness-Ziona, Israel

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 LD₅₀ 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 pre-treatment 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 acetyl-cholinesterases 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 (PEGy-lated) rHuAChE, which is characterized by a significantly extended circulatory residence both in mice and monkeys ( Biochem J 357: 795-802, 2001[CrossRef][Medline] ; Biochem J 378: 117-128, 2004[CrossRef][Medline] ), 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 LD₅₀). 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.

Received for publication May 1, 2006.

Accepted for publication June 22, 2006.

Address correspondence to: Dr. Avigdor Shafferman, Israel Institute for Biological Research, Ness-Ziona 74100, Israel. E-mail: avigdor{at}iibr.gov.il

This article has been cited by other articles:

				O. Mazor, O. Cohen, C. Kronman, L. Raveh, D. Stein, A. Ordentlich, and A. Shafferman Aging-Resistant Organophosphate Bioscavenger Based on Polyethylene Glycol-Conjugated F338A Human Acetylcholinesterase Mol. Pharmacol., September 1, 2008; 74(3): 755 - 763. [Abstract] [Full Text] [PDF]

				O. Cohen, C. Kronman, A. Lazar, B. Velan, and A. Shafferman Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants J. Biol. Chem., December 7, 2007; 282(49): 35491 - 35501. [Abstract] [Full Text] [PDF]