Catalytic organophosphorus compounds scavenging by acetylcholinesterase assisted with aldoximes (CROSBI ID 628053)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Žunec, Suzana ; Katalinić, Maja ; Taylor, Palmer ; Radić, Zoran
engleski
Catalytic organophosphorus compounds scavenging by acetylcholinesterase assisted with aldoximes
The high toxicity of organophosphorus compounds (OP ; tabun, soman and VX) originates from the irreversible inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life‐threatening toxic manifestations call for immediate treatment, which usually consists of a combined administration of anticholinergic drugs and an aldoxime as the reactivator of AChE. A new approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers – enzymes that could react with a nerve agent before it inhibits AChE. Butyrylcholinesterase (BChE), naturally present in plasma, the liver, the small intestine, smooth muscles, heart, adipose tissue, and the brain, is considered an endogenous stoichiometric bioscavenger of OP. Due to the limited concentration of BChE in the organism, a stoichiometric reduction of OP is not sufficient. Furthermore, the stoichiometric approach alone has limitations mostly due to the necessity to reactivate tissue AChE efficiently, particularly when it is repeatedly phosphorylated by an excess of OP that remain in circulation upon exposure. Our studies show that AChE mutagenesis enables aldoximes to substantially accelerate the reactivation of OP‐enzyme conjugates. We here demonstrate the oxime‐mutant hAChE assisted hydrolysis of OPs to be effective both ex vivo in human blood and in vivo in mice. The catalytic scavenging of OPs in mice improved the therapeutic outcome and resulted in a delayed onset of toxicity symptoms. Supported by the NIH (U01 NS058046 and R21NS072086) and CSF (4307)
tabun; soman; VX; reactivation
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Podaci o prilogu
44-x.
2015.
objavljeno
Podaci o matičnoj publikaciji
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference, Elche, Španjolska, Program
Podaci o skupu
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference
pozvano predavanje
27.09.2015-02.10.2015
Elche, Španjolska