Naslov
Catalytic organophosphorus compounds scavenging by acetylcholinesterase assisted with aldoximes

Autori
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Žunec, Suzana ; Katalinić, Maja ; Taylor, Palmer ; Radić, Zoran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference, Elche, Španjolska, Program / - , 2015

Skup
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference

Mjesto i datum
Elche, Španjolska, 27.09.2015. - 02.10.2015

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
tabun; soman; VX; reactivation

Sažetak
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)

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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