Maček Hrvat Nikolina, Žunec Suzana, Taylor Palmer, Radić Zoran, Kovarik Zrinka
Institute for Medical Research and Occupational Health, Zagreb, Croatia.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093-0650, USA.
Chem Biol Interact. 2016 Nov 25;259(Pt B):148-153. doi: 10.1016/j.cbi.2016.04.023. Epub 2016 Apr 12.
The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms.
有机磷化合物的高毒性源于对乙酰胆碱酯酶（AChE）的共价抑制，AChE是胆碱能神经传递中的一种关键酶。导致危及生命的毒性表现的中毒需要立即进行治疗，联合使用抗胆碱能药物和一种肟类化合物作为AChE的重活化剂。降低有机磷化合物体内毒性的另一种方法是使用针对母体有机磷酸酯的生物解毒剂。我们之前的研究表明，AChE诱变可使肟类化合物大幅加速有机磷 - 酶缀合物的重活化，同时显著减慢有机磷 - 缀合物脱烷基化（老化）的速率。在此，我们证明了在胆碱结合位点修饰的人AChE突变体（Y337A和Y337A/F338A）在体外人血液和体内小鼠中均可实现高效的HI - 6辅助VX解毒。小鼠体内VX的催化解毒改善了治疗效果并预防了致死性，还导致毒性症状的出现延迟。
