Protection of Acetylcholinesterase from Organophosphates: Kinetic Insight into Bioscavengers

Publisher Summary This chapter discusses the critical role that binding affinity (Km) and substrate specificity (kcat/Km) play in protecting acetylcholinesterase (AchE) against organophosphorous (OP)-induced AChE inhibition. OP neurotoxicant-induced inhibition of AChE, EC 3.1.1.7 results in an accumulation of acetylcholine (ACh) in the neural synaptic junctions. The resulting enhancement of nerve impulses leads to a wide variety of hypercholinergic effects that ultimately result in muscular dysfunction and nerve damage. Traditional treatment of OP poisoning has utilized three categories of drugs: muscarinic receptor blocking agents, such as atropine, cholinesterase reactivators, such as pralidoxime chloride (2-PAM), and emetics, cathartics, and adsorbents to decrease further absorption. While this combined treatment is useful in nerve agent poisoning mitigation, it can have toxic effects of its own and is not always successful in treating extreme OP poisonings. The addition of catalytic bioscavengers to the exposure treatment procedures has proven effective at mitigating and even preventing the cholinergic effects of toxic OP exposures in mice. Similarly, it is possible to raise the LD50 for paraoxon from 400–800 LD50. Furthermore, both of the OP hydrolytic enzymes demonstrate significant protective effects as determined by the AChE-protector/inhibitor:protection ratio in vitro .