Nerve agents AChE inhibition

TABLE 12. Stereoselectivity in nerve agent AChE inhibition and acute toxicity (reprinted in part with permission from ref 58 Copyright 1988 American Chemical Society). 

The destruction of acetylcholine by AChE is a very rapid reaction. Approximately 104 molecules of acetylcholine are hydrolyzed per second by a single AChE molecule. In contrast, hydrolysis of the nerve agent-AChE complex is much slower than hydrolysis of the acetylated enzyme that is produced by complexation with the normal substrate, ACh. The result is that the activity of AChE is inhibited for a prolonged period. 

The primary mechanism of conventional OP-containiiig chemical nerve agents is inhibition of cholinesterase and the concomitant accumulation of ACh. Logically, vascular smooth muscle contractility will be altered if substantially high levels of circulating ACh remain. Freeman et al. (1986) reported that the disruption of ACh signaling... 

Pyridostigmine is one of a class of neuroactive compounds called carbamates. Its chemical structure and that of a related carbamate, physostigmine, are shown below. Like the nerve agents, carbamates inhibit the enzymatic activity of AChE. As a quaternary amine, pyridostigmine is ionized under normal physiological conditions and penetrates poorly into the central nervous system... 

All what applies to CW agents is basically also true for toxic industrial compounds (TIC) like pesticides, etc. Organophosphorus pesticides are used extensively to control agricultural pests. Similary to nerve agents, they inhibit the enzyme acetylcholinesterase (AChE) [8]. Expositions mainly might occur in pesticide production plants and dnring their application in forestry, agriculture, and horticulture. Chemically similar compounds are used as flexibilizers or additives in lubrication solvents. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

The kinetic scheme for the reactivation of OP-inhibited AChE is depicted in equation 20 for pyridinium-based aldoximes, where R = CH3 or an alkoxy group, and = alkyl or aryl. The nerve agents that generate the covalent OP-AChE conjugates are those with R = CH3 and R = ethyl(VX), isopropyl (sarin), cyclohexyl (cyclosarin) and pinacolyl (soman). For tabun-inhibited AChE, R = Af,A-dimethylamido and R = ethyl. 

The pX a (6.5-8.2) and nucleophilicity of MINA, 44, and of a series of aliphatic oximes derived from it, were found to be consistent with their ability to reactivate AChE inhibited by the nerve agents, sarin and VX. Yet, despite their ability to significantly reactivate AChE in the brains of sarin-intoxicated rats, these aliphatic oximes are not used as antidotes for treatment of OP poisoning in humans this is presumably due to their poor stability in aqueous solution and to their rapid clearance from the circulation. 

OPs have been in use for several decades as important chemicals for the control of crop pests. With their chemical and biochemical reactions, OPs have been well established as extremely poisonous chemicals. This classification is due to the inhibition of the marker enzyme ChE, which is produced in the liver. Blood enzymes provide an estimate of tissue enzyme activity. After acute exposure to OPs or a nerve agent, the erythrocyte enzyme activity most closely reflects the activity of the tissue enzyme. Once the OPs inhibit the tissue enzyme, it cannot hydrolyze ACh, and the accumulation stimulates the affected organ. Based on the manner of exposure (dose and duration) to different OPs, a series of toxicity signs and symptoms set in the organism, leading to death. These are important aspects to be closely monitored among pest control operators and occupational workers exposed to OPs. 

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