Chemical warfare, acetylcholinesterase

Field First Aid Nerve agents are the most toxic of the known chemical warfare agents. Chemically similar to organophosphate pesticides, their method of acting is to inhibit acetylcholinesterase enzymes. Individuals whose skin or clothing is contaminated with... 

Nerve Agent Substances that interfere with the central nervous system. Organic esters of phosphoric acid used as a chemical warfare agent because of their extreme toxicity (tabun-GA, sarin-GB, soman-GD, GF, and VX). All are potent inhibitors of the enzyme, acetylcholinesterase, which is responsible for the degradation of the neurotransmitter, acetylcholine in neuronal synapses or myoneural junctions. Nerve agents are readily absorbed by inhalation and/or through intact skin. 

Inhibitors of acetylcholinesterase are useful as pesticides and for treatment of Alzheimer s disease. In addition, they are chemical warfare agents. 

Even more reactive towards acetylcholinesterase are the organophosphorus derivatives developed as chemical warfare nerve agents, e.g. sarin. Such compounds react readily with the enzyme and form very stable addition intermediates. It is unusual to see fluoride as a leaving group, as in sarin, but its presence provides a huge inductive effect, thus accelerating the initial nucleophilic addition step (see also Section 13.7). 

A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with reversible enzyme inhibitors to prevent binding of the irreversible organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess. 

Atomic Absorption Spectrometry Acetylcholinesterase British Anti-Lewisite Carboxylesterase Central Nervous System Chemical Warfare Agent 2-chlorovinylarsonous Acid Enzyme-linked Immunosorbent Assay Environmental Protection Agency... 

Neurotransmitters are removed by translocation into vesicles or destroyed in enzyme-catalysed reactions. Acetylcholine must be removed from the synaptic cleft to permit repolarization and relaxation. A high affinity acetylcholinesterase (AChE) (the true or specific AChE) catalyses the hydrolysis of acetylcholine to acetate and choline. A plasma AChE (pseudo-AChE or non-specific AChE) also hydrolyses acetylcholine. A variety of plant-derived substances inhibit AChE and there is considerable interest in AChE inhibitors as potential therapies for cognition enhancement and for Alzheimer s disease. Organophosphorous compounds alkylate an active site serine on AChE and the AChE inhibition by this mechanism is the basis for the use of such compounds as insecticides (and unfortunately also as chemical warfare agents). Other synthetics with insecticidal and medical applications carbamoylate and thus inactivate AChE (Table 6.4). 

In clinical diagnosis of OP exposure, the tissue most readily available for study is blood. OP adducts of butyrylcholinesterase are better candidates for study than OP adducts on acetylcholinesterase for the following reasons. Human blood contains 5 mg of butyrylcholinesterase and 0.5 mg of acetylcholinesterase per liter. The butyrylcholinesterase is in plasma, whereas the acetylcholinesterase is bound to the membranes of red and white cells. Most OPs, with the exception of chemical warfare nerve agents, react more rapidly with butyrylcholinesterase than with acetylcholinesterase. 

Irreversible inhibition occurs with organophos-phorus insecticides and chemical warfare agents (see p. 437) which combine covalently with the active site of acetylcholinesterase recovery of cholinesterase activity depends on the formation of new enzyme. Covalent binding of aspirin to cyclo-oxygenase... 

Some useful relationships can then be derived, e.g. k = ki/Kn (Main and Iverson, 1966). In addition, k, = In 2//50 (Aldridge, 1950) which allows easy estimation of, (The I50 is the concentration of inhibitor, which inhibits the enzyme by 50%). These constants have been measured for many OP chemical warfare agents and also pesticides (e.g. Gray and Dawson, 1987). The hydrolysis reaction for acetylated acetylcholinesterase is fast (Koelle, 1992), in the region of 100 ps (Lawler, 1961 O Brien, 1976). The key to the powerful anticholinesterase effects of OPs is what happens after inhibition by these compounds. In the case of OPs, hydrolysis of the phosphylated serine residue is much slower2 than the acetylated analogue. 

Organophosphate A compound with a specific phosphate group that inhibits acetylcholinesterase. Used in chemical warfare and as an insecticide. 

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