Chemical warfare, acetylcholinesterase inhibition

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... 

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. 

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). 

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. 

The structure-activity requirements for inhibition of acetylcholinesterase and NTE are different this is demonstrated by the fact that many OPs with powerful anticholinesterase properties do not have the capability to produce OPIDP. Thus, the OP chemical warfare nerve agents that are very potent anticholinesterases, have little propensity to cause OPIDP, ° although, at supralethal doses, sarin can cause delayed neuropathy in antidote-protected chickens while tri-o-cresyl phosphate, which has little anticholinesterase activity, is powerfully neuropathic. ... 

Many individuals have genetic susceptibility to certain chemicals (Calabrese 1978). The influence of these genetic differences likely produces sub- and supersensitivity to OP insecticides and warfare agents (Russell and Overstreet 1987). Several enzymes with variations or polymorphisms control sensitivity to OPs red blood cell acetylcholinesterase, serum cholinesterase or pseudocholinesterase, lymphocyte neuropathy target esterase or platelet neuropathy target esterase (NTE), serum paroxonase, butyrylcholinesterase, and serum arylesterase (Costa et al. 1999 LaDu 1988 Li et al. 1993 Mutch et al. 1992). Inhibition of red blood cell acetylcholinesterase, in both the central and the peripheral nervous systems, produces acute symptoms (Mutch et al. 1992). Paroxonase and arylesterase further modify the response (LaDu 1988 Li et al. 1993). Variant, inactive butyrylcho-linesterases increase sensitivity to OPs (Lockridge and Masson 2000 Schwarz et al. 1995). OP-induced delayed polyneuropathy results... 

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