Anti-cholinesterase

Cholinesterase inhibitor (anti-cholinesterase, ChEI) is a chemical that prevents cholinesterases (ChEs) from breaking down. ACh, which consequently increases the level and duration of action of this neurotransmitter. ChEIs such as organophosphates (esters of phosphoric acid) and carbamates (esters of carbamic acid) - serve as insecticides, pesticides, warfare agents and drugs. 

Lander, F. and Hinke, K. (1992) Indoor application of anti-cholinesterase agents and the influence of personal protection on uptake, Arch. Environ. Contam. Toxicol., 22 163-166. 

A smouldering bag in a pesticide warehouse, believed to be of this, led to an explosion, killing three firemen, and fire which took six days to extinguish (possibly because of caution concerning anti-cholinesterase toxicity). This is a moderately high energy compound by virtue of the triazene function. Other pesticides present were of less energetic structure. 

Organophosphate and carbamate pesticides are potent inhibitors of the enzyme cholinesterase. The inhibition of cholinesterase activity by the pesticide leads to the formation of stable covalent intermediates such as phosphoryl-enzyme complexes, which makes the hydrolysis of the substrate very slow. Both organophosphorus and carbamate pesticides can react with AChE in the same manner because the acetylation of the serine residue at the catalytic center is analogous to phosphorylation and carbamylation. Carbamated enzyme can restore its catalytic activity more rapidly than phosphorylated enzyme [17,42], Kok and Hasirci [43] reported that the total anti-cholinesterase activity of binary pesticide mixtures was lower than the sum of the individual inhibition values. 

M. Altstein, G. Segev, N. Aharonson, O. Ben-Aziz, A. Turniansky, and D. Avnir, Sol-gel-entrapped cholinesterases a microtiter plate method for monitoring anti-cholinesterase compounds. J. Agric. Food Chem. 46, 3318-3324 (1998). 

Based on features of their interaction with ChE, anti-cholinesterase substances are classified as reversible and irreversible inhibitors. Referred to the reversible anti-cholinesterase substances are quaternary ammonium compounds and aminoformic acid esters OPC are referred to the irreversible anti-cholinesterase substances. 

Dose-effect dependence is shared by many OPC in both the acute and chronic tests. The higher dose of an anti-cholinesterase substance, the higher degree of both acetyl cholinesterase (AChE) inhibition in neural tissue and intoxication evidence. 

The mechanism of diethyxime therapeutic action on the neuromuscular conduction in poisonings with anti-cholinesterase... 

As stated previously (pp. 62 etseq.) there is often correlation between anticholinesterase activity in vitro and gross mammalian toxicity. The toxicity of O.M.P.A. is not very muoh less than that of tabun, D.F.P. and T.E.P.P., yet the anti-cholinesterase activity of O.M.P.A. in vitro is negligible (50 per cent inhibition, 4-5x10 2m). On the other hand, O.M.P.A. produces all the symptoms of acetylcholine poisoning when administered to animals. Moreover, the serum cholinesterase of such animals is almost completely inhibited. Another anomaly of O.M.P.A. is that toxic action is slower than that of D.F.P. or tabun, an hour s delay being usual compared to the very quick knock-out action of D.F.P., etc. (see p. 2). 

Parathion when highly purified has low anti-cholinesterase activity in vitro compared to its activity in vivo. Diggle and Gage3 considered this to be due to isomerization to the -ethyl ester, but it may also be due to the formation4 of paroxan itself 0 II... 

Lord and Potter1 have claimed that it is important not to generalize the known anti-cholinesterase activity of organo-phosphorus insecticides in mammals to account for their action in insects. They could find no specific cholinesterase in two species of insect, but there was a general esterase inhibited by the insecticides. 

In this connexion we will stress again that, although there is often a correspondence between toxic action of organo-phosphorus insecticides and anti-cholinesterase activity (p. 67), the relationship is not always simple. Thus parathion (p. 178), not itself an esterase inhibitor, is converted in vivo into an enzyme inhibitor.1 On the other hand, Aldridge2 has shown that the inhibitor paroxan can be hydrolysed enzymically to produce non-inhibitory substances. 

Many workers in the organo phosphorus field have from time to time suggested theories to explain anti cholinesterase activity.1 These theories differ in certain respects, but some features are common to them all. Nothing, however, can be at all certain until pure cholinesterase has been obtained. 

The phosphorus compounds are always esters (or ester derivatives, e.g. amides). It was shown2 among many examples, that whereas D.F.P. (I) is a powerful anti-cholinesterase material, the diammonium salt (II) is virtually inactive. 

The ester must in addition contain some group which will initiate the approach of the ester to the surface of the enzyme. In this connexion it should be noted that di-isopropyl phos-phorochloridate (III, X = Cl), in which the chlorine atom is chemically very reactive,3 has no toxic properties, is devoid of myotic and anti-cholinesterase activity. In this compound, the chlorine is hydrolysed very quickly in water and would probably be destroyed extremely quickly in vivo. We have shown, quite conclusively, that in non-polar solvents the phosphorochloridate... 

A. Fidder, D. Noort, A.G. Hulst, R. De Ruiter, M.J. Van der Schans, H.P. Benschop and J.P. Langenberg, Retrospective detection of exposure to organophosphorus anti-cholinesterases mass spectrometric analysis of phosphylated human butyrylcholinesterase, Chem. Res. Toxicol., 15, 582-590 (2002). 

Lowenstein-Lichtenstein, Y., M. Schwarz, D. Click, B. Norgaard-Pederson, H. Zakut, and H. Soreq. 1995. Genetic predisposition to adverse consequences of anti-cholinesterases in "atypical" BCHE carriers. Nat. Med. 1 1082-1085. 

Amitai, G., Adani, R., Fishbein, E., Meshulam, H., Laish, I., Dachir, S. (2005). Bifunctional compounds eliciting antiinflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning. Chem. Biol. Interact. 157-8 361-2. 

SAFETY PROFILE A poison by ingestion, skin contact, and intraperitoneal routes. Experimental reproductive effects. Animal experiments show an anti-cholinesterase effect. When heated to decomposition it emits toxic fumes of POx and SOx. See also PARATHION, PHOSPHATES, ESTERS, and SULFATES. 

Intra-arterial injection of conventional ionic contrast media results in vasodilatation. This is due mainly to hypertonicity of the medium, but toxicity is also a factor. The vasodilatation may in addition be partly due to an anti-cholinesterase action, since it is partially blocked by atropine. In clinical practice, aortography and peripheral arteriography are usually associated with a slight fall in blood pressure, tachycardia and discomfort in the limbs, such as heat or pain. 

Derivatives of aminoformic acid react with ChE similarly to OPC, i.e. in two stages with establishing a covalent bond. A degree of the anti-cholinesterase action of carbamates depends upon strength of the complexes formed. Evidently, the phosphorylated ChE becomes disabled for a more prolonged period, as compared with the carbamylated ChE. Rapidity of the initial activity restoration of the enzyme inhibited by carbamates is determined, respectively, by the carbamylated enzyme hydrolysis speed, which depends upon the inhibitor structure. Carbamy-... 

Because of the fact that ChE and cholinoreceptors (ChR) have in their structures much in common, their interaction not only with the enzyme, but with ChR as well can be of certain importance in the mechanism of anti-cholinesterase compound action. At that, some OPC (phosphacol, DFP, parathyon, armin, etc.) can manifest both the stimulating and blocking actions on ChR [16-18], The blocking action of such substances as diisopropylfluorophosphate, armin and phosphacol on ChR seems to be connected with their interaction with an esterophilic zone of ChR [7], The effect on N-cholinoreactive systems is mainly manifested in case of the large-dosed administration of such substances. 

Organophosphorus substances are the most pronounced blockers of cholinesterase among all the anti-cholinesterase substances therefore, poisoning pathogenesis and antidote therapy will be considered in this review by the example of this group of substances. 

With a rise in dose of the substance entered, effect grows up irrespective of route of its entry into the organism. The higher dose of an anti-cholinesterase substance, the higher degree of both acetyl cholinesterase (AChE) inhibition in neural tissue and intoxication evidence. At high levels of exposure, any dose-effect dependence can be described by an exponential curve. The dynamics of efficient doses of lower level shows different variations, which however always come to either S-like or exponential curves [5, 8, 13],... 

---