Anti-cholinesterase activity

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. 

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 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... 

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. 

Besides compounds in which Jf = F, toxicity and anti-cholinesterase activity are observed in compounds in which X represents an anhydride , e.g. alkyl pyrophosphates (T.E.P.P.), p-nitrophenyl esters. 

Oh, M.H., P.J. Houghton, W.K. Whang, and J.H. Cho. 2004 Screening of Korean herbal medicines used to improve cognitive function for anti-cholinesterase activity. Phytomedicine 11 (6) 544-548. 

No significant anti-cholinesterase activity of a methanol extract of poria was observed in a screening of plants for anti-cholinesterase activity (Oh et al. 2004). 

The cholinesterase surfaces described here, as in the case of OPH, are broad spectrum. The TAC and TBC surfaces indicate only the presence of a competitive inhibitor of the enzyme and not its identity, so a positive result would be observed upon exposure to an organophosphate or carbamate pesticide, nerve agent, or drug with anti-cholinesterase activity. When the two enzymes are combined on a single surface, classes of compounds can be distinguished, that is, the surface discriminates between competitive inhibitors of AChE only, competitive inhibitors of BChE only, and competitive inhibitors of AChE and BChE. Inhibitor identification can be made by comparison of the change in absorbance at the AChE peak as compared to that for the BChE peak on the combined surface. 

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