Inhibition of cholinesterase

Izmirova H, Shalash S, Kaloianova F. 1984. [Dynamics of inhibition of cholinesterase activity in methyl parathion intoxication]. Probl Khig 9 42-49. (Russian)... 

The inhibition of brain cholinesterase is a biomarker assay for organophosphorous (OP) and carbamate insecticides (Chapter 10, Section 10.2.4). OPs inhibit the enzyme by forming covalent bonds with a serine residue at the active center. Inhibition is, at best, slowly reversible. The degree of toxic effect depends upon the extent of cholinesterase inhibition caused by one or more OP and/or carbamate insecticides. In the case of OPs administered to vertebrates, a typical scenario is as follows sublethal symptoms begin to appear at 40-50% inhibition of cholinesterase, lethal toxicity above 70% inhibition. 

DF and its precursor, methylphosphonic dichloride (DC), are organophos-phonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. 

DF and its precursor, DC are organophosphonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. Because DF and DC are relatively volatile compounds, the primary route of exposure is expected to be the respiratory system. However, ingestion also results from inhalation exposures in animals and could occur in humans. DF and DC vapors have a pungent odor and may cause severe and painful irritation of the eyes, nose, throat, and lungs. Data provided is for DF only, DC has similar properties. 

Observations The reaction lasts 1 h. The results are expressed in pM s 1kg" 1 of fresh mass. As shown in our experiments, the rates of hydrolysis of acetylthiocholine of studied plant cells varied from 0.4 0.05 pM s 1kg 1 of fresh mass for pollen of knights star up to 0.105 0.01 pM s 1kg 1 of fresh mass for horsetail vegetative microspores. Table 1 shows I50 for inhibition of cholinesterase from microspores by used inhibitors. 

Table 2 l50 for inhibition of cholinesterase from microspores by biologically... 

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. 

The answer is c. (Hardman, p 1022.) Pyrantel pamoate is an antihelminthic that acts primarily as a depolarizing neuromuscular blocker. In certain worms, a spastic neuromuscular paralysis occurs, resulting in the expulsion of the worms from the intestinal tract of the host. Pyrantel also exerts its effect against parasites via release of acetylcholine and inhibition of cholinesterase. 

To test this possibility, they first examined the effect of phosphorofluoridates on isolated rabbit s intestine. On such a preparation the action of drugs, like acetylcholine, which act directly on the muscle differs characteristically from the action of those, like eserine, which act by inhibition of cholinesterase activity. The directly acting drugs produce an immediate contraction which proceeds rapidly to a maximum, and after the drug has been washed out the muscle again quickly relaxes. The contraction produced by cholinesterase-inhibiting drugs, such as... 

With lower concentrations, the inhibition produced varied with the time of incubation. Fig. 12 shows the inhibition of cholinesterase by di-tsopropyl phosphorofluoridate, and by a comparable amount of eserine, after varying times. The action of eserine reaches a maximum within 5 min., while the inhibition by phosphorofluoridate is initially less rapid, but is progressive and ultimately more complete. The latter effect suggests an irreversible inactivation of the enzyme rather than an equilibrium. 

The above proof of the extremely high affinity for cholinesterase of the phosphorofluoridates, especially those with branched-chain alkyl groups, suggested that the toxic and myotic power was due to inhibition of cholinesterase in vivo. Bloch1 showed... 

II) differed markedly from the toxic di-isopropyl phosphoro-fluoridate (IV), in that the latter showed powerful myotic action. It is to be noted also that, whereas (IV) caused 50 per cent inhibition of cholinesterase activity at a concentration of the order of 10 10 M, a concentration of ca. 8 x 10 5 M of (II) was necessary to produce the same percentage inhibition.2... 

These authors claim, therefore, that it cannot safely be assumed that the toxic action of organo-phosphorus insecticides to insects is due to the inhibition of cholinesterase, although in the case of some insect species there is considerable evidence that an enzyme capable of hydrolysing acetylcholine may be important in the toxic action of the organo-phosphorus compounds.5 Further evidence on this point6 showed that with... 

It has been suggested by Augustinsson1 that adrenaline and noradrenaline can protect cholinesterase. However, adrenaline cannot protect below a concentration of 0-1 mM, and it is therefore unlikely that mobilization of adrenaline in vivo could influence the inhibition of cholinesterase. 

Direct kinetic assays are the only valid methods for the measurement of activators and inhibitors and calibration plots of the percentage activation or inhibition by known amounts of the substance can be made. Examples of inhibition assays include the quantitation of organophosphorus pesticides using the inhibition of cholinesterase (EC 3.1.1.7) while manganese can be measured in amounts as low as 1 X 10-12 mol using its activating effect on isocitrate dehydrogenase (EC 1.1.1.41). 

The maximum level of HMMA in the urine occurred 72 hours after exposure, which coincides with the time period for maximum urine catecholamine levels. There was a direct relationship between blood cholinesterase inhibition and catecholamine (adrenaline and noradrenaline) levels in the urine and blood (Brzezinski and Ludwicki 1973). Maximum inhibition of cholinesterase activity and maximum plasma catecholamine occurred during the first I-2 hours after exposure. However, catecholamine levels returned to normal more rapidly than cholinesterase activity. It was proposed that high levels of acetylcholine, which are normally associated with cholinesterase activity inhibition, caused a release of catecholamines from the stores in the adrenals. 

Westfall DP, McPhillips JJ, Foley DJ. 1974. Inhibition of cholinesterase activity after postganglionic denervation of the rat vas deferens Evidence for prejunctional supersensitivity to acetylcholine. J Pharmacol Exp Ther 189 493-498. 

In the 1960s and 1970s, the organophosphate and carbamate compounds replaced the chlorinated hydrocarbons as the most prominently used insecticides. These two families of insecticides share a common toxicological mechanism, the inhibition of cholinesterase enzymes in the nervous systems of... 

Exposure to disulfoton can result in inhibition of cholinesterase activity in blood and at nerve synapses of muscles, secretory organs, and nervous tissue in the brain and spinal cord. Central nervous system signs and symptoms include anxiety, restlessness, depression of respiratory and circulatory centers, ataxia, convulsions, and coma. 

C) Inhibition of cholinesterase leading to increased acetylcholine levels... 

Because atropine has never been found to have reactivating activity in vitro, the reactivation that occurred in the rats treated with atropine sulfate is assumed to be spontaneous. It is apparent from Table 3 that addition of 2-PAM I to atropine increased cholinesterase reactivation by 40.5% in the parotid gland, by 127.8% in the gastrocnemius muscle, and by 8.2% in the brain. The especially large change in cholinesterase activity in skeletal muscle suggests that this may be the principal site at which 2-PAM I antagonizes inhibition of cholinesterase. 

Hobbiger, F. Inhibition of cholinesterases by irreversible inhibitors in vitro and in vivo. Br. J. Pharmacol. Chemother. 6 21-30, 1951. 

One exception is the slight inhibition of cholinesterase caused by a single dose of TMB-4 (dibromide form).61... 

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