Cholinesterase production

Respiratory ailments, recent exposure to cholinesterase inhibitors, impaired cholinesterase production, or liver malfunction may potentiate the toxicity of dimethoate. Also, high environmental temperatures or exposure of dimethoate to light (visible or UV) may enhance its toxicity. 

The undefined effect of Induced plasma ChE or pseudo-cholinesterase production which can have a buffering effect upon further OP responses. 

In addition to the regulation on cholinesterase production, other regulation pathways keep the cholinergic system in balance. For example, acute exposure to anti-ChEs induces brain increases in AChE transcripts accompanied by massive decreases in the vesicular ACh transporter, which together compensate for at least part of the exposure consequences (Kaufer et al., 1998). Also, increased hydrolysis of ACh in AChE-overexpressing transgenic mice was at least partially counterbalanced by a parallel daytime increase in ACh synthesis (Farchi et al., 2003). 

Several medical tests can determine whether you have been exposed to methyl parathion. The first medical test measures methyl parathion in your blood or measures 4-nitrophenol, which is a breakdown product of methyl parathion, in your urine. These tests are only reliable for about 24 hours after you are exposed because methyl parathion breaks down quickly and leaves your body. These tests cannot tell whether you will have harmful health effects or what those effects may be. The next medical test measures the levels of a substance called cholinesterase in your blood. If cholinesterase levels are less than half of what they should be and you have been exposed to methyl parathion, then you may get symptoms of poisoning. However, lower cholinesterase levels may also only indicate exposure and not necessarily harmful effects. The action of methyl parathion may cause lower cholinesterase levels in your red blood cells or your blood plasma. Such lowering, however, can also be caused by factors other than methyl parathion. For example, cholinesterase values may already be low in some people, because of heredity or disease. However, a lowering of cholinesterase levels can often show whether methyl parathion or similar compounds have acted on your nerves. Cholinesterase levels in red blood cells can stay low for more than a month after you have been exposed to methyl parathion or similar chemicals. For more information, see Chapters 3 and 7. 

Oxime carbamates are generally applied either directly to the tilled soil or sprayed on crops. One of the advantages of oxime carbamates is their short persistence on plants. They are readily degraded into their metabolites shortly after application. However, some of these metabolites have insecticidal properties even more potent than those of the parent compound. For example, the oxidative product of aldicarb is aldicarb sulfoxide, which is observed to be 10-20 times more active as a cholinesterase inhibitor than aldicarb. Other oxime carbamates (e.g., methomyl) have degradates which show no insecticidal activity, have low to negligible ecotoxicity and mammalian toxicity relative to the parent, and are normally nondetectable in crops. Therefore, the residue definition may include the parent oxime carbamate (e.g., methomyl) or parent and metabolites (e.g., aldicarb and its sulfoxide and sulfone metabolites). The tolerance or maximum residue limit (MRL) of pesticides on any food commodity is based on the highest residue concentration detected on mature crops at harvest or the LOQ of the method submitted for enforcement purposes if no detectable residues are found. For example, the tolerances of methomyl in US food commodities range from 0.1 to 6 mg kg for food items and up to 40 mg kg for feed items. ... 

Blue colour ring concentrated on plasmalemma of pollen (A). Arrows on B (lower part) shows a difference in the colour between cellular surface (blue color) and apperture for the output of pollen tube (red colour). Pistil excreted blue colour product, which covers the red coloured surface of pistil. The cholinesterase activity in plants is considered as sensitive test to study the allelopathic activity (Roshchina and Roshchina 1993 Roshchina,1999 2001a). 

In AChE-based biosensors acetylthiocholine is commonly used as a substrate. The thiocholine produced during the catalytic reaction can be monitored using spectromet-ric, amperometric [44] (Fig. 2.2) or potentiometric methods. The enzyme activity is indirectly proportional to the pesticide concentration. La Rosa et al. [45] used 4-ami-nophenyl acetate as the enzyme substrate for a cholinesterase sensor for pesticide determination. This system allowed the determination of esterase activities via oxidation of the enzymatic product 4-aminophenol rather than the typical thiocholine. Sulfonylureas are reversible inhibitors of acetolactate synthase (ALS). By taking advantage of this inhibition mechanism ALS has been entrapped in photo cured polymer of polyvinyl alcohol bearing styrylpyridinium groups (PVA-SbQ) to prepare an amperometric biosensor for... 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Disulfoton and its breakdown products can be measured in the blood, urine, feces, liver, kidney, or body fat of exposed people. In cases of occupational or accidental exposure to disulfoton, the breakdown products are often measured in the urine. The breakdown products are relatively specific for disulfoton and a few other similar organophosphate pesticides and can be detected in urine for up to one week after people were last exposed. Because disulfoton inhibits cholinesterase in blood and in blood cells, inhibition of this enzyme activity may also suggest exposure to disulfoton. Cholinesterase activity in blood and in blood cells may remain inhibited for as long as 1-2 weeks after the last exposure. Because other organophosphate pesticides also inhibit cholinesterase activity in blood and blood cells, this test is not specific for disulfoton. The measurement of cholinesterase in blood and blood cells and the amount of disulfoton breakdown products in the urine cannot always predict how much disulfoton you were exposed to. Your doctor can send samples of your blood or urine to special laboratories that perform these tests. Chapters 2 and 6 provide more information about medical tests. 

Sarin Pure sarin is a colorless, odorless, volatile, and highly lethal compound. It inhibits the enzyme action of cholinesterase, causing the production of excessive amounts of acetylcholine, which in turn affects the central nervous system. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Photolytic. Based on data for phenol, a structurally related compound, an aqueous solution containing 1-naphthoxide ion (3 x 10 M) in room light would be expected to photooxidize to give 2-hydroxy-1,4-naphthoquinone (Tomkiewicz et al., 1971). 1-Naphthol, methyl isocyanate, and other unidentified cholinesterase inhibitors were reported as products formed from the direct photolysis of carbaryl by sunlight (Wolfe et al., 1976). In an aqueous solution at 25 °C, the photolysis half-life of carbaryl by natural sunlight or UV light (X = 313 nm) is 6.6 d (Wolfe et al, 1978a). 

Photolytic. When aminocarb in ethanol was irradiated by UV light, extensive degradation was observed. No degradation products were identified however, two unidentified cholinesterase inhibitors were reported (Crosby et al., 1965). 

When propoxur in ethanol was irradiated by UV light, only one unidentified cholinesterase inhibitor formed. Exposure to sunlight for 3 h yielded no photodecomposition products (Crosby et ah, 1965). 

The classic cholinesterase inhibitor is the alkaloid physostigmine (6)/ eserine (7). It was first isolated from the calabar bean, the seeds of Physostigma venenosum. Many novel natural products with AchE-inhibifing properties have shown promise as therapeutics for AD. Some examples of such products (pure compounds/plant extracts or formulations) are briefly reviewed here. 

Many organosulfur compounds undergo biological oxidation at the sulfur atom to yield products which have pronounced physiological activity or serve as intermediates in generating bioactive compounds. Three examples are the lachrymating agent in onions ( ) (1), the oxo intermediate ( ) in metabolic desulfuration of phosphorothionate insecticides to form potent cholinesterase inhibitors (2), and the sulfoxides QJ produced on metabolism of thiocarbamate herbicides (3). 

Galantamine is used for the treatment of mild to moderate Alzheimer s disease. However in 2005 the U.S. Food and Drug Administration sent out a warning indicating that the product should not be used in patients with mild cognitive impairment (MCI) because of increased mortality observed in trials for MCI with galantamine. Galantamine is a competitive and reversible cholinesterase inhibitor. 

Mechanism of Action A benzimidazole carbamate anthelmintic that degrades parasite cytoplasmic microtubules, irreversibly blocks cholinesterase secretion, glucose uptake in helminth and larvae (depletes glycogen, decreases ATP production, depletes energy). Vermicidal. Therapeutic Effect Immobilizes and kills worms. Pharmacokinetics Poorly and variably absorbed from GI tract. Widely distributed, cyst fluid and including cerebrospinal fluid (CSF). Protein binding 70%. Extensively metabolized in liver. Primarily excreted in urine and bile. Not removed by hemodialysis. Half-life 8-12 hr. 

The second-order rate constant for the reaction between sarin and either 2-PAM I or II was found to be 170 L/mol per minute. If a phosphorylated or phosphonylated oxime that does not enter rapidly into the second step above is formed, that product may be an Inhibitor of cholinesterase. 7,88 Hydrolysis of sarin in the presence of 200-fold concentrations of V and II took place more rapidly in plasma from rats with the former oxime than with the... 

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