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The common explanation as to what the primary mechanism of action for organophosphates (and carbamates) is is the inhibition of the enzyme acetylcholinesterase and resulting buildup of acetylcholine at neuromuscular junctions, which ultimately results in respiratory failure. However, there is evidence that this may not be the case.

Firstly, a study reported that the nerve agent VX has been found to attack at least 132 different proteins, some of which were associated with metabolism. Source: https://www.ncbi.nlm.nih.gov/pubmed/28267914

Also, another study showed that, even when the enzyme was protected against the action of organophosphates, nerve agents still exhibited toxicity. Source: (http://www.rand.org/publications/MR/MR1018.5/MR1018.5.chap5.html) (Found in the Chapter 5 PDF, under "Non-AchE Effects")

Also also, another study was conducted on the matter. The test subjects were mice genetically engineered to lack acetylcholinesterase. The study found that the mice that totally lacked the enzyme not only lived (For over 34 days, no less), but were also twice as susceptible to OP poisoning as mice with the enzyme and exhibited the same symptoms. Source:https://www.ncbi.nlm.nih.gov/pubmed/11602663

So, how do organophoshates actually act to cause the symptoms associated with OP poisoning? What proteins do they affect? There seems to be a great abundance of evidence that the effects of poisoning are not due to AchE inhibition.

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  • $\begingroup$ Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, without proper and early antidotal treatment, death. Most OP compounds are highly lipophilic. Sulfur mustard is a toxic lipophilic alkylating agent, exerting its damage through alkylation of cellular macromolecules (e.g., DNA, proteins) and intense activation of pro-inflammatory pathways $\endgroup$ – com.prehensible May 12 '19 at 8:53
  • $\begingroup$ @com.prehensible If cholinesterase is a vital enzyme, then how come test mice that were engineered to lack it entirely could survive for over 34 days? $\endgroup$ – user73910 May 15 '19 at 1:49
  • $\begingroup$ there are multiple genes for cholinesterase enzymes, for acétylcholine, butyrylcholine, This document states that they found that BchE was equally important as AchE. The knokout mice did die faster from VX. If you look on the reference it gives many, many different targets for OP's did you see it? it's very well written. scielo.br/img/revistas/jbchs/v27n5//… OP's are very volatile and they can put lots of chlorine and sulphur esthers inside the body, which react with 100ds of metabolites even DNA, the known list is given in the above pic $\endgroup$ – com.prehensible May 15 '19 at 9:11
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Hundreds of OP's have been made since the 1930's. Phosphoric acid is used in Coca-Cola and organophosphates are esters of H3PO4, you can study ester lipid/aqueous drug chemistry. They have many different targets: http://www.scielo.br/img/revistas/jbchs/v27n5//0103-5053-jbchs-27-05-0809-gf04.jpg

OP's are lipophilic. Lipophilic substances can dissolve into cell walls which are lipid bi-layers, straight into the DNA of cells and also into the nervous system.

They can travel through cellular membrane, alveolar and dermal membranes, through dermal glands, cell walls and from one organ to another. The degree of lipophilicity of drugs cause them to either stay inside the cell membrane or go through. Prozac also being lipophilic. The body is made of a mostly aqueous phase and also a lipid phase.

Many OP's contain Sulphur and they are bioactivated through desulfurative oxidation and turned into the corresponding oxon form by the liver so the organic chemistry inside the body is very complex: dealkylation, dearylation, phosphyrylation, carboxylation, hydrolysis and they are very reactive with metabolic compounds in different phases. They can be combined with absorption facilitators to pass the skin barrier and paired with radicals which are activated by the liver.

A recommended text on the toxicity: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000500809

OP and acetylcholine are both esters.

Here's a good chemistry animation of AChE enzyme inhibitor process: https://youtu.be/fIvF1rhp1nA

And this one, about non-competetive inhibition of AChE: https://youtu.be/_jfGKbbZStw general AChE info: https://www.youtube.com/watch?v=-gIqZ8IxctE

AChE inhibitors that affect lots of organs such as peripheral and central nervous systems, muscles, liver, pancreas, and brain.

They lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and without an antidote, death.

They can bind to fatty elements inside the body, like the central nervous system. They can exert damage through phosphorous-alkylation of cellular macromolecules (e.g., DNA, proteins) and intense activation of pro-inflammatory pathways.

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Actions: (1) Phosphoryliodide can combine with phosphatidylcholinesterase to form a complex of phosphatidylcholinesterase and phosphatidylcholine iodide. The latter can be further cleaved into phosphatidylcholine iodide to free the cholinesterase and restore its activity. 2) Phosphodium iodide can also bind with free organic phosphate esters in vivo, and become a non-toxic phosphatidyl iodide phosphate, which is excreted from urine. The mechanism of action is to inhibit cholinesterase and indirectly activate M-receptor, and the organic ester poisoning is also due to the inhibition of cholinesterase, which is equivalent to the original organic ester poisoning, atropine rescue overdose, and organic ester treatment.

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