Arsenic poisoning mechanism and targets

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(Last Updated On: May 26, 2017)
Different arsenic compounds responsible for arsenic poisoning

Different arsenic compounds

A short introduction

An Arsenic poisoning is a type of food poisoning that occurs due ingestion of foods contaminated with Arsenic ions and compounds containing Arsenic. An Arsenic poisoning or arsenicosis is known since ancient time though its mechanism was unknown until the era of medical advancements. Arsenic is an element that belongs to the Nitrogen family. It shows two valencies while forming a compound; trivalent as well pentavalent compounds. As(III) compounds such as arsenite (AsO33-), organic arsenicals and As(IV) compound such as Arsenate (AsO43-) are toxic. That’s because they bind to different metabolic intermediates. Upon binding, these compounds uncouple or halting the key reactions. The ultimate result of the Arsenic poisoning is the stoppage of respiration and finally, ATP production is also stopped.

Different targets of an arsenic poisoning

  1. Glycolytic pathway.
  2. Pyruvate dehydrogenase complex.
  3. α-ketoglutarate dehydrogenase complex of TCA cycle

Arsenic poisoning in glycolysis

Arsenate (AsO43-) is an analog of inorganic phosphate. During an Arsenic poisoning, glycolysis continues to produce pyruvate; however, there is no net production of ATP. That is because Arsenate reacts with the glyceraldehyde-3-phosphate to form 1-arseno, 3-phosphoglycerate.

Glyceraldehyde phosphate dehydrogenase (GAPDH) is an enzyme that converts glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate. However, it can also catalyze the reaction between Arsenate and glyceraldehyde-3-phosphate. Arsenate actually competes with the inorganic phosphate for the GAPDH.

In normal condition, GAPDH converts glyceraldehydes-3-phosphate to 1,3-biosphosphoglycerate. After that, Phosphoglycerate kinase converts 1,3-bispohsophglycerate to 3-phosphoglycerate, releasing one molecule of ATP. However, when there is an arsenate, GAPDH converts glyceraldehyde-3-phosphate to 1-arseno, 3-phosphoglycerate, an analog of 1,3-bisphosphoglycerate.

Each 1-arseno, 3-phosphoglycerate non-enzymatically breaks down into an Arsenate and a 3-phosphoglycerate molecule. This is how 3-phosphoglycerate forms without forming an ATP molecule. This event keeps happening in a cyclic manner. Released Arsenate reacts back to the glyceraldehyde-3-phosphate and ATP production is skipped. Therefore, Arsenate poisoning uncouples the ATP formation in the glycolytic pathway and the result is that there is no net production of ATP.

Normally, each glucose molecules leads to the production of 4 ATP molecules; 1) 2 ATP molecules formed during the conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate and 2) 2 ATP molecules forms during the conversion of phosphoenolpyruvate to pyruvate. However, two molecules of ATP are spent; one at phosphorylation of glucose molecule and one at phosphorylation of fructose-6-phosphate.

Arsenic inhibits pyruvate dehydrogenase complex

Pyruvate dehydrogenase (PDH) complex is a multienzyme complex containing three different enzymes: a) Pyruvate dehydrogenase (E1), which decarboxylates the pyruvate. b) Dihydrolipoyl transacetylase (E2), which transfers an acetyl group to CoA forming acetyl CoA. c) Dihydrolipoyl dehydrogenase (E3), which reoxidizes dihydrolipoamide to continue the conversion of pyruvate to acetyl-CoA

Arsenite and organic arsenicals form an adduct with dihydrolipoamide preventing the regeneration of dihydrolipoamide thus halts the function of pyruvate complex and the formation of acetyl-CoA from pyruvate stops.

Arsenic poisoning in TCA Cycle

α ketoglutarate dehydrogenase is also a multienzyme complex similar to that of the pyruvate dehydrogenase complex. It lies in the mitochondrial matrix and participates in the TCA cycle. It catalyzes the reaction, conversion of α-ketoglutarate into succinyl-CoA. The α-KG dehydrogenase contains three different enzymes; 1) α-ketoglutarate dehydrogenase (E1), 2) Dihydrolipoyl succinyltransferase (E2), and 3) Dihydrolipoyl dehydrogenase (E3)

The third enzyme dihydro lipoyl dehydrogenase also performs the similar functions to that of the pyruvate dehydrogenase complex oxidizing the dihydrolipoamide. Here again, arsenite and organic arsenicals alter the enzyme activity in the same manner as in the case of pyruvate dehydrogenase complex. As a result, the formation of succinyl-CoA is stopped. This is how Arsenic poisoning halts the TCA cycle and ultimately respiration is ceased.

Sensitivity of the arsenic poisoning

However, organic arsenicals are more toxic to the microorganisms than they are to humans. This is because of differences in the sensitivities of these chemicals to the various enzymes mentioned above. This differential toxicity is the basis for the early twentieth-century use of organic arsenicals in the treatment of Syphilis and Trypanosomiasis. These compounds were actually the first antibiotic although they produce several side effects.

Arsenic poisoning symptoms

If a person ingests foods contaminated with a toxic level of Arsenic compounds, he/she may show the following symptoms within few minutes of ingestion. These symptoms include; drowsiness, headache, confusion, and diarrhea. In severe cases, people may show the following symptoms; metallic taste in mouth, production of excess saliva, difficulties in swallowing, muscle cramping, hair loss, excessive sweating, vomiting, and diarrhea. In addition to that, the breath of the patient may smell like garlic.

Diagnosis

Arsenic poisoning is treatable and treatment methods involve the removal of Arsenic from the body system. We have to remove Arsenic from the body before it can cause any damages. Doctors often prescribe the urine test to diagnose the Arsenic poisoning. To make an accurate indication, urine test has to be done within 1-2 days of the initial Arsenic exposure. Hairs and fingernails can also be tested to determine the level of Arsenic exposure.

Treatment

Treatment of Arsenic poisoning includes complete removal of arsenic from the body. The followings are the procedures that doctors use to treat the patients with Arsenic poisoning.

  1. Bowel irrigation by passing a large amount of an osmotically balanced polyethylene glycol solution through the entire GI tract. It helps flush out the GI track and removes the Arsenic traces. Thereby, it prevents absorption of the Arsenic from GI tract.
  2. Removal of the cloth from the exposed area.
  3. Thoroughly washing and rinsing the exposed skin.
  4. Use of the chelating agents; dimercaptosuccinic acid and dimercaprol to trap and remove the Arsenic from the blood proteins.
  5. Use of mineral supplements to prevent the risk of potentially fatal heart problems.

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