Question

Why is arsenate toxic(way of action, enzyme)? And does arsenate inhibit gluconeogenesis? Explain why or why not.

Answer 1

Arsenate toxic:-

The poisoning of arsenic is a medical condition that occurs due to elevated levels of arsenic in the body. If exposure occurs over a brief period of time symptoms may include vomiting, abdominal pain, encephalopathy, and watery diarrhea that contains blood. Long-term exposure can result in thickening of the skin, darker skin, abdominal pain, diarrhea, heart disease, numbness, and cancer. The most common reason for long-term exposure is contaminated drinking water. Groundwater most often becomes contaminated naturally; however, contamination may also occur from mining or agriculture. Recommended levels in water are less than 10–50 µg/L (10–50 parts per billion). Other routes of exposure include toxic waste sites and traditional medicines. Most cases of poisoning are accidental. Arsenic acts via changing the functioning of around 200 enzymes. Diagnosis is by testing the urine, blood, or hair. Prevention is by using water that does not contain high levels of arsenic. This may be achieved by the use of special filters or using rainwater. There is not good evidence to support specific treatments for long-term poisoning. For acute poisonings treating dehydration is important. Dimercaptosuccinic acid (DMSA) or dimercaptopropane sulfonate (DMPS) may be used while dimercaprol (BAL) is not recommended. Hemodialysis may also be used. Through drinking water, more than 200 million people globally are exposed to higher than safe levels of arsenic. The areas most affected are Bangladesh and West Bengal. Acute poisoning is uncommon. The toxicity of arsenic has been described as far back as 1500 BC in the Ebers papyrus.

Inhibition of gluconeogenesis by arsenate:-

The effect of As₂O₃ and As₂O₅ on gluconeogenesis from various substrates in the liver and kidney of rats was investigated. A concentration-dependent inhibition by As2O3 was found. The effect was not dependent on the amount of investigated material (hepatocytes or kidney tubules). For either hepatocytes or kidney tubules, the extent of inhibition depended strongly on the substrate used. The highest degree of inhibition was observed in incubations with pyruvate. The inhibition of glucose formation was accompanied to a lesser extent by a diminution in O₂ consumption and ATP content. The effect was also dependent on the substrate used. The maximum effect was found in incubations with pyruvate. Oleate, 0.5 mmol/L, increased gluconeogenesis from pyruvate. The effect was not abolished by As₂O₃. A decrease in the content of acetyl-CoA, 3-hydroxybutyrate, and reduced glutathione was found in suspensions of isolated rat kidney tubules or hepatocytes incubated with As₂O₃. About 10 times higher concentrations of As₂O₅ were necessary to induce a similar extent of inhibition of gluconeogenesis, decrease in O₂ consumption, and in ATP content as compared with As₂O₃. The extent of the As₂O₅ effect depended on the concentration of the toxicant and on the substrate used. Gluconeogenesis from pyruvate exhibited the highest sensitivity to As₂O₅. All findings can be largely explained by inhibition of pyruvate dehydrogenase as the central target for arsenicals. The subsequent depletion of acetyl CoA results in the impaired formation of reducing equivalents in the citric acid cycle, decrease in high-energy phosphates and, acetyl CoA being a strong positive modulator of pyruvate carboxylase, in gluconeogenesis inhibition.