1. Mechanisms of Arsenic Poisoning
PHM Fall 2017
Instructor: Dr. Jeffrey Henderson
Eun Young Jeong
Rebecca Sammy
Selvie Jegarajaratnam
Zakiya Mittal
Presentation Date: October 10, 2017
PHM142H1

2. Introduction Metalloid - both metal and nonmetal properties
Exists in 3 oxidation states → +5, +3, -3
Poisoning occurs due to contaminated drinking water
Symptoms include vomiting, abdominal pain, diarrhea, but can also lead to anemia and even death
Mostly prevalent in Bangladesh (found in well water)

3. Arsenate in Glycolysis
Pentavalent arsenic (arsenate) is chemically similar to phosphate
Creation of 1-arseno-3-phosphoglycerate instead of 1,3-bisphosphoglycerate
1-arseno-3-phosphoglycerate is hydrolyzed by water to create 3-phosphoglycerate and glycolysis may proceed
However, 1 ATP molecule (per G3P) has been lost
No net ATP produced

4. Inhibition of PDH Complex
Monomethylarsonous acid (MMAIII) is a metabolite of inorganic arsenic
Targets thiol/sulfhydryl groups
PDH links glycolysis to the citric acid cycle
Oxidizes pyruvate to generate acetyl-CoA

5. Devlin, T. M. (2011). Textbook of biochemistry: with clinical correlations (5th ed.)

6. https://goo.gl/TbaWuk

7. Arsenic-Induced Diabetes Mellitus
Gamma-Peroxisome Proliferator-Activated Receptor (PPARγ)
Is a target for most anti-diabetic drugs because it allows liver, fat and muscle tissues to have increased sensitivity to insulin.
Arsenic leads to the decreased expression of this receptor
Less glucose is absorbed by these tissues, thus more glucose remains circulating in the blood stream
Increase in reactive oxygen species (ROS)
Due to glucose oxidation
Result in insulin resistance
Dysfunctioning of the beta cells of Islet of Langerhans

8. Arsenic Induced Neurotoxicity
Exposure to arsenic can induce memory loss, poor concentration, Parkinson’s disease and other neurological conditions
Arsenite (arsenic trioxide) induces apoptosis of cerebral neurons by stimulating p38 Mitogen activated protein kinase (MAPK) or c-Jun N terminal Kinase (JNK) MAPK pathways
Arsenite can also lead to the degradation of axons by destabilizing and disrupting the neuronal cytoskeleton
Arsenic induced oxidative stress in the brain can cause DNA damage, resulting in the death of brain cells and further degeneration of neurons
The degeneration of dopaminergic neurons leads to Parkinson’s disease

9. Arsenic on erythrocytes
Chronic exposure to arsenic can trigger hemolytic mechanism and lead to anemia
Two main oxidation state of arsenic can have impact on hemolytic pathway
Trivalent arsenic (Arsenite)
Pentavalent arsenic (arsenate)

10. Arsenic Induced Hemolysis
Source of the image:
Diagram:
Glucose-6-arsenate:
Since arsenate resembles phosphate it can replace many of the biochemical reactions that phosphate depend on. It is possible that arsenate readily react with glucose to glucose 6- arsenate where it can bind and inhibit the action of G6PD (glucose 6 phosphate dehydrogenase).
Trivalent arsenic
Prolonged exposure of arsenic can contribute to hemolysis and anemia.
Arsenic can deplete the GSH since it uses GSH to reduce arsenate into arsenite. The reduced form of glutathione donates an electron to the arsenate reducing to arsenite.
Arsenic also has high affinity for sulfhydryl groups which readily binds to glutathione and cysteine residue.
And by reducing NADPH level, it further reduces the GSH level which contributes to the depletion and consequently increase in reactive oxygen species that puts the cell in oxidative stress.

11. Treatments
Chelation therapy: 2,3-dimercaptosuccinic acid (DMSA), Dimercaprol (BAL)
Metal chelators bind to arsenic and allow for their excretion in urine (main treatment)
Hemodialysis for arsenic induced nephrotoxicity

12. Summary
Arsenic is a metalloid found in three oxidation states (+5, +3, and -3). It enters our bodies through contaminated drinking water and initial symptoms are vomiting, and diarrhea, but with chronic exposure can lead to anemia and death.
Arsenic affects the following metabolic pathways:
Glycolysis: Prevents the production of net ATP by forming 1-arseno-3-phosphoglycerate. Which is hydrolyzed to form 3-phosphoglycerate and continue glycolysis normally.
Pyruvate Oxidation: Arsenite has a high affinity for thiol/sulfhydryl groups. Binds to lipoic acid in pyruvate dehydrogenase and inhibits the enzyme. Net result is no NADH and acetyl-CoA formation, which ultimately causes decreased ATP levels
Prolonged exposure to arsenic can induce:
Neurotoxicity: Induces cerebral neuronal apoptosis via p38 or JNK MAPK, induces oxidative stress leading to DNA damage, and degradation of neuronal axons
Hemolysis: The pentavalent (arsenate) and trivalent (arsenite) arsenic depletes the G6PD and GSH in erythrocytes and lead to toxicity of the cells through oxidative stress and cause anemia.
Diabetes: Decreased expression of y-PPAR which decreases absorption of glucose in the muscle, fat and liver tissues
Treatments:
Chelation Therapy with BAL or DMSA
Hemodialysis

13. References
Abdul, K. S. M., Jayasinghe, S. S., Chandana, E. P., Jayasumana, C., & De Silva, P. M. C. (2015). Arsenic and human health effects: A review. Environmental toxicology and pharmacology, 40(3),
Biswas, D., Banerjee, M., Sen, G., Das, J. K., Banerjee, A., Sau, T. J., ... & Biswas, T. (2008). Mechanism of erythrocyte death in human population exposed to arsenic through drinking water. Toxicology and applied pharmacology, 230(1),
Devlin, T. M. (2011). Textbook of biochemistry: with clinical correlations (5th ed.). Hoboken, NJ: John Wiley.
Flanagan, S.V., Johnston, R.B., and Zheng, Y. (2012). Arsenic in tube well water in Bangladesh: health and economic impacts and implications for arsesnic mitigation. Bull World Health Organ, 90,
Flora, S. J. S., & Pachauri, V. (2010). Chelation in Metal Intoxication. International Journal of Environmental Research and Public Health, 7(7), 2745–
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Patel, M. S., Nemeria, N. S., Furey, W., & Jordan, F. (2014). The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation. The Journal of Biological Chemistry, 289(24), 16615–
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Pillai, R. K. (1938). Action of arsenate in glycolysis. Biochemical Journal, 32(11), 1961–1973.
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