Download presentation
Presentation is loading. Please wait.
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– Hughes, M. F. (2002). Arsenic toxicity and potential mechanisms of action. Toxicology letters, 133(1), 1-16. Kosnett, M. J. (2013). The Role of Chelation in the Treatment of Arsenic and Mercury Poisoning. Journal of Medical Toxicology, 9(4), 347–354. Namgung, U., & Xia, Z. (2001). Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicology and Applied Pharmacology, 174(2), doi: /taap 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– Petrick, J. S., Bhumasamudram, J., Mash, E. A., Aposhian, V. H. (2001). Monomethylarsonous acid (MMAIII) and Arsenite: LD50 in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chemical Research in toxicology, 14(6), Pillai, R. K. (1938). Action of arsenate in glycolysis. Biochemical Journal, 32(11), 1961–1973. Singh, A. P., Goel, R. K., & Kaur, T. (2011). Mechanisms Pertaining to Arsenic Toxicity. Toxicology International, 18(2), 87–93. Vahter, M., Concha, G. (2001). Role of metabolism in arsenic toxicity. Pharmacology and Toxicology, 89(1), Vaziri, N. D., Upham, T., & Barton, C. H. (1980). Hemodialysis clearance of arsenic. Clinical Toxicology, 17(3), doi: /
Similar presentations
© 2025 SlidePlayer.com Inc.
All rights reserved.