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PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson. Arsenic Poisoning. PHM142H1-F October 9, 2013. Presented by: Nirojan Balachandran Saranga Sreeskantharajan Kimberly Stobo Tian Qi Wang. As 33 74.99. What is Arsenic . An element found in many natural sources

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Arsenic Poisoning

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    1. PHM142 Fall 2013 Instructor: Dr. Jeffrey Henderson Arsenic Poisoning PHM142H1-F October 9, 2013 Presented by: NirojanBalachandran SarangaSreeskantharajan Kimberly Stobo TianQi Wang

    2. As 33 • 74.99 What is Arsenic • An element found in many natural sources • Many uses including: • Agriculture (Wood preservative) • Medicine (Arsenic trioxide treatment for certain leukemia) • Arsenic recognized as a carcinogen • Arsenic poisoning most commonly through sources such as contamination of groundwater • Many cases throughout the world

    3. Sign and Symptoms • Headaches • Drowsiness • Diarrhea • Vomiting • Bloody urine • Convulsions • Changes in fingernail pigmentation (leukonychiastriata) • Coma  Death

    4. How Arsenic Enters the Body • Mainly through inhalation and ingestion • To a lesser extent, through the skin • Enters cells via Aquaporin channels

    5. Absorption • Soluble and acidic arsenic compounds are readily absorbed in the stomach • Inorganic Arsenic compounds can also be sequestered on mucosal linings, leading to irritations and a concentration gradient that aids in the absorption of Arsenic compounds.

    6. Distribution • The largest quantity of arsenic is found in the liver. • Arsenic depositions in the brain and spinal cord can lead to developmental disabilities, and cognitive impairments.

    7. Metabolism • Main organ for arsenic metabolism is the liver

    8. Metabolism continued Step 1 • Inorganic pentavalent arsenate is reduced to trivalent arsenite in the blood stream before entering the cells • Can occur non-enzymatically in the presence of a thiol such as glutathione (GSH)

    9. Metabolism continued Step 2 • Methylation to monomethylarsonic acid (MMA) and to dimethyl- arsinic acid (DMA) is enzymatic, requiring S- adenosylmethionine (SAM) and a methyltransferase • MMA and DMA are excreted in the urine (thousandfold less-potent as mutagenic agents than inorganic arsenic) • Methylation has long been considered the main route of detoxification, but there is growing literature supporting other methods such as transport and antioxidant defenses

    10. Mechanism of Action of (As3+) • Reacts with thiol-containing molecules (R-SH) • Arsenite inhibits GSH Reductase by interacting with critical thiol groups • Blocks production of GSH (glutathione, important antioxidant) causing increased free radicals and oxidative damage • Increased production of ROS such as superoxide radical, singlet Oxygen, hydroxyl radicals, hydrogen peroxide

    11. Mechanism of Action of (As3+) • Inhibits lipoicacid (a dithiol) which is an important cofactor for Pyruvate Dehydroxygenase (PDH) • As [Acetyl CoA] decreases  Citric Acid Cycle activity decrease, causing: • Decreased ATP production • Decreased Gluconeogenesis (synthesis of glucose from carbohydrates, fatty acids, proteins, etc) Function of PyruvateDehydroxygenase: Oxidize Pyruvate to Acetyl CoA before Citric Acid Cycle Arsenic binds to Lipoid Acid-PDH to form 6-member ring Lipoic Acid-PDH

    12. Arsenate resembles Inorganic Phosphate Competitively inhibits phosphate for active site in G3P-Dehydroxygenase Replaces phosphate in many biochemical reactions in cellular respiration ATP ADP-arsenate (arsenolytic mechanism – uncouples ATP formation) Glucose-6-Phosphate  Glucose-6-Arsenate Glyceraldehyde-3-Phosphate  Glyceraldehyde-3-Arsenate Mechanism of Action of (As5+) Inorganic Phosphate is chemically similar to Inorganic Arsenate

    13. Inhibition of Pyruvate Dehydrogenase

    14. Inhibition of Glyceraldehyde-3-Phosphate dehydrogenase

    15. Arsenic is a Carcinogen • Associated with oxidative stress, cell arrest in the G2/M phase, chromosomal abnormalities, and DNA aneuploidy. • Inhibits p53

    16. Treatment of Arsenic Poisoning • Chelation therapy removes heavy metals • Dimercaprol • First antidote • Intramuscular Injection (painful) • Narrow therapeutic window • DMSA • Currently used • Fewer side effects • Can be administered orally Dimercaprol Dimercaptosuccinic acid (DMSA) Dimercaptosuccinic acid (DMSA)

    17. Summary • Symptoms include headache, drowsiness, diarrhea, vomiting, bloody urine, convulsions, changes in fingernail pigmentation • Enters body via inhalation and/or ingestion and mainly distributes to liver • Inorganic arsenate is metabolized in liver by methylation to MMA and DMA. • Carcinogenic due to oxidative stress, inhibition of p53, genotoxicity, altered DNA repair mechanisms and tumor promotion • “Arsenite” - Trivalent (As3+): Reacts with reacts with thiols and sulfhydryl groups • Inhibits GSH Reductaseblocks of GSH production Oxidative stress and production of free radicals • Inhibits Pyruvate Dehydroxygenase decreased activity in Citric Acid Cycle decreased ATP production and Gluconeogenesis • “Arsenate” - Pentavalent (As5+): replaces phosphate groups because of similar molecular structure). • Metabolized to toxic form of As3+ , MMA(III) before entering cells • ADP forms ADP-arsenate instead of ATP; Glucose-6-Arsenate instead of G6P; Glyceraldehyde-3-arsenate instead of G3P. • Recommended treatment is Dimercaptosuccinic acid (DMSA)

    18. References Caballero, B.(2009). Guide to Nutritional Supplements. Toronto: Oxford UP, 2009. Print. (2013). Arsenic. Retrieved from Hughes,M, F. Beck, B,D et al. (2011). Arsenic Exposure and Toxicology: A Historical Perspective Hughes, M. (2002). Arsenic toxicity and potential mechanisms of action. Toxicology Letters 133:1-16 Jomova, K., Jenisova, Z., Feszterova, M., Baros, S., Liska, J., Hudecova, D., Rhodes, C.J., Valko, M. (2010). Arsenic: toxicity, oxidative stress and human disease. Journal of Applied Toxicology. 31:95-107. Mandal, B. K., & Suzuki, K. T. (2002). Arsenic round the world: a review. Talanta, 58, 201-235. Miller, W., Schipper, H., Lee, S., et al. (2002). Mechanisms of Action of Arsenic Trioxide. Cancer Research. 62:3893-3903 Mcintyre, D, O. Linton, T, K. (2011). Homeostasis and Toxicology of Non-Essential Metals. Alsevier Inc. Rosen, B. Arsenic toxicity and methods of detection. Wayne State University School of Medicine [PDF Document]. Retrieved from Lecture Notes Online Website: Sears, M. E. (2013). Chelation: Harnessing and Enhancing Heavy Metal Detoxification- a review. The Scientific World Journal, 2013, 13 Pages. Sullivan, John B. and Gary R. Krieger. Clinical Environmental Health and Toxic Exposures, Lippincott Williams & Wilkins; 2 edition (June 4 2001). p.861-864.