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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

PHM142 Fall 2013

Instructor: Dr. Jeffrey Henderson

Arsenic Poisoning

PHM142H1-F

October 9, 2013

Presented by:

NirojanBalachandran

SarangaSreeskantharajan

Kimberly Stobo

TianQi Wang

what is arsenic

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
sign and symptoms
Sign and Symptoms
  • Headaches
  • Drowsiness
  • Diarrhea
  • Vomiting
  • Bloody urine
  • Convulsions
  • Changes in fingernail pigmentation (leukonychiastriata)
  • Coma  Death
how arsenic enters the body
How Arsenic Enters the Body
  • Mainly through inhalation and ingestion
  • To a lesser extent, through the skin
  • Enters cells via Aquaporin channels
absorption
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.
distribution
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.
metabolism
Metabolism
  • Main organ for arsenic metabolism is the liver
metabolism continued
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)
metabolism continued1
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
mechanism of action of as 3
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
mechanism of action of as 31
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

mechanism of action of as 5

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

arsenic is a carcinogen
Arsenic is a Carcinogen
  • Associated with oxidative stress, cell arrest in the G2/M phase, chromosomal abnormalities, and DNA aneuploidy.
  • Inhibits p53
slide16

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)

summary
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)
references
References

Caballero, B.(2009). Guide to Nutritional Supplements. Toronto: Oxford UP, 2009. Print. (2013). Arsenic. EvironmnetalChemistry.com. Retrieved from http://library.concordia.ca/help/howto/apa.php#online

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. http://dx.doi.org/10.1016/S0039-9140(02)00268-0

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: http://mstc.csmu.edu.tw/ezcatfiles/mstc/img/img/466/961008-BarryPhilipRosen.pdf

Sears, M. E. (2013). Chelation: Harnessing and Enhancing Heavy Metal Detoxification- a review. The Scientific World Journal, 2013, 13 Pages. http://dx.doi.org/10.1155/2013/219840

Sullivan, John B. and Gary R. Krieger. Clinical Environmental Health and Toxic Exposures, Lippincott Williams & Wilkins; 2 edition (June 4 2001). p.861-864.