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TOXIC MIn.pptx

  1. BIOCHEM 612 Chromium and Selenium metabolism and their Toxic effects
  2. INTRODUCTION • Chromium is an essential trace mineral widely distributed throughout the body. • Chromium is a micronutrient found in several oxidation states, being trivalent chromium and hexavalent chromium Dietary sources of chromium include  Whole grain products  Green beans  Broccoli RDA 35pg/day for men and 25pg/day for women.
  3. • Blood level: Serum level of chromium in normal healthy adult is about 6 to 20 μg/100 ml. Requirements: Recommended daily requirement for an adult is approximately 50– 200 μg/day.
  4. METBOLISM • Cr is believed to be absorbed from the SMALL INTESTINE by passive diffusion. • Transported from the bloodstream to tissues by the iron transport protein transferrin. • Transported from the tissues back to the bloodstream and ultimately to the urine for elimination by the peptide low-molecular- weight chromium-binding peptide (LMWCr).
  5. ABSORPTION • Trivalent chromium is the type found in food and supplements and is not toxic. • Chromium is absorbed poorly in the diet. • Only 5% of dietary chromium is absorbed. • Cr3+ is solubilized and complexed with ligands in the stomach prior to absorption through the small intestine, especially in the jejunum. • Mainly absorbed by passive diffusion. • In cytosol it exists in two forms bounded (with metalothioneine) and free from which is transported to blood. • The homeostasis of free and bounded cellular chromium is maintained by MBSP (Metal binding stabilizing peptide).
  6. PROMOTERS • Cr absorption from food is enhanced by the presence of amino acids, the ascorbic acid,and high carbohydrate. INHIBITORS • Phytates and antacids (natrium hydrogen carbonate, magnesium hydroxide) reduce Cr absorption.
  7. Transportation • Transported in the bloodstream to tissues in bounded form with transferrin (90%). • 10% is transported with albumin (loosly bounded or free form). • It is transported from the tissues back to the bloodstream and ultimately to the urine for elimination by the peptide low-molecular- weight chromium-binding peptide (LMWCr) or also known as chromodulin.
  8. CELLULAR UPTAKE AND UTILIZATION • Insulin dependent (free form) • Insulin independent (bounded form)
  9. CELLULAR UPTAKE AND UTILIZATION OF BOUNDED FORM Insulin independent • Cellular uptake takes place by transferin receptors TFR. • After Cr-Tf complex binds to TfR, the complex undergoes endocytosis to form vesicles. • The acidic pH inside late endosome (by proton pump ATPase to pH5.5) causes Cr to dissociate from Tf. • Tf still remains bound to TfR inside endosome. • DMT1 present on endosomal membrane transports the free Cr. • It can bound to metalothioniene in kidney and liver for its subsequent cellular use or also as chromodulin in other tissues. • TfR1-apoTf complex is recycled back to cell membrane. • ApoTf is released from TfR .
  10. CELLULAR UPTAKE AND UTILIZATION OF FREE FORM Insulin dependent  It is triggered in high insulin level in the blood.  Insulin binds to its insulin receptors it causes conformational changes in alpha subunits which stimulated movement of chromium from blood to inside of active cells where it binds to low- molecular-weight chromium-binding peptide ‘chromodulin’.  Active chromodulin then binds to beta subunits of insulin receptors to enhance kinase activity which in turn will enhance glucose uptake from cell membrane after activation of GLUT4.  Chromium bonded to chromodulin enhances the response of insulin receptors and uptake of glucose special in insulin resistant cells.  As insulin and glucose levels fall to normal concentration the LMWCB peptide chromodulin is released from the cell.
  11. REGULATION OF CHROMIUM HOMEOSTATIC CONDITION • Regulation takes place by release of cortisol under low chromium level. • Under stressor influence, secretion of the cortisol increases, acting as an insulin antagonist through increasing blood glucose concentration.
  12. FUNCTIONS Chromium plays an important role in carbohydrate, lipid and protein metabolism. 1. Role in Carbohydrate Metabolism: Chromium is a true potentiator of insulin and is known as Glucose tolerance factor (GTF). 2. Role in Lipid Metabolism: Chromium supplementation in deficient diets decreases serum cholesterol levels and preventsdecreases atheromatous plaque formation in aorta. 3. Role in Protein Metabolism: • it improves the incorporation of amino acids into heart and muscle tissue proteins. 4. Role in nucleic acid Metabolism: • Chromium participates in gene expression by binding to chromatin, causing an increase in initiation loci and consequently, an increase in RNA synthesis. • Chromium protects RNA from heat denaturation.
  13. Chromium toxicity • The induction of the hexavalent form of Cr is responsible for oxidative damage of the DNA. • Cr toxicity caused fragmentation of DNA by generating 8-hydroxy- dG. • Hexavalent state of Cr may cause a decline in the fidelity of replication when given at lesser doses. • Hexavalent chromium has also been found to interfere with certain heat shock protein expressions like Hsp90α and Hsp72. • Cr has been found to directly interconnect and damage the DNA by causing breakage in strands or adducts formation with them • It inhibited the synthesis of DNA, generated cross-links (interstrand). adducts, and oxidized bases in the DNA, causing considerable damage to the liver tissue.
  14. SELENIUM • Selenium as an essential trace element for all species including humans. • Many positive roles of selenium in human health has been suggested. However excess selenium is harmful and produces toxic manifestations.
  15. Occurrence and Distribution • Biological forms of selenium which occur in animal body are selenium analogues of S- containing amino acids, viz. selenomethionine, selenocysteine found at a mean concentration of 0.2 μg/g. • It is widely distributed in all the tissues, highest concentrations are found in liver, kidneys and fingernails. • Muscles, bones, blood and adipose tissues show a low concentration of selenium.
  16. Source • Principal source of selenium for the food is plant material. richest food sources are: • Organ meats: • cereals and grains • fruits and vegetables
  17. METABOLISM Selenium metabolism is a systemic process that includes the absorption, transportation, transformation, and excretion of selenium ABSORPTION • Absorption of selenium occurs mainly at the lower end of the small intestine. • Selenium is obtained in organic forms (SeMet and Sec) and inorganic forms (selenite and selenate) from diet. • All forms of selenium, organic as well as inorganic, are readily absorbed. • Absorption of selenate (Na2SeO4) takes places by a sodium-mediated carrier transport mechanism. • Selenite (Na2SeO3 ) is absorbed by passive diffusion. • Both forms of inorganic selenium compete with organic selenium for absorption. • Organic form (selenomethionine) is absorbed using the Amino acid transporter (ASCT2) enzyme transport system as does methionine.
  18. TRANSPORT • Absorbed selenium is, Initially reduced within the erythrocytes to selenide (involves the enzyme glutathione reductase ) and transported in the blood mainly bound to ß- lipoprotein protein.
  19. UPTAKE AND UTILIZATION • Selenium is taken up by the liver. • Selenium plays biological roles predominantly in the form of selenoproteins synthesized by the selenium metabolic system.
  20. excreted
  21. • The biological functions of selenium are mostly exerted through selenoprotein domains that contain Sec residues. • Twenty-five selenoprotein genes have been identified in the human genome. • Selenium-responsive genes are the genes whose expression patterns are influenced by supplementation with selenium or selenium-containing compounds. • These responsive genes were closely associated with annotations related to cell cycle regulation, androgen-responsive genes. • Selenium supplementation diminished the expression of pro- inflammatory genes such as cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α). suggesting that selenium has anti- inflammatory effects on the immune system.
  22. REGULATION • The expression levels of several selenoproteins GENES are influenced by the extent of selenium uptake. • The selenoprotein GENE expression is more apparent when the intracellular level of selenium is limited.
  23. Active under low selenium High concentration of selenium inhibits SEPSECS
  24. Selenium Toxicity • Organic selenocystine and seleno-cystamine are converted to selenols (RSeH) in presence of thiols which also results oxygen free radical generation. • Besides free radical formation selenium can have inhibitory effects on thiol proteins, for instance those which have antioxidant affects.
  25. • Selenium toxicosis causes DNA damage by generating 8-hydroxyguanosine DNA adducts. • As an effect of the oxidative stress, lipid peroxidation membranes (e.g. cell- organelle membranes) loose their integrity thus lysosomal enzymes can leak out of them causing serious necrotic damage in tissues.
  26. CLASS ACTIVITIES • What is pharmaceu-tical application of selenium compounds ? • What is the organ that is affected the most due to selenium toxicity? • Selenocysteine is endcoded by the codon? • Selenium is cofactor of which enzyme? • Homeostasis of free and bounded cellular chromium is maintained by which protein? • What is chromodulin? • What are the types of chromium uptake mechanisms? • What is DNA adduct?
  27. Suggested Readings • Miklós Mézes*, Krisztián Balogh. Prooxidant mechanisms of selenium toxicity – a review. Volume 53(Suppl.1): 2009Acta Biologica Szegediensis. • MN Chatterjea and R.Shinde. Text book of Medical biochemistry. Eighth Edition, 2013.