Minerals by fanzhongqing

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									      TUMS




Azin Nowrouzi, PhD   1
            Minerals in nature
– There are 92 naturally occurring elements on earth but only eight
  elements make over 98% of the minerals on the Earth's crust.
– They are, in decreasing quantity, 1 oxygen, 2 silicon, 3 aluminum, 4
  iron, 5 calcium, 6 sodium, 7 potassium, 8 magnesium. The graph
  below shows you the amounts of these elements in the Earth's crust.




                                                                   2
    Minerals in human body
• Minerals are elements of the periodic table
• More than 25 have been isolated from the
  body.

• 22 elements have been shown to be
  essential (excluding C,H, and O)

• minerals make up about 4 to 5% of body
  weight (for a 70 kg individual: 2.8 kg)

• many minerals are found in ionic form
  (others as ligands or covalent compounds)3
                    Minerals (function)
Minerals = Inorganic elemental atoms that are essential nutrients and
     electrolytes.

    1.       Nutritionally essential
         •      Serve both structural and functional roles in the body.
                –   Structural minerals (calcium and phosphorus) are the major inorganic matrix of
                    bone and teeth.
                –   Functional minerals (calcium, phosphorus and all the others)
                     1. Participation in all cellular activities
                     2. Serve as enzyme cofactors or in oxidation/reduction reactions.
                     3. Maintain the delicate cellular fluid balance
                     4. Maintain the acid-base balance in body fluids
                     5. Control the osmolarity in the fluid compartment
                     6. provide for electrochemical nerve activity
                     7. Regulate muscle tone and activity (including organ muscles like heart, stomach,
                         liver, etc

    2.       Nutritionally beneficial
         •      Effects of boron in the presence of Vitamin D depletion

    3.       Pharmacologically beneficial
         •      Fluoride to prevent dental caries
         •      Lithium salts to treat maniac depression                                           4
       Minerals and Toxicity
• Minerals are stored in bone and muscle
  tissue
  – So toxicity is a possibility although it is rare.
     • Occurs when one isolated mineral is ingested
       without any supportive cofactor nutrients.
     • Toxic levels accumulate only if massive overdoses
       are used for a long period of time.
• There is a dose-effect relationship.



                                                        5
                      Classification
• Macro or Major                        • Micro or Trace
  minerals                                minerals (body needs
    – Sodium, potassium,                  relatively less)
                                             – Chromium, manganese,
      magnesium, calcium,                      iron, cobalt, molybdenum,
      phosphorus, sulfur,                      copper, zinc, fluoride, iodine,
      chloride                                 selenium, silicon, tin,
                                               arsenic, nickel…
• Present in body tissues               • Present in body
  at concentrations >50                   tissues at
  mg/kg (50 ppm)                          concentrations <50
                                          mg/kg (50 ppm)
Those present at (g/dL) in body fluids or (mg/kg) in tissue = Trace elements
Those found at ng/dL or g/kg = Ultratrace elements
                                                                            6
          Important minerals
Macro               Trace
Element      g/kg   Element    mg/kg

Ca           15     Fe         20-50
P            10     Zn         10-50
K             2     Cu          1-5
Na           1.6    Mo          1-4
Cl           1.1    Se          1-2
S            1.5    I         0.3-0.6
Mg           0.4    Mn        0.2-0.5
                    Co        0.02-0.1

                                         7
       Minerals Homeostasis
 Varying dietary intakes; so mechanisms of
 mineral homeostasis include:
1. Regulation of intestinal absorption.
2. Transport systems in blood.
3. Uptake and storage mechanisms in tissue.
   •    There are specific metalloproteins for transport and safe
        storage of very reactive metal ions; examples:
   •    Metallothionein (Cu, Zn)
   •    Transferrin, ferritin, hemosiderin (Fe)
   •    Ceruloplasmin (Cu)
4. Control of excretion.
   •    Feces (Cu, Zn), Urine (halides as I, F and Se, B, Mo, Cr),
        Hair, Nails, Skin cell desquamation.
                                                                     8
     Food as source of minerals
Bioavailability of minerals in intestines
• Found in all food groups.
• More reliably found in animal products.
• Often other substances in foods decrease absorption
  (bioavailability) of minerals:
   – Oxalate, found in spinach, prevents absorption of most
     calcium in spinach.
   – Phytate, form of phosphorous in most plants; In the
     plant, this molecule is a regulator of signaling in the
     cell; and in seeds, it acts as a phosphate storage
     molecule. It binds such minerals as calcium and iron
     and zinc very well, and since it is not digested, animals
     that consume grains with phytate will lose these
     minerals as the phytate passes through their gut.
                                                             9
     Antagonistic interactions
• Dietary calcium aggravates phytic acid
  blocking of zinc absorption by forming
  insoluble Ca-Zn-phytate complex.
• Zinc ions block copper (Cu) absorption
  – Formation of intestinal metallothionein that
    binds copper.
  – Pharmacological use in Wilson’s disease.


• Molybdate ion forms insoluble Cu-Mo
  complex, limits Cu absorption.
                                                   10
    Synergistic interactions
• Interaction between selenium and iodine.
  – Important for thyroid function. Deiodinase
    enzymes are selenoproteins, remove iodine
    from T4 to form T3,
  – Glutatione peroxidase = a selenoprotein in
    thyroid in removing H2O2.

• Selenium deficiency is exacerbated by
  Vitamin E depletion.

• Zinc and Vitamin A are interrelated.
                                                 11
Mineral interaction




                      12
Factors affecting requirements

1. Physiological state/level of production
2. Interactions with other minerals
3. Tissue storage




                                             13
                    (1)Sodium
• RDA (recommended daily allowance): 0.5 g
• ADI (average daily intake): 5 g
• Above 45 mg per day interferes with riboflavin and
  phosphorus uptake.
• One of the three main electrolytes in the body.
• Deficiency symptoms: excessive sweating,
  chronic diarrhea, nausea, respiratory failure, heat
  exhaustion, impaired carbohydrate digestion.
• Functions:
  –   Fluid balance
  –   Neuromuscular excitability
  –   Maintenance of viscosity of blood
  –   Role in resting membrane potential
  –   Role in action potential
                                                  14
                    Sodium absorption
• Occurs by sodium pump
  situated in basal and
  lateral plasma
  membrane or intestinal
  and renal cells.
• Na-pump actively
  transports Na into
  extracellular fluid.

Total sodium            4000 mmol
Unexchangeable             30%
(complexed in bone)
Exchangeable              (70%)
   •Extracellular     135 -145 mmol/L
   •Intracellular      4 – 10 mmol/L
      •Plasma
                      135-145 mmol/L    15
Simplified potassium daily balance
         Fluid           Na+       K+     Ca2+ Mg2+            Cl-     Amino Glucose
                                                                       acids  mg%
      Extracellular 142             4        5         3      103         5               90
      Intracellular       10      140        1        58        4        40          0-20
  •    Potassium is the major intracellular cation (150 mEq/L).
  •    Extracellular fluid (ECF) and the normal concentration of plasma
       potassium is 3.5 to 5.5 mEq/L (or 20mg/dl).
  •    Total body content of potassium is about 200 mg/dl or 50 mEq/Kg (40
       mEq/kg in females).
  •    Disruption of potassium balance usually caused by:
         –   Increase in renal, gastrointestinal, or skin losses which produce negative
             balance.
         –   Decreases in renal excretion which produces a positive balance.
  •    K+ is actively transported in exchange for Na+ by Na+-K+-ATPase.




                                                                                               16
                        (2)Potassium
•   RDA: 3500 mg
•   ADI: 2500 mg
•   Up to 5 grams is safe.
•   Plasma concentration of K+ is 3.5-5 mEq/L.
•   Functions:
     –   Influences muscular activity
     –   Involved in acid-base balance
     –   Important for cardiac function
     –   Cofactor for certain enzymes (pyruvate kinase)
     –   Neuromuscular irritability and nerve conduction process
•   Individuals with kidney diseases should not take supplemental K.
•   K on empty stomach can cause nausea.
•   Processing of foods fills it with sodium.
•   Diet is better to be high in K and low in Na.
•   K+ balance in the kidney:
     – Acute regulation: Hormonal control;
       Release of insulin  uptake of K+ by cells
     – Chronic regulation: K+ adaptation
                                                                       17
Potassium inside the kidney




                              18
Factors that regulate the distribution of
               potassium
 •   Potassium concentration in ECF depends
     on:
     1. External balance (matching daily intake and
        output)
     2. Internal balance (distributing potassium between
        extracellular and intracellular fluid)
 •   Factors Regulating Internal balance (Plasma
     Potassium)
 •   Factors Regulating External balance (Body
     Potassium Content)
                                                      19
Factors Regulating Plasma Potassium (Internal Balance)
 1. Blood pH
     –   Acidemia causes a shift of K+ from the intracellular space of cells into the plasma.
     –   Alkalemia causes a shift of K+ from the plasma into cells.
     –   Plasma K+ may rise about 0.6 mEq/L for each decrease in pH of 0.1 units.
     –   Different types of acids result in different magnitudes of potassium shifts
          •   shifts in the distribution of potassium usually do not result from acidosis caused by
              nonmineral or organic acidosis
     – At constant blood pH, infusion of sodium bicarbonate leads to a decrease in plasma
       potassium concentration
 2. Insulin
     – Insulin is the first-line defense against hyperkalemia.
     – A rise in plasma K+ stimulates insulin release by the pancreatic beta cell.
     – Insulin, in turn, enhances cellular potassium uptake, returning plasma K+ towards
       normal.
     – plasma potassium and insulin participate in a feedback control mechanism.
 3. Catecholamines
     – Beta-2-agonists lower plasma potassium (by causing a cellular uptake of potassium).
     – Alpha agonists increase plasma potassium concentration.
 4. Physical Conditioning and Exercise
     – Strenuous exertion may injure muscle cells and allow leakage of K+ into the ECF.
 5. Activity of Cell Membrane Na-K ATPase
     – insulin, physical training, catecholamines may exert their effect by altering the activity
       of the sodium potassium ATPase in
                                                                                                      20
     Factors Regulating Body Potassium Content (External Balance)
1.    Renal Excretion of K+
       –   The Kidney can rapidly excrete large loads of potassium, 200-300 mEq/day, without a change in plasma K+ or body K+
           content.
       –   Potassium is filtered freely at the gomerulus but 90-95% is reabsorbed in the proximal tubule
       –   The major site of renal regulation of potassium excretion occurs in the distal tubules and collecting ducts
       –   the ability to reduce excretion to zero or very low levels is slow, taking perhaps 2 to 4 weeks
•     major determinants of urinary potassium excretion include:
       –   Aldosterone
             •   Aldosterone stimulates distal nephron secretion of potassium.
             •   In the absence of aldosterone, body potassium content and plasma K+ are increased due to a decrease in renal excretion of potassium
             •   An increased plasma K+ stimulates aldosterone secretion and decreased plasma K+ suppresses it.
       –   Urine Flow Rate
             •   Increase urinary flow rate increases urinary potassium excretion
       –   Urinary Sodium Concentration
             •   Sodium delivery to distal nephron may promote K+ excretion (Na-K exchange)
       –   Non Reabsorbable Anions (Urinary Cl- Concentration)
             •   Sulfates and others create favorable electrical (lumen negative) gradients for passive secretion of potassium into the urine
       –   Plasma K+ Concentration
             •   Increased plasma K+ leads to an increased rate of secretion
       –   pH of the Blood
             •   Alkalosis leads to an increase in the K+ concentration of the cells of the distal tubule, this leads to a more favorable gradient that is
                 associated with increased urinary secretion of potassium.
             •   Acidosis has the opposite effect.
2.    Gastrointestinal Potassium Excretion
       –   Normally 10 – 15% of K+ intake is excreted by the gut.
       –   Aldosterone is one of the regulators of secretion of potassium by the gastrointestinal tract.
       –   Diarrhea increased fecal K+ losses, particularly laxative-related diarrhea. Diarrhea may contain 100 mEq/L of K+
3.    Skin Potassium Excretion
       –   Working in hot temperatures may produce up to 10-12 liters of sweat per day containing 10 mEq/L of K+. Thus major K+
           losses may occur via this route.
       –   Sweat K+ is also under control of the hormone aldosterone.
                                                                                                                                                       21
  Consequences of Hypokalemia
• Metabolic effects: Hypokalemia supresses
  insulin release     glucose intolerance.
• K+ deficiency in children retards growth.
• Cardiovascular effects: Electrophysiologic
  abnormalities      changes in EKG




  Decreases amplitude or inversion of the T wave
  Increases amplitude of the U wave
  Prolongation of the Q-U interval
  Increased amplitude of the P wave, prolongation of the P-R interval
  Widening of the QRS complex                                           22
Consequence of Hyperkalemia
• Cardiac effects:
• Acute rise in plasma K+ raises cell membrane
  potential toward threshold potential.
• ECG effects:




   ca. 6 mEq/l increased amplitude of T wave with shortened Q-T
   interval
   ca. 7-8 mEq/l widening of QRS complex, decreased amplitude of
   P wave with eventual loss of P wave
   following these changes ventricular fibrillation, cardiac standstill.   23
                      (3)Magnesium
• RDA: 350 mg/day
   – pregnancy and lactation: 450 mg
• Second most plentiful cation in intracellular fluids.
• Normal plasma Mg concentration ranges from 1.4 to 2.1
  mEq/L (0.70 to 1.05 mmol/L).
   –   ~50% of total amount in bone.
   –   ~45% in muscle and nervous tissue.
   –   ~ 5% in extracellular fluids.
   –   blood plasma magnesium : ~ 2 -3 mg/dl.
        • 60% is ionized
        • 10% complexed with other ions
        • 30% bound with proteins
a. Functions in more than 300 enzyme systems:
   – cofactor of all enzymes involved in phosphate transfer reactions that
     use ATP and other nucleotide triphosphates such as:
   – phosphatases
   – pyrophosphatases                                                   24
                      Magnesium…
b. Most metabolically active tissues: brain, heart, liver and
   kidney
   – Essential for the conversion of vitamin D to its biologically active
     form to help absorb and use calcium.
   – Prevents cardiovascular disease.
   – CNS (central nervous system):
       • hypomagnesemia ---- CNS irritability, disorientation, psychotic
         behavior, convulsions.
   – neuromuscular system:
       • magnesium has a direct depressant effect on skeletal muscle.
       • magnesium also causes a decrease in Ach release at motor end
         plate (used in treatment of eclamptic seizures).
       • Abnormally low concentrations of Mg in the extracellular fluid ----
         increased Ach release ---- increased muscle excitability (tetany).
   – Effective against Chronic Fatigue syndrome (CFS), and noise-
     induced hearing loss.
• Prevents the calcification of soft tissue
• Bone strength and springiness
• food sources: all green plants (chlorophyll); meats                          25
    Transcellular shifts
under acidosis and alkalosis




                               26
     (4)Roles of Chloride in the Body
1.        Chloride is an “essential” mineral for humans.
2.        Chloride is the major negatively charged ion of the extracellular fluid.
3.        The normal serum (ECF) range for chloride is 98 - 108 mmol/L.
4.        The suggested amount of chloride intake ranges from 750 to 900 milligrams per day
5.        Total obligatory loss of chloride in the average person is close to 530 milligrams per
          day.

6.        Functions as an electrolyte,
      •       plays a key role in maintaining proper water distribution, osmotic balance

7.        Combines with hydrogen in the stomach to make hydrochloric acid. On average, the
          stomach produces 2 liters of HCl daily
      –       break down of proteins
      –       absorption of other metallic minerals
      –       activation of intrinsic factor, (absorption of vitamin B12)

8.        Chloride is transported into the gastric lumen, in exchange for another negatively
          charged electrolyte (bicarbonate), in order to maintain electrical neutrality across the
          stomach membrane.

9.        Exchange of chloride and bicarbonate, between red blood cells and the plasma helps to
          govern the pH balance and transport of carbon dioxide from the body.

10.       With sodium and potassium, chloride works in the nervous system to aid in the
          transport of electrical impulses throughout the body.                                 27
CO2 transport




                28
Chloride shift




                 29
                            (5)Calcium
• RDA: 1200 mg
• ADI: 743 mg. Above 2500 mg per day may stress the kidneys, kidney
  stones.
• In the elementary composition of the human body, it ranks fifth after
  oxygen, carbon, hydrogen, and nitrogen
• Most Ca is contained in bones, about 1% is used for nerve impulses
  and muscle contraction.
• Deficiencies are linked to high blood pressure (Populations with low
   calcium intakes have high rates of high blood pressure).
• Calcium reduces symptoms of premenstrual syndrome (PMS), protects
  against colon cancer.
• If inadequate intake, body steals Ca from bones.
• Resorption of Ca2+ and Na+ go in parallel.
• The site of resorption of Ca2+ is entire nephron except (!!!!) thin part of
  loop of Henle !!!!
• The site of fine adjustment: late distal tubules.
• Parathyroid hormone (PTH) and 1,25-(OH)2-calciferol (calcitriol)
  decrease ca2+ excretion.
                                                                          30
                         (6)Phosphorus
• ADI: 1500 mg
     – Adults: 800 mg/day
     – Pregnancy and lactation: 1200 mg/day
• Megadoses cause body to lose Calcium.
• 800 grams of P in body; 88% in bones (structural).
•   12% is very active metabolically:
•   Energy transfer, Acid-base balance, Enzyme action.
         •   High energy phosphate compounds
         •   Nucleic acids
         •   Phospholipids
         •   Phosphoproteins
         •   Coenzymes (vitamins)
     – metabolism of RBC,
     – ATP production.
• Found in many foods.


• Slight fall in PO4 after a carbohydrate rich meal.
• Deficiency (hypophosphatemia) not common.
• 80 – 95% are reabsorbed, mainly in proximal tubule
                                                         31
                       (7)Sulfur
• Structural part of most proteins
  – Most sulfur in the diet comes in from protein sources
    containing sulfur amino acids such as cysteine, cystine
    and methionine.
  – Some enters as inorganic sulfur (sulfate, sulfide,
    chondroitin sulfate and certain other sulfate esters)
  – Sulfur is also present in thiamine, biotin, sulfolipids,
    conjugated bile acids and coenzyme A
  – Found in anticoagulant heparin and in chondroitin
    sulfate, and glucosamine sulfate.
• Takes part in enzymatic, antibody and tissue
  activities.
• Deficiency: degeneration of collagen,
  cartilage, ligaments and tendons.          32
                             (8)Iron
• RDA: 15 mg
• More than 100 mg daily, there is risk of infection and
  toxic side effects.
• 70% of iron in body is functional; found in enzymes
  and other molecules.
  – >80% of this found in red blood cells.
• 30% of iron is in storage depots or transport
  proteins.
• 2 types of body iron:
  – heme iron
     • hemoglobin, myoglobin, catalases, peroxidases, cytochromes (a,
       b and c – involved in electron transport), cytochrome P450
       (involved in drug metabolism)
  – non-heme iron
     • ferritin, hemosiderin, hemofuscin, transferrin, ferroflavoproteins,
       aromatic amino acid hydroxylases.
                                                                        33
    Iron distribution and storage
• Carried in blood stream
  via transferrin (a -      Transferrin and
                             transferrin
  globulin)                  receptor (TfR)



• Stored in 2 forms:
      • ferritin
      • hemosiderin


• Stored in liver, spleen,
  bone marrow, intestinal
  mucosal cells and
  plasma


                                               34
Cellular uptake of iron




                     Transferrin and
                     transferrin
                     receptor (TfR)




                                   35
    Iron absorption and elimination
• There is no mechanism
  for excretion of iron.

• Iron is normally lost by
  exfoliation of intestinal
  mucosal cells into the
  stools.

• Trace amounts are lost in
  bile, urine and sweat (no
  more than 1 mg per day).

• Bleeding (vaginal,
  intestinal) is a more
  serious mechanism of
  elimination.
    – 50% of women are iron
      deficient.
                                      36
                       Iron deficiency
 Initial symptoms are vague and ill-defined
          •   easy fatigability
          •   lack of appetite
          •   headache
          •   dizziness
          •   palpitations

 then: hypochromic-microcytic anemia
          •   microcytosis (small RBCs)
          •   hypochromia (poor fill of hemoglobin)
          •   poikilocytosis (bizarre shapes)
          •   anisocytosis (variable sizes)
Low Fe levels correlated with akathisia (Greek word meaning “can’t sit down”) or
the “restless leg syndrome” (RLS)
Over supplementation with Fe causes recurrent illnesses in athletes and infants.
                                                                              37
                       Iron deficiency
• A deficit in total body iron
• Three stages of iron deficiency are:
   – Iron depletion: earliest stage
      • Not recognizable by the patient
      • Storage iron (serum ferritin) is decreased or absent.
      • Serum iron and hemoglobin concentrations are preserved.
   – Iron deficiency without anemia
      • Additional decrease in iron storage (stores, serum ferritin, are almost
        exhausted)
      • Low serum iron
      • Low transferrin saturation
      • Erythrocyte protoporphyrin increases.
      • Hemoglobine falls to the lowest limit of normal
      • But without frank anemia
   – Iron deficiency anemia (hypochromic microcytic anemia)
      •   Most advanced stage
      •   Hemoglobin or haematocrit continues to fall
      •   Decreased or absent iron stores
      •   Decreased serum iron and transferrin saturation
      •   Erythrocyte protoporphyrin increases to upper limit of normal           38
                      Iron overload
• Causes:
1. Increased intestinal absorption
    –   Either acutely (as in iron poisoning)
    –   Chronically (southern Africa brew their beer in iron vessels (Bantu
        siderosis).
2. Increased parenteral iron administration
3. Repeated blood transfusions
    –   for treatment of refractory anemias
•   Two broad types of iron overload disorders.:
    –   Hemochromatosis (when iron overload is associated with damage
        to cells. a hereditary disease characterized by improper
        processing by the body of dietary iron which causes
        iron to accumulate in a number of body tissues,
        eventually causing organ dysfunction. Periodic
        phlebotomies (venesection).
    –   Hemosiderosis (without cell damage)
    –   Excess iron is deposited mainly as hemosiderin in RE cells in the
        liver and spleen (harmless) but with time parenchymal deposition
        may lead to hepatic fibrosis and myochardial damage.            39
                 (9)Copper (Cu)
• RDA: 1.5 mg – 3.0 mg.
• Cu1+ and Cu2+ in biological systems.
• High dosage (15 to 35 mg) could adversely affect
  Zinc metabolism.
• High concentrations are found in brain.
• Found in organ meat, liver, kidney, shellfish, nuts,
  cocoa containing products, whole grain cereals.

• Important trace elements, involved in many body
  functions:
   – Helps build bones and blood, elastin, collagen.
   – Involved in healing process, energy production, hair and
     skin coloring, taste sensitivity.
   – Needed for healthy nerves and joints.
                                                           40
                         Cu functions
1.   Energy Production Cytochrome c oxidase is a multi-subunit complex
     containing copper and iron and is essential for oxidative
     phosphorylation.
2.   Connective tissue formation Lysyl oxidase is a cuproenzyme
     essential for stabilization of extracellular matrixes. Enzymatic cross-
     linking of collagen and elastin.
3.   Iron metabolism Ferroxidase I (ceruloplasmin) and ferroxidase II,
     oxidize ferrous iron to ferric iron.
4.   Central nervous system Dopamine monooxygenase (DMO) requires
     copper as cofactor and ascorbate as electron donor. It catalyzes
     conversion of dopamine to norepinephrine, important neurotransmitter.
     Monoamine oxidase catalyzes the degradation of serotonin in the brain
     and is involved in the metabolism of catecholamine.
5.   Melanin synthesis Tyrosinase is copper-containing enzyme, present
     in melanocytes and catalyzes synthesis of melanin.
6.   Antioxidant functions SODs (superoxide dismutase) are Cu and Zn
     containing enzymes that convert superoxide radical to H2O2.
7.   Regulation of gene expression Cu-dependent proteins act as
     transcription factors
                                                                        41
Inborn errors of copper metabolism
 • Menkes’ disease: Impaired intestinal transport
   of copper caused by mutation in ATP7A gene
   leads to severe copper deficiency.
 • Wilson’s disease: Mutation in ATP7B gene
   affects incorporation of copper into
   ceruloplasmin and copper excretion, leading to
   accumulation of copper in liver, brain, kidney,
   cornea, other tissues.
 • Aceruloplasminemia: Failure in hepatic
   synthesis of ceruloplasmin.
 • Carciovascular disease: due to deficiency in
   animals, but in humans increased plasma
   copper is a cardiovascular risk factor.         42
                       (10)Fluoride
• 99% is found in bones and teeth
• Functions (cariostatic activity and anti-osteoporotic activity):
    – Interacts with hydroxyapatite to form fluorhydroxyapatite that less
      acid soluble.
    – promotes the remineralization of enamel in early caries.
    – Inhibits bacterial growth in mouth  decreases cavity formation.
• Fluoride is thought to have osteoblastic activity and, in
  partnership with calcium, stimulates the production of new bone.
    – Calcium needs F and nine other elements to build bone.
    – promotes mineralization of calcium and phosphate.
• Molybdenum combined with F is more effective in fighting
  cavities. “New and improved” toothpastes are on their way to
  market.
• Main sources include drinking water and plants (spinach, lettuce,
  onions).
• Added to water in 0.7-1.2 mg/L (ppm). >2ppm intestinal upset.
• Excess can cause mottled enamel (fluorosis) (> 5ppm).


                                                                            43
                                  (11)Iodine
•   RDA: 150 mcg
•   25-30 mg in the body.
•   5-10 µg/dl blood.
•   Not toxic up to 2000 mcg daily, but may exacerbate acne.
•   Iodine is necessary for the formation of thyroid hormones (T-4 and T-3)
•   Regulation in body:
     – 30% of Iodine in food is absorbed.
     – Excess removed in urine.
•   Salt water fish best food source. Even breathing sea air prevents goiter.
•   Iodine can be absorbed by the skin.
•   Some food prevent utilization of iodine (called goiterogenous substances); for
    example, cabbage contains thiocyanate which inhibits iodine uptake by thyroid.
•   Deficiency:
•   Goiter (less severe)
     – Enlarged thyroid gland due to body’s attempt to increase thyroid hormone production.
•   Cretinism (more severe)
     – Severe iodine deficiency during pregnancy  serious problems in baby.
         • Stunted growth, deaf, mute, mentally retarded.
•   To prevent the development of endemic goiter, table salt has been spiked with
    sodium iodide.
                                                                                       44
                              (12)Zinc
• RDA: 15 mg to 19 mg, ADI: 8.6 mg
• Toxicity is low up to 500 mg/day.
• Zinc absorption appears to be dependent on a transport
  protein, metallothionein.
• Helps fight acne. Similar results to tetracycline in superficial
  acne and good results in deep acne. For blemish-free skin.
• Deficiencies include poor growth, delayed wound healing,
  impairment of sexual development and decreased taste
  acuity
       • zinc is present in gustin, a salivary polypeptide that is necessary for the
         development of taste buds.
• Deficiency  Acrodermatitis Enteropathica

• Adverse effects: Inhibits copper utilization, increase
  plasma cholesterol.
                                                                                 45
                       Biological roles
• Part of every cell.
• Over 200 enzymes depend on Zn (over 20 metalloenzymes):
       • Carbonic anhydrase
       • Carboxypeptidase A
           – Four types of proteases
               » Serine
               » Cysteine
               » Aspartic acid
               » Zinc
       • ACE (angiotensin I convering enzyme)
       • RNA and DNA polymerases
• Important for body immunity (fights common cold) and
  strength.
• Male sexual function, male hormone metabolism, sperm
  formation, sperm motility. Deficiency may cause infertility.
• Vital role during pregnancy; Dose should increase;
  problems:
   – premature births, low birth weight, growth retardation,
     preeclampsia (pregnancy-induced hypertension), small head
     circumference.
                                                                 46
Zinc Fingers




               47
                       (13)Manganese
• RDA: 2.0 to 5.0 mg
• ADI: 2.7 mg
• Total body Mn is 15 mg.
    – Maximum concentration is in liver.
    – In blood it is bound to transmanganin (specific carrier protein).
    – In the cells, it is seen inside nuclei complexed with nucleic acids.
• Low levels of toxicity causes permanent insanity. Industrial manganese
  dust, causes locura manganica (manganese madness).
• Role in proper bone and cartilage formation and glucose and lipid
  metabolism, and reproductive functions.
    – Deficiency causes similar bone problems as osteoporosis.
• Dietary sources: Whole grain foods, nuts, leafy vegetables, soy
  products, teas.
    –   3% is absorbed
    –   Absorption inhibited by iron.
    –   75% lost when wheat is refined to white flour.
    –   Excreted through bile and pancreatic juice.


                                                                             48
          Manganese functions
• Maganese is an activator of several different enzymes:
      • Phosphoglucomutase
      • Isocitrate dehydrogenase
      • Cholinesterase
      • Intestinal peptidase
      • Carboxylases
      • ATPases
      • Superoxide dismutase (SOD)
      • Pyruvate carboxylase
      • Arginase
      • Glycosyl transferases (responsible for synthesis of
        glycoproteins and chondroitin sulfate, organic matrix of bone
        and cartilage)
      • hexokinase

   – However, magnesium and cobalt can replace Mn in several
     enzymes.
                                                                    49
                          (14)Boron
• Before 1981 it was thought to be unimportant.
• But it is essential for:
   – normal growth
   – hormones involved in bone metabolism
   – normal balanced levels of estrogen and testosterone.
• A study:
   – Within 8 days of boron supplementation of 3mg,
     postmenopausal women showed 40% less loss of Ca and 33%
     less loss of Mg through urine.
• Supplementation causes:
   –   increase in 25-(OH) cholecalciferol,
   –   decreased calcitonin,
   –   decreased serum glucose,
   –   increased serum triglycerides
• Boron has not yet been included in “Essential Nutrient”
  list and no RDA intake levels has been given.                50
                          (15)Chromium
•   RDA: 50 g -200 g.
•   Trivalent chromium (Cr3+) is very safe
•   Hexavalent industrial Cr6+ is toxic and carcinogenic.
•   In 1957, Cr was identified as the active component of “glucose tolerance
    factor” (GTF).
     – Very important but Cr was added to the list of RDA handbook in 1989.
• Signs of Cr deficiency resemble Type II diabetes (a cofactor for
  insulin?)
     – Important in normal glucose, insulin, fatty acid metabolism and muscle
       growth.
     – 98% of Cr is destroyed when flour is refined; May be why adult diabetes is
       winning.
• Helps lose fat and gain muscle.
     – It makes even pigs to lose weight.
• Helps raise HDL cholesterol or the Good Cholesterol
     – Prevents cardiovascular disease.
• Found in: meat, whole grain products, green beans, broccoli, some
  spices, corn oil, clams, drinking water (variable)
     – Foodstuff rich in sucrose and fructose are low in chromium.
• High doses of Chromium picolinate, dietary supplement can damage
  kidney and liver.                                                             51
                      (16)Lithium
• Optimum concentration in plasma is 7-10 µg/ml.
• It is an essential growth factor at least in tissue culture.
   – Human skeletal muscle contains 2-200 nanograms/g of wet
     weight.
   – Higher concentrations are seen in nerves, and brain.
   – Helps transport sodium metabolism in brain, nerves and
     muscles.
• Deficiency symptoms: Nerve, mental disorders. Higher
  intrauterine and neonatal deaths.
• Therapeutic uses: Paranoid schizophrenic.
   – Lithium toxicity leads to hypothyroidism.
   – Lithium treatment caused increased [inositol phosphate] in brain
     by inhibiting inositophosphatase.
• Natural sources: Seafood

                                                                    52
                     (17)Molybdenum
•   RDA: 50 µg to 250 µg
•   ADI: 109 µg
•   Toxicity starts at 10 mg daily, causing gout-like disease.
•   Dietary sources: legumes, peas, lentils, beans nuts
     – Meats, fruits and many vegetables are poor sources.
• Component of several enzymes involved in alcohol detoxification, uric
  acid formation, sulfur metabolism.
     – Sulfite oxidase (catalyses the last step in degradation of sulfur amino
       acids)
     – Xanthine dehydrogenase
     – Aldehyde oxidase
     – flavoproteins,
     – xanthine oxidase (oxidizes xanthine to uric acid).
• Low levels are associated with esophageal cancer and methionine
  intolerance.
     – Anticancer effect stems from role in detoxification of cancer causing
       chemicals.
     – Enhances fluoride in cavity prevention.
     – Small amounts of Mo helps in utilization of copper.
     – High Mo can cause copper deficiency.                                      53
               (18)Selenium
                                                    A
• RDA: 70 mcg, ADI: 108 mcg
• Only a small amount is needed.
• Megadoses cause toxicity: hair and fingernail
  loss.
• Works as antioxidant with Vitamin E to destroy
  hyperoxides, free radicals that damage cell
  membranes.
• Fights cancers (respiratory and gastrointestinal),
  cardiovascular disease, diabetes, arthritis.
• Some biologically active compounds contain
  selenocysteine, where Se is substituted for S in
  cysteine.
  – Selenocysteine is now considered the twenty-first
    amino acid with the codon UGA.
                                                        54
         Functions of Selenium
• Component of glutathione peroxidase (GSHPx-1 –
  GSHPx-4)
   – catalyzes removal of hydrogen peroxide
        GSH + H2O2                     GSSG + H2O
         GSH = reduced glutathione
         GSSG = oxidized glutathione
• Component of iodothyronine-5’- deiodinase
   – Converts T4 to T3
• Improves killing ability of neutrophils.
   – Reduces the prevalence and severity of mastitis (inflammation of
     the breast)
• Selenoprotien P (Se carrier in plasma)
• Selenoprotein W (in muscle)
                                                                   55
                    Selenium ...
• Selenium deficiency can cause cataract.
  –   Because lens depends on
  –   superoxide dismutase
  –   catalase
  –   glutathione peroxidase
  –   adequate levels of Vitamin E, Vitamin C and
      selenium.
• Keshan disease (cardiomyopathy) in Keshan
  region of China
• Kashin-Beck disease (Big Bone Disease). China
• Reproductive disorders
• Mood disorders

                                                    56
                          (19)Silicon
•   ADI: 329 mg
•   Nontoxic. But high levels observed in Alzheimer’s disease.
•   After oxygen, Silicon is the most abundant element on earth.
•   Regarded as essential element in 1972.
•   Silicon breast implants are toxic.
•   As a nutrient, Silicon is important for normal bone growth,
    integrity of skin.
    – appears to play an important role in the development and
      maintenance of cartilage (chondroitin sulfate, hyaluronic acid, keratin
      sulfate).
    – may have a protective role in cardiovascular diseases
      (atherosclerosis).
• Anti aging. Colloidal silicic acid causes improvements in
  thickness of skin, strength of the skin, wrinkles, and health of
  hair and nails.
• Found in unrefined grains and beer.                         57
                (20)Vanadium
• RDA: 10 mcg to 60 mcg.
• Excessive amounts lead to cramping and diarrhea.
• Essential role in human nutrition: it improves insulin
  action and even mimics the functionality of insulin.
• Deficiency during pregnancy: kids with serious birth
  defects, bone deformity, death. Less milk in
  mothers.
• natural source: Fish
• Therapeutic uses: heart attack prevention, high
  blood pressure, arteriosclerosis, diabetes.
• may also function as an oxidation-reduction
  catalyst.
                                                     58
                   (21)Tin
• Produces accelerated growth in deficient
  rats.
• Tin is similar to carbon in its tendency to form
  covalent bonds.
• May have a role with heme-containing
  enzymes:
  – heme oxygenase
  – cytochrome P-450
• largest quantities are found in kidneys and
  skin and the thymus gland.
• human intake: ~ 1.5 - 3.5mg/day


                                                59
(22)Cobalt, essential part of Vitamin B12




                                       60
 Functions of Cobalt and Vitamin B12
• Essential coenzyme for
  – Propionate metabolism
     • methylmalonyl CoA to succinyl CoA
  – DNA synthesis
  – Bacterial synthesis of methionine
• Microflora of human intestine cannot use cobalt to
  synthesize physiologically active cobalamine.
  – Human vitamin B12 requirements must be supplied in the
    diet
  – Free (nonvitamin B12) cobalt does not interact with the
    body vitamin B12 pool.

                                                       61
            NPK Fertilizers

• NPK fertilizers have reduced soil quality
  because they can replace only
  nitrate/phosphate/potassium in the soil
  and not many other minerals that are
  essential for human growth.




                                              62
        Definition of terms
   • RDA: Recommended Daily Allowance.
   • FDA: Food and Drug Administration
   • ADI: Average Daily Intake

• Dietary intakes of trace elements can be
  assessed by direct dietary analysis and by
  taking dietary histories.
• To estimate positive or negative balances:
  Direct measurement of total dietary intake
  over several days + measurement of output
  in urine, feces and other routes
                                               63

								
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