Trace Minerals: Iron, Zinc, Copper, Selenium PDF

TRACE AND ULTRATRACE MINERALS 13 1 Learning Objectives 13.1 Identify good food sources of the essential minerals 13.2 Explain how the essential minerals are digested, absorbed, transported in the...

TRACE AND ULTRATRACE MINERALS 13 1 Learning Objectives 13.1 Identify good food sources of the essential minerals 13.2 Explain how the essential minerals are digested, absorbed, transported in the blood, stored, and excreted 13.3 Describe the functions and mechanisms of action of the essential minerals 13.4 Describe recommended intakes, deficiencies, and toxicities associated with the essential minerals 13.7 Explain how essential mineral status is assessed 2 IRON Several oxidation states, Fe6+ to Fe2-, only ferrous (Fe2+) and ferric (Fe3+) are stable in the body and food Sources: Heme: from hemoglobin and myoglobin is 50-60% of the Fe in meats, fish and poultry Esp. red meats, oysters & clams Nonheme: plant foods, dairy (poor source) Whole grains, nuts, legumes, tofu, spinach Usually bound to components in foods, needs to be hydrolyzed to be absorbed Breads, rolls, pasta, cereals, & flour are fortified with Fe Oral supplements (high doses can cause constipation, stomach pain, and nausea) 3 1  Iron Content of Selected Foods Food Iron (mg) Percent DV Breakfast cereals, 100% of DV for iron, 1 serving 18 100 Oysters, eastern, cooked with moist heat, 3 oz 8 44 White beans, canned, 1 cup 8 44 Chocolate, dark, 45%–69% cacao solids, 3 oz 7 39 Beef liver, pan fried, 3 ounces 5 28 Lentils, boiled and drained, ½ cup 3 17 Spinach, boiled and drained, ½ cup 3 17 Tofu, firm, ½ cup 3 17 Kidney beans, canned, ½ cup 2 11 Chickpeas, boiled and drained, ½ cup 2 11 Tomatoes, canned, stewed, ½ cup 2 11 Beef, braised bottom round, trimmed to 1/8” fat, 3 oz 2 11 Potato, baked, flesh and skin, 1 medium 2 11 Cashew nuts, oil roasted, 1 oz (~18) 2 11 DV= 18 mg 4 Digestion & Absorption Heme Iron (Fe2+) Proteases hydrolyze heme from the globin The globin is digested, the heme is absorbed intact by a carrier In the enterocyte, heme is hydrolyzed Þ Fe2+ + protoporphyrin Nonheme Iron (Fe3+) Must be hydrolyzed from food components and reduced to cross membrane Some Fe3+ Þ Fe2+ in the stomach (HCl) Fe3+ Þ Fe2+ at the brush border (reductases) 5 Enhancers Sugars Acids Acidic pH Mucin Animal protein Low Fe status Hypoxia Fe2+ Fe3+ Fe3+ Fe 3+ D CYTB Inhibitors Fe2+ Fe2+ Fe3+ Alkaline pH Polyphenols Fe2+ Fe2+ Oxalate Fe2+ Phytate Fe3+ Casein Ferroportin Egg yolks Divalent cations Antacids High Fe status Fe3+ Increased Fe D M T1: divalent m etal transporter 1 excretion in feces H C P1: hem e carrier protein1 D CYTB: duodenal cytochrom e b reductase PC PB2: poly (rC )-binding protein 6 2  Absorption ­ Nonheme Iron Absorption ¯ Iron Absorption Some acids (ascorbic, citric, lactic acid Polyphenols (tannins in tea or coffee) Fe 3+ ® Fe 2+) Oxalate (spinach, chocolate, tea) Sugars (fructose, sorbitol) Phytate (whole grains, legumes, nuts) Meat, fish or poultry eaten with nonheme Divalent cations (Ca, Zn, Mn) Mucin Phosvitin – phosphorylated Ser in egg yolk Low iron status protein Hypoxia Alkalinization of GI tract: H2 receptor blockers (Tagamet, Pepcid) and proton pump inhibitors (Prevacid, Nexium) High Fe status 7 Iron Must Be Oxidized for Transport Fe crosses the basolateral membrane through ferroportin Two Cu-dependent proteins oxidize Fe2+ as it leaves the cell Intestine: hephaestin Other cells and plasma: ceruloplasmin Ferric iron can then bind to transferrin 8 Transport and Cellular Uptake Free iron can be lethal Tf delivers Fe via transferrin receptors (TfR) Two negative consequences of free Fe TfR1 - expressed almost everywhere in ­ free radical production the body Fe2+ + H2 O2 ® Fe3+ + OH- + ·OH Levels respond to iron status infectious bacteria can use it for growth TfR2 - expressed in hepatocytes and Transferrin (Tf) transports and delivers Fe erythroblasts; associated with iron to cells sensing Glycoprotein with two Fe-binding sites Levels do not change with iron status 20-40% Fe-saturated in adequate Fe Regulates systemic iron homeostasis status; the remainder is latent capacity via liver Fe and hepcidin synthesis Tf can bind other minerals: Cr > Cu > Mn > Cd > Zn > Ni 9 3 10 Fe Storage Stored in liver (60%), bone marrow, and spleen Ferritin: Primary storage form of iron (up to 4500 atoms), some is in the circulation but most intracellularly Spherical protein made of 24 subunits with a hollow core Iron is deposited in the center as a variety of ferric compounds Constantly degraded and resynthesized, making iron readily available Hemosiderin Composed of damaged ferritin Fe released from hemosiderin at a slower rate Formed in iron excess Ferritin capacity has been exceeded Liver is trying to protect the body 11 Systemic Iron Regulation Liver acts a sensor of Fe status detecting Tf saturation via TfR1 – Tf interaction Hepcidin (hepatic bactericidal protein, HAMP) Main regulator of Fe absorption and metabolism in the body Released from liver when Fe stores are high Binds ferroportin, disabling Fe transport into blood from enterocytes, hepatocytes, and reticuloendothelial macrophages In these cells, ferroportin regulates iron absorption, recycling, and storage, respectively Iron accumulates in those cells 12 4  HFE: Hemochromatosis protein BMP6: Bone morphogenic protein 6 HJV: Hemojuvelin IL6: Interleukin 6 13 14 Cellular Iron Regulation Iron regulatory proteins 1 and 2 (IRP1 and IRP2): Cytoplasmic, bind to iron response elements (IREs) in specific mRNA segments and regulate synthesis of Fe- related proteins In low iron: ↑ DMT1, TfR, DCYTB, ferroportin ↓ Ferritin, δ ALAS In high iron: ↑ Ferritin, δ ALAS ↓ DMT1, TfR, DCYTB, ferroportin 15 5 16 Roles Biochemical reactions usually classified as: oxygen transport and storage electron transfer substrate oxidation-reduction 17 Heme group Iron-sulfur clusters Iron metalloenzymes Active species 5-lipooxygenase Cytochrome c oxidase Inactive species 18 6  Functions and Mechanisms of Action Heme proteins Largest group hemoglobin: transports O 2 to tissue (> 65% of Fe in body) myoglobin: stores O 2 in tissue, especially muscle (£ 10%) cytochromes: transport of electrons through respiratory chain Iron-sulfur proteins Involved in electron transport, TCA cycle, heme synthesis Iron metalloenzymes Monooxygenases, dioxygenases, peroxidases Insert oxygen into a substrate 19 Functions and Mechanisms of Action Oxygen transport and storage (Hb, myoglobin) Oxygenases Electron transport and energy transformation: Amino acid metabolism: phe, tyr, trp, and Cytochromes and coenzyme Q - arg cytochrome c reductase (catalyzes the Synthesis of reduction of cytochrome c by oxidizing CoQ) Niacin Glycerol phosphate dehydrogenase Carnitine (glycolysis) and phosphoenolpyruvate Procollagen carboxykinase (gluconeogenesis) Nitric oxide Antioxidant and beneficial prooxidant DNA synthesis: Ribonucleotide reductase functions: Cytochrome P450 family Catalase and peroxidase: Collagen synthesis Synthesis of thyroid hormone by thyroperoxidase Neutrophjils hypochlorite synthesis: myeloperoxidase 20 Turnover Fe homeostasis depends on the recycling of body Fe The amount absorbed is ~ 0.06% of total body iron Most of the iron in Tf comes from the destruction of Hb, ferritin, and hemosiderin Old RBC (~120 days) are taken up by macrophages in spleen, bone marrow or liver and degraded Hemoglobin is degraded Heme ® biliverdin ® bilirubin ® bile ® excretion Fe (20-25 mg/d) is released and transported by transferrin for reuse in erythropoiesis, or Fe-dependent enzymes, or is stored in macrophages and reticuloendothelial cells in bone marrow, liver, and spleen 21 7  Iron turnover 22 Excretion Excretion Most Fe losses (~0.6 mg) through the GI tract, ~0.45 mg through minute (~1 mL) blood loss, and rest in bile and desquamated mucosal cells Skin losses of ~0.2–0.3 mg with desquamation A very small amount, about ~0.05 mg in urine Losses greater in people with gastrointestinal ulcers or intestinal parasites, or with hemorrhage On average: adult males ~0.9-1.0 mg/day; postmenopausal women ~0.7-0.9 mg/day menstruating person ~1.3-1.4 mg/day due to menses Average loss of blood during menses: 35 – 80 mL; 0.5 mg Fe/mL; 17.5-45 mg Fe lost; 27.6 mg calculated into requirements 23 Requirements RDA Adult male: 8 mg/d, adolescent male: 11 mg/d Female adult: 18 mg, adolescent female: 15 mg post-menopausal: 8 mg pregnancy: 27 mg lactating: 9 mg The average daily iron intake from foods and supplements is 19.3–20.5 mg/d in men and 17.0–18.9 mg/ in women The median dietary iron intake in pregnant women is 14.7 mg/day UL: 45 mg/d 24 8  Deficiency Results from: Insufficient dietary iron ¯ absorption Pathological blood loss: nosebleed, occult blood loss, wounds, parasites, blood donations Signs & Symptoms Hypochromic microcytic anemia Pallor, listlessness, impaired cognitive performance Fingernails: brittle, flattened or concaved (spoon nails) Pica: ingestion of non-food substances 25 26 Stages of iron status Depleted Iron Iron deficiency Overload Normal stores deficiency anemia Serum ferritin ↑ N ↓ ↓ ↓↓ Transferrin saturation ↑↑ N N ↓ ↓ Erythrocyte protoporphyrin N N N ↑ ↑↑ MCV N N N N ↓ Hemoglobin N N N N ↓ 27 9  At-risk populations Infants and young children: low iron content of milk, low body stores and rapid growth rate Adolescents during growth spurt Premenopausal women: menses, low intake, caloric restriction Pregnant women: ­ blood volume, use by placenta and fetus, blood loss in childbirth People with hemorrhage, protein calorie malnutrition, dialysis patients, achlorhydria, chronic use of alkaline-based drugs, ¯ transit time, steatorrhea, parasites 28 Iron Deficiency Worldwide One of the top 10 most serious health problems in the modern world (WHO) As many as 4-5 billion people (66-80% of population) may be iron deficient 2 billion people (>30% of population) are anemic Iron deficiency in young children is the rule rather than the exception (45-70% prevalence) Associated with developmental delays of cognitive and motor skills Iron deficient children tend to be pale, weak, eat less, tire easily, be more irritable, have shorter attention spans, fall ill more frequently, and fail to grow normally 29 Anemia Low hemoglobin Iron deficiency anemia Low hemoglobin due to low iron Iron deficiency Low levels of iron World population 30 10  Toxicity Acute Ÿ Usually due to ingestion of iron supplements Ÿ Occurs mainly in children Ÿ Average lethal dose for adults: 200 - 500 mg Fe/kg body weight For a 2-year-old the lethal dose is about 3 grams Chronic Ÿ Accumulation of excess iron Þ destruction of cells of organs including the pancreas (diabetes), liver (liver failure), and heart (heart failure) 1. Excessive supplement intake 2. Iron tonic ingestion 3. Parenteral 4. Iron loading diseases (hemochromatosis) 31 Iron Toxicity – Genetic Defect Hemochromatosis arises from a hereditary defect that results in excessive Fe absorption and storage Affects 5 in 1,000 people of Northern European origin Leads to excess Fe in body Treatment: reduce dietary iron avoid high vitamin C intake blood removal chelation drugs 32 Assessment of Iron Status Most common: Hemoglobin (Hgb): amount of hemoglobin per dL of blood Hematocrit (Hct): proportion of total blood volume that is RBC [percentage] RBC details: MCV: size of the RBC (most popular) MCH: average Hgb content of each RBC MCHC: amount of Hgb/dL RBC TIBC (total iron binding capacity) Plasma ferritin can be used to assess iron stores (Stage 1) Serum transferrin receptor levels ­ (Stage 2) 33 11  ZINC A metal, mostly found as Zn2+ (divalent) Sources Usually associated with amino acids and nucleic acids 40-70% of Zn in US diet is from animal products Very good sources: red meats (organ meats) and seafood Good sources: poultry, pork, dairy Moderate: whole grains, leafy and root vegetables Plant sources are less bioavailable Zinc in pancreatic and biliary secretions are also absorbed for reuse Heating can cause Zn to complex with other compounds in foods Þ ¯ bioavailability Supplements: pills, lozenges, sprays, nasal gels 34 Selected Food Sources of Zinc Food Zinc (mg/serving) Percent DV* Oysters, Eastern, farmed, raw, 3 c 32 291 Beef, bottom sirloin, roasted, 3 oz 3.8 35 Blue crab, cooked, 3 oz 3.2 29 Breakfast cereals, 25% fortified, 1 serving 2.8 25 Oats, unenriched, cooked with water, 1 c 2.3 21 Pumpkin seeds, roasted, 1 ounce 2.2 20 Pork, chops, bone-in, broiled, 3 oz 1.9 17 Turkey breast, meat only, roasted, 3 oz 1.5 14 Cheese, cheddar, 1.5 oz 1.5 14 Shrimp, cooked, 3 oz 1.4 13 Lentils, boiled, ½ c 1.3 12 Sardines, canned in oil, with bone, 3 oz 1.1 10 Greek yogurt, plain, 6 oz 1.0 9 Milk, 1% milkfat, 1 c 1.0 9 DV: 11 mg 35 Zinc Transporters Two families of zinc transporter proteins: 14 ZIP transporters increase cytoplasmic Zn concentration by facilitating Zn influx from extracellular space or from cellular compartments 10 ZnT transporters facilitate Zn efflux across the cell membrane or into cellular vesicles and decrease intracellular Zn concentration ZnT and ZIP genes exhibit either up- or down-regulation in response to Zn and contribute to the tight homeostatic control of zinc Some transporters exhibit multiple ion specificity - could explain some metal- metal interactions (ZIP8: Zn & Mn, ZIP14: Zn & Fe) 36 12  ¯ Zn intake, ­ ZIP4 ­ Zn intake, ¯ ZIP4 D M T1 37 Factors Influencing Absorption ¯ absorption: ­ absorption: antacid use Organic acids (citric acid, etc) ¯ HCl in stomach Amino acids (His, Cys) H2 receptor blockers (Zantac, Glutathione Tagamet, Pepcid) Acidic environment proton pump inhibitors (Prilosec) phytate, oxalate, polyphenols divalent cations (Ca2+, Fe2+) 38 Transport, Storage, and Excretion Transport Distribution and storage Blood - bound loosely to albumin Found in all organs, especially liver, Also, transferrin, a-2 macroglobulin, kidneys, muscle, skin, bones histidine-Zn-cysteine (