chapter 12

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Chapter 12

Microminerals

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Introduction• Precise definition of “essential

micromineral” not established– Sometimes defined as mineral

needed in amounts of <100 mg/day• RDAs established for 6• AIs for 3 others

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Iron• Sources

– Heme iron: meat, fish, poultry– Nonheme iron: nuts, fruits,

vegetables, grains, tofu, dairy– Grain foods fortified with iron

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Iron• Digestion, absorption, transport,

storage, & uptake– Heme iron digestion & absorption

• Hydrolyzed from hemoglobin/myoglobin in stomach & small intestine

• Heme absorbed intact by heme carrier protein 1 (hcp 1)

• Hydrolyzed to inorganic ferrous Fe & protoporphyrin

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Iron– Nonheme iron digestion & absorption

• Hydrolyzed from food components in stomach• Mostly ferric iron released into small intestine,

some ferrous• Fe3+ may complex to ferric hydroxide Fe(OH)3 -

relatively insoluble• Fe2+ remains fairly soluble• Fe2+ absorbed via divalent cation transporter 1

(DMT1)• Absorption of Fe3+ increased by acidic

environment & chelation of the iron

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Iron– Factors

influencing iron absorption

• Enhancers of iron absorption

– Sugars– Acids (e.g.

ascorbic, citric, lactic, tartaric)

– Meat, poultry fish– Mucin

• Inhibitors of iron absorption

– Polyphenols– Oxalic acid– Phytates– Phosvitin– Calcium, calcium

phosphate salts– Zinc– Manganese– Nickel

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Iron– Intestinal cell iron use

• 3 options– Transported through cytosol, across

basolateril membrane to enter circulation– Stored for use or elimination– Used in a functional capacity

• Regulation of iron absorption– Hepcidin– Ferroportin– Other basolateral membrane proteins

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Iron– Transport

• Ferric Fe in blood - attached to transferrin• Ferrous Fe converted to ferric - catalyzed

by hephaestin (enterocytes) & ceruloplasmin (throughout body)

• Importance of transferrin

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Iron– Storage

• Sites: liver, bone marrow, spleen• Storage proteins

– Ferritin» H form or L form» Unstable - constantly degraded &

resynthesized» Body & serum stores equalize

– Hemosiderin» Increases during iron overload

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Iron– Uptake by tissues

• Affected by transferrin saturation level• Transferrin binds to transferrin receptors

(TfR1, TfR2) to form a complex• Complex internalized into vesicle• Protons pumped in to reduce pH• Iron released from transferrin• Apotransferrin returned to plasma• # of receptors affected by intracelluar Fe

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Iron• Functions & mechanisms of action

– Hemoglobin & myoglobin– Cytochromes & other enzymes involved in

electron transport– Monooxygenases & dioxygenases– Peroxidases– Oxidoreductases– Other iron-containing proteins– Iron as a pro-oxidant

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Iron• Interactions with other nutrients

– Vitamin C– Copper– Zinc– Vitamin A– Lead– Selenium

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Iron• Turnover

– Hemoglobin, ferritin & hemosiderin degradation yield plasma iron

• Excretion– Most through GI tract (blood, bile,

desquamated mucosal cells)– Skin (desquamation of surface cells)– Urine– Larger losses with hemorrhage, menses

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Iron• Recommended Dietary Allowance

– Men: 8 mg– Women: premenopausal 18 mg,

postmenopausal 8 mg– Pregnancy: 27 mg; lactation: 9 mg

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Iron• Deficiency: iron deficiency with &

without anemia– Vulnerable:

• Infants/young children• Adolescents• Menstruating females• Pregnant women

– Supplements

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Iron• Toxicity: hemochromatosis

– Mutations in HFE gene – Body cannot accurately sense iron

stores and down-regulate intestinal absorption

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Iron• Assessment of nutriture - progression of

deficiency– Serum ferritin decreases unless there is

inflammation/infection– Ferritin & transferrin saturation decrease– Free protoporphyrin rises– Anemia occurs - hemoglobin & hematocrit

typically altered– Blood cells indicators: MCV, MCH, MCHC

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Zinc• Sources

– Red meats, seafood, poultry, pork, dairy

– Whole grains, vegetables– Availability affected by heat, Maillard

reaction products– Recycled from pancreatic & biliary

secretions

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Zinc• Digestion, absorption, transport,

uptake, & storage– Digestion

• Hydrolyzed from amino/nucleic acids in stomach & small intestine

– Absorption• Carrier-mediated process

– Zrt- & Irt-like protein (ZIP) 4• Passive diffusion & paracellular absorption

with high intake

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Zinc– Factors influencing zinc absorption

• Enhancers of zinc absorption– Ligands - citric acid, picolinic acid,

prostaglandins, amino acids– Low zinc status

• Inhibitors of zinc absorption– Phytate– Oxalate– Polyphenols– Nutrients, e.g. folate, iron, calcium, copper

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Zinc– Intestinal cell zinc use - may be:

• Used functionally• Stored• Transported across basolateral

membrane into plasma for transport– Transport

• Blood - bound loosely to albumin– Also transferrin, alpha-2 macroglobulin,

immunoglobulin G– Histidine, cysteine

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Zinc– Uptake by tissues

• ZIP carriers 1, 2, 4, 6, 7, 8, 14• ZnT transporters

– Distribution & storage• Found in all organs, especially liver,

kidneys, muscle, skin, bones• Usually stored bound to thionein as

metallothionein

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Zinc• Functions &

mechanisms of action– Zinc-dependent

enzymes• Carbonic

anhydrase• Alkaline

phosphatase• Alcohol

dehydrogenase

• Carboxypeptidase• Aminopeptidase• Delta-aminolevulinic

acid dehydratase• Superoxide dismutase

(SOD)• Collagenases• Phospholipase C• Polyglutamate

hydrolase• Polymerases, kinases,

nucleases, transferases, phosphorylases, transcriptases

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Zinc– Other roles

• Growth - regulation of transcription• Cell replication• Bone formation• Skin integrity• Cell-mediated immunity• Generalized host defense• Carbohydrate metabolism

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Zinc• Interactions with other nutrients

– Vitamin A– Copper– Calcium– Cadmium

• Excretion– Mostly through GI tract– Small amount in urine & through skin

exfoliation/sweat

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Zinc• Recommended Dietary Allowance

– Men: 11 mg; women: 8 mg– Pregnancy: 11 mg; lactation: 12 mg

• Deficiency– Elderly & vegetarians– Needs increased by alcoholism,

chronic illness, stress, trauama, surgery, malabsorption

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Zinc• Supplements• Toxicity

– UL = 40 mg• Assessment of nutriture

– Zinc in RBCs, leukocytes, neutrophils, plasma/serum

– Metallothionein concentrations– Urinary or hair zinc– Activity of zinc-dependent enzymes

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Copper• Sources

– Organ meats, shellfish– Nuts, seeds, legumes, dried fruits

• Digestion, absorption, transport, uptake, & storage– Digestion

• Bound to organic components in food• Released in stomach, small intestine

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Copper– Absorption

• Small amount via stomach (low pH)• Small intestine

– Active carrier-mediated transporters– Nonsaturable, passive diffusion process

• Transporters: Ctr1, DMT1• Most reduced before absorption

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Copper– Factors influencing copper absorption

• Enchancers of copper absorption– Amino acids– Organic acids other than vitamin C

• Inhibitors of copper absorption– Phytate– Zinc– Iron– Molybdenum– Calcium & phosphorus– Vitamin C– Excessive antacid ingestion/high pH

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Copper– Intestinal cell copper use

• Stored, used, or moved into blood– Transport & uptake

• In blood: bound loosely to albumin or bound to transcuprein (Tc), amino acids

• In liver: binds to metallothionein, then to apoceruloplasmin to form ceruloplasmin

• Ceruloplasmin delivers Cu to tissues

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Copper– Storage

• Concentrates in liver, brain & kidneys• Stored bound to amino acids, proteins, &

chaperones• Metallothionein - stores up to 12 Cu

atoms

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Copper• Functions & mechanisms of action

– Ceruloplasmin– Superoxide dismutase– Cytochrome c oxidase– Amine oxidases– Tyrosine metabolism--dopamin

monooxygenase & p-hydroxyphenylpyruvate hydroxylase

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Copper– Lysyl oxidase– Peptidylglycine alpha-amidating

monooxygenase– Other roles

• Angiogenesis• Immune system function• Nervy myelination• Endorphin action• Pro-oxidant• Influences gene expression

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Copper• Interactions with other nutrients

– Ascorbic acid– Zinc– Iron– Molybdenum & sulfur (animals)– Selenium– Cadmium, silver, mercury

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Copper• Excretion

– Primarily through bile– Small amounts in urine, menstrual flow,

hair, nails, semen– Involves P-type ATPase: ATP7B

• Recommended Dietary Allowance– Adults: 900 µg– Pregnancy: 1,000 µg; lactation: 1,300 µg

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Copper• Deficiency

– Excessive zinc consumption, nephrosis, GI malabsorption

• Toxicity– UL = 10 mg– Wilson’s disease– Supplements

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Copper• Assessment of nutriture

– Serum/plasma/RBC Cu– Serum ceruloplasmin– Response of serum ceruloplasmin to

Cu supplements– Cu concentrations in hair not useful

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Selenium• Sources

– Plant content variable based on soil– Seafood

• Absorption, transport, uptake, storage, & metabolism– Absorption

• Selenoamino acid absorption• Factors influencing selenium absorption

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Selenium– Transport

• Bound to sulfhydryl groups in alpha & beta-globulins (e.g. VLDL, LDL)

• Selenoprotein P– Uptake & storage

• High concentrations in thyroid gland, kidney, liver, heart, pancreas, muscle

• Also lungs, brain, bone, RBCs

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Selenium– Metabolism

• Selenomethionine• Selenocysteine• Free Se converted to selenide• Selenate converted to selenite to

selenodiglutathione to selenide

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Selenium• Functions & mechanisms of action

– Glutathione peroxidase (GPX)– Thioredoxin reductase (TrxR or TRR)– Selenophosphate synthetase (SPS)– Selenoprotein P (SEL P)– Selenoprotein W (SEL W)– Methionine R sulfoxide reductase (SEL R)– Other selenoproteins

• SEL 15; SEL S; SEL H, K, M, N

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Selenium• Interactions with other nutrients

– Iron & copper– Methionine intake

• Excretion– About equally in urine & feces– Lungs & skin

• Exhalation of dimethylselenide

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Selenium• Recommended Dietary Allowance

– Adults: 55 µg– Pregnancy: 60 µg; lactation: 70 µg

• Deficiency– Keshan disease– Kashin-Beck’s disease– People on total parenteral nutrition

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Selenium• Toxicity

– UL = 400 µg• Assessment of nutriture

– Blood & plasma concentrations– Activities & concentrations of

selenoproteins• SEL P, glutathione peroxidase

– Toenails, urinary concentration

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Chromium• Sources

– Trivalent form - Cr3+

– Meats, fish, poultry, whole grains• Absorption, transport, & storage

– Absorption• Small intestine, especially jejunum• Diffusion or by carrier-mediated

transporter

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Chromium– Factors influencing chromium

absorption• Enhancers of chromium absorption

– Amino acids– Picolinate– Vitamin C

• Inhibitors of chromium absorption– Neutral or alkaline environment - antacids– Phytates

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Chromium– Transport

• Cr3+ binds with transferrin in blood• No transferrin - albumin• Globulins, possibly lipoproteins

– Storage• Concentrates in kidneys, liver, muscle,

spleen, heart, pancrease, bone• Thought to be stored with ferric Fe

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Chromium• Functions & mechanisms of action

– Potentiates action of insulin– Glucose & lipid metabolism– Nucleic acid metabolism

• Interactions with other nutrients– Potential to displace iron in transferrin

unclear

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Chromium• Excretion

– Mostly in urine, also desquamation of skin cells

• Adequate Intake– Adults 50 or <

• Men: 35 µg; women: 25 µg– Adults >50

• Men: 30 µg; women: 20 µg– Pregnancy: 30 µg; lactation: 45 µg

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Chromium• Deficiency

– TPN, severe trauma & stress– Supplements

• Toxicity• Assessment of nutriture

– No specific tests– Observation of effects of Cr

supplementation

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Iodine• Sources

– Food content variable based on soil– Seafoods, iodized salt

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Iodine• Digestion, absorption, transport, &

storage– Organic bound I freed via digestion– Absorbed rapidly & completely– Travels as free iodide in blood– Concentrates in thyroid gland

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Iodine• Functions & mechanisms of action

– Synthesis of thyroid hormones• Thyroxine (T4)• Triiodothyronine (T3)

– Transport of thyroid hormones in the blood• Thyroxine-binding globulin, albumin,

transthyretin

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Iodine• Interactions with other nutrients

– Goitrogens• Excretion

– Most in urine, also in feces• Recommended Dietary Allowance

– Adults: 150 µg– Pregnancy: 220 µg; lactation: 290 µg

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Iodine• Deficiency

– Thyroid hormone release as related to iodide deficiency

– Iodine deficiency & iodine deficiency disorders• Goiter• Iodine deficiency disorders (IDDs) • Cretinism: neurological or hypothyroid

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Iodine• Toxicity

– UL = 1,100 µg• Assessment of nutriture

– Urinary excretion– Thyroid size– Radioactive iodide (131I) uptake– Serum TSH concentrations

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Manganese• Sources

– Whole grains, dried fruits, nuts, leafy vegetables

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Manganese• Absorption, transport, & storage

– Absorption• Probably low-capacity, high affinity, active

transport mechanism• Factors influencing absorption

– Fiber, phytate, oxalate, iron, copper– Transport & storage

• Free or bound as Mn2+ to alpha-2 macroglobulin, albumin, beta globulin, gamma globulin

• Accumulates in mitochondria

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Manganese• Functions & mechanisms of action

– Transferases– Hydrolases– Lyases– Oxido-reductases– Ligases/synthetases– Other roles

• Modulator of second messenger pathways

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Manganese• Interactions with other nutrients

– Iron; possibly calcium, zinc• Excretion

– Mostly in bile– Little in urine– Sweat, skin desquamation

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Manganese• Adequate Intake

– Men: 2.3 mg; women: 1.8 mg– Pregnancy: 2 mg; lactation: 2.6 mg

• Deficiency• Toxicity

– Liver failure, neonatal TPN– Miners who inhale Mn dust– UL = 11 mg

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Manganese• Assessment of nutriture

– Mononuclear blood cell/plasma/ serum/whole blood concentrations

– Enzyme activity• Lymphocyte Mn-SOD

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Molybdenum• Sources

– Legumes, meat, fish, poultry, grains• Absorption, transport, & storage

– Thought to be passive absorption– Thought to travel in blood as

molybdate (MoO42+)

– Most found in liver, kidneys, bone

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Molybdenum• Functions & mechanisms of action

– Sulfite oxidase– Aldehyde oxidase– Xanthine dehydrogenase & xanthine oxidase

• Interactions with other nutrients– Tungsten– Sulfur & copper– Manganese, zinc, iron, lead, ascorbic acid,

methionine, cysteine, protein

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Molybdenum• Excretion

– Most as molybdate in urine– Small amounts in bile, sweat, hair

• Recommended Dietary Allowance– Adults: 45 µg– Pregnancy/lactation: 50 µg

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Molybdenum• Deficiency

– Diet rich in antagonistic substances (e.g. sulfate, Cu, tungstate)

• Toxicity– UL = 2 mg

• Assessment of nutriture– No validated indicators

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Fluoride• Sources

– Fluoridated water– Some grains, some marine fish– Tea

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Fluoride• Digestion, absorption, transport, &

storage– Protein-bound F hydrolyzed– Thought to be absorbed by passive

diffusion (rapid in stomach)– Transported as ionic F or hydrofluoric

acid, or bound (nonionic/organic)– Most found in bones & teeth

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Fluoride• Functions & mechanisms of action

– Promotes mineral precipitation from amorphous solutions of Ca & phosphate - formation of apatite

– Can replace hydroxide ions in apatite– Topical F appears to decrease

production of acid by oral bacteria

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Fluoride• Interactions with other nutrients

– Aluminum, calcium, magnesium, chloride

• Excretion– Mostly in urine, also feces, sweat

• Adequate Intake– Men: 4 mg; women: 3 mg

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Fluoride• Deficiency• Toxicity

– Fluorosis– UL = 1.3 mg for children 1-3– 10 mg for children >8 & adults

• Assessment of nutriture– Plasma or urine concentrations– Ion-specific electrode potentiometry

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Perspective 12

Nutrient-Drug Interactions

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Nutrient-Drug Interactions• Effects of foods/nutrients on drug

absorption• Effects of foods on drug

metabolism• Effects of foods/nutrients on the

actions of drugs• Effects of foods/nutrients on drug

excretion

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Drug-Nutrient Interactions• Effects of drugs on nutrient

absorption• Effects of drugs on nutrient

metabolism• Effects of drugs on nutrient

excretion• Summary