Flashcards in Metabolism - Exam #4, Part Two Deck (204):
How are the Macrominerals ranked in the body?
How is Magnesium found within the body?
Human body contains about 25 g of magnesium (~1% of body weight);
-50 to 60% is located in BONE;
-About 39 to 49% in soft TISSUES
-About 1% in extracellular FLUIDS
What are the FOOD sources of magnesium?
-Coffee and cocoa (drinks);
-Nuts, legumes, and whole grain cereals (especially oats and barley);
-Green leafy vegetables are also VERY GOOD found in chlorophyll;
-Milk, yogurt, chocolate, blackstrap molasses, corn, peas, brown rice;
-Hard tap water (not soft water) has a good amount
**Food processing and preparation can cause LOSSES of magnesium,
EX: removal of wheat germ reduces Mg by 75%
What are the Magnesium supps?
1. Magnesium sulfate (MgSO4 called Epsom salts)
2. Magnesium oxide (MgO)
3. Magnesium chloride (MgCl2)
4. Magnesium lactate
5. Magnesium gluconate
6. Magnesium citrate
**Supps are often needed with fat malabsorption;
Mg supps should NOT be taken with other sups such as iron
How is Magnesium absorbed?
-Small intestine occurs mainly in the DISTAL JEJUNUM and ILEUM;
-Large intestine can provide important absorption, especially if there is interference with small intestine absorption;
1. a saturable, carrier-mediated ACTIVE transporter at LOW magnesium intakes using transient receptor potential (TRP) cation channel called TRPM6 found mostly in the DUODENUM ;
2. Simple diffusion, functions at HIGHER magnesium intakes by a paracellular transport → MOST absorption
What is the mechanism of Mg absorption?
1. Mg2+ crosses the brush border membrane of the enterocyte through TRPM6;
2. Mg2+ also may be absorbed b/w (paracellular) influenced by the electron chemical gradient and solvent drag;
3. Mg2+ is pumped out of the cell across the basolateral membrane by Na-dependent ATPase
Where is the TRPM6 channel found?
BRUSH BORDER of the duodenum and in the kidney
How MUCH Mg is typically absorbed?
-MALE range of usual intake is 323 to 516 mg/day;
-FEMALE range of usual intake is 228 to 342 mg/day
**About 30 to 60% of absorbed with usual intakes
-Absorption DECLINES to below 30% intakes go ABOVE 550 mg/day → Increased intakes, decreased absorption because it is not needed
•**Efficiency of absorption increases as with most nutrients when there is poor or low status or when intake is low
How is Mg transported in the PLASMA?
-Mostly FREE in ionic form = 50 to 55% → Mg2+;
-Bound to PROTEIN (albumin [most]and globulins) = 33%
-COMPLEXED with citrate, phosphate, sulfate, and other negative ions
What substances ENHANCE Mg absorption in the intestine?
What substances INHIBIT Mg absorption in the intestine?
-Excessive unabsorbed fatty acids
What controls Mg transport and concentration in the BLOOD?
-Plasma concentrations ~ 1.7 and 2.2 mg/dl → mechanisms for this are not clear;
-GI tract absorption, renal excretion, and flux across membranes of cells seems to affect blood levels with NO hormonal regulation → some hormones affect, but not regulate;
-PTH increases magnesium absorption, diminishes renal excretion, and enhances magnesium release from bone, and all these increase plasma magnesium
How is Mg found intracellular (within the cell)?
-FREE intracellular Mg is TIGHTLY REGULATED between ~0.2 to 1 mmol/L;
-Several cellular magnesium transporters have been identified =
1. TRPM7 (adipose tissue, heart and bone)
2. Mag1 (epithelial cells)
3. NIPA Mg2+ (?)
4. SLC41 Mg2+ (may mediate cellular efflux)
5. MMgT1 and 2 (may control magnesium within Golgi complex and post-Golgi vesicles)
What are the functions of Mg in the BONE?
-Like calcium and phosphorus and probably other minerals in bone, a large amount is found in crystalline bone, and on the surface of bone as amorphous bone (exchangeable);
-Magnesium appears to be present in bone as Mg(OH)2 and Mg3(PO4)2
What are the other roles of Mg?
-Outside of bones Mg is in extracellular fluids and in soft tissues =
-Muscle, liver and kidney are the main soft tissues that contain Mg;
1. . Functions include:
2. Binding to phospholipids in membranes to stabilize
3. Associated with nucleic acids and proteins (enzymes) → 90% of intracellular Mg may be associated with ATP or ADP and associated enzymes
4. Affects tyrosine kinase activity of insulin receptor, post-receptor signaling, and glucose uptake itself
5. DNA replication
*TONS of functions
What other nutrients does Mg interact with?
How do Calcium and Mg interact?
-25-hydroxylation of bit D in the LIVER requires magnesium → Converting Vitamin D3 to 25OHD (not tightly regulated);
-Calcium and magnesium use OVERLAPPING reabsorption transport systems;
-Mg may also bind to calcium binding sites and elicits a similar response;
-Mg may affect calcium distribution by displacing calcium from intracellular binding sites and inhibiting calcium’s release from the sarcoplasmic reticulum in muscles (bound to Colequestrin in muscle)
How does the interaction of Calcium and Mg affect muscle contraction?
-Ratio of these two minerals affect MUSCLE CONTRACTION as Mg can displace calcium binding to troponin C and myosin;
-Troponin C → uses Ca2+ during contraction and then sends it back to sarcoplasmic reticulum to rebind with Colequestin, which holds it in the reticulum;
-In smooth muscle, CALCUM binding promotes acetylcholine release and contraction → MAGNESIUM competes with calcium and prevents;
*however, too much calcium can promote bronchial smooth muscle contraction in people with respiratory disease
How do Calcium and Mg interact for Blood Coagulation?
-In blood coagulation, magnesium and calcium are ANATAGONISTIC (work against each other) → calcium promotes coagulation
How do Mg and Phosphorous interact?
-Recall that magnesium INHIBITS phosphorus absorption;
-As dietary magnesium increases, phosphorus absorption decreases;
-They PRECIPITATE as Mg3(PO4)2→ for absorption need SOLUBLE (dissolved) minerals
How do Mg and Potassium interact?
-Magnesium also interacts with potassium → magnesium is SECOND most intracellular CATION with potassium as the first;
-Magnesium influences the balance between extracellular and intracellular potassium → magnesium depletion is associated with potassium efflux from cells and renal excretion
How is Mg EXCRETED?
-Most excreted through the KIDNEYS;
-Most filtered through the glomerulus is REABSORBED with normal intakes → Changes in dietary intake affect this reabsorption;
-Diuretic medications, and increased protein, alcohol, and caffeine INCREASE Mg excretion in urine;
-PTH reduces magnesium excretion in urine by promoting reabsorption;
-Fecal Mg is mainly UNABSORBED with small amounts (25 to 50 mg/day) of endogenous magnesium secreted into the gut;
-LOSSES in sweat are about 15 mg/day
What is the RDA for Mg?
-Males 19 to 30 years = 400 mg/day ;
-Male > 30 years = 420 mg/day;
-Females 19-30 years = 310 mg/day ;
- Females > 30 years = 320 mg/day
→ Magnesium balance studies were used for determining the requirements
What is the deficiency of Mg?
-Pure deficiencies of magnesium from inadequate intakes have NOT reported;
-Research studies have INDUCED deficiencies;
-Rare genetic disorder or with nausea or vomiting that can cause deficiency → Symptoms can include =
Nausea, vomiting, anorexia, muscle weakness, spasms and tremors, personality changes, and hallucinations; death can come from cardiac arrythmias
What is Hypomagnesemia?
-Low magnesium is < ~1.7 mg/dl
(Keenan had no measureable magnesium in blood)
What does a Mg deficiency affect?
*Affects calcitriol, potassium, and calcium;
1. Hypokalemia is the result of altered potassium transport processes → Hypokalemia = Hypopoatassemia = Low blood potassium concentration;
2. Calcitriol is DECREASED as response to PTH is IMPAIRED and develop hypocalcemia (low Ca2+)→ Need PTH to stimulate the kidney hydroxylase to create Calcitriiol (1,25OH2D) ;
-Bone loss is increased as neuropeptide P secretion is increased at nerve endings to bone that stimulate osteoclastic bone resorption
What disease affect Mg status?
-DM, but studies do not show that low magnesium causes diabetes;
-Also studies with magnesium (hard water) and lower risk of heart disease are inconsistent.
What is the Toxicity of Mg?
-Magnesium toxicity is RARE because kidneys are very good at eliminating excess magnesium;
-UL for ages 9 years and older = 350 mg from NONFOOD sources;
-Based on diarrhea
How is Mg status assessed?
-SERUM Mg content may NOT reflect intracellular magnesium availability, but it is the most common test;
-Low plasma levels show affected cellular levels;
*Serum concentration <0.7 mmol/L (1.7 mg/dl) is thought to indicate magnesium depletion;
-Possibly Mg load test and measuring excretion of magnesium by the kidney → but DRI mentions some problems;
-But taking blood and doing measurements is fairly easy for a clinical lab
How is Sodium found within the body?
-Sodium = ~0.15% of body weight;
-About 30% of the ~105 g of body sodium for a 70 kg human) is on the surface of BONE CRYSTALS;
-Bone surface sodium can be released into the bloodstream in case of hyponatremia → low blood sodium;
-Other 70% is in extracellular fluids, blood plasma, and nerve and muscle tissues;
-Meaning of “sodium constitutes about 93% of the CATIONS in the body, making it by far the most abundant member in this family” is in regards to body fluids
How is Potassium found within the body?
-Potassium is the major intracellular cation → phosphorus was major intracellular anion;
-About 95 to 98% of body potassium is INTRACELLULAR = in CONTRAST to sodium;
-About 245 g of potassium in 70 kg man (0.35%)
How is Chloride found within the body?
-Most abundant ANION in the EXTRACELLULAR (88%);
-12% is intracellular;
-Chloride balances the positive charge of sodium→ maintains electrolyte balance;
-Chloride has similar amounts in the body as sodium (~105 g per 70 kg human or 0.15% of body weight)
What is the form of Sodium found in foods?
-Added salt that is in the form of SODIUM CHLORIDE → NaCl;
-Sodium is 40% of weight of sodium chloride and a teaspoon of salt is 2.3 g of sodium;
-Salt is very extensively used in food processing for manufacture, and processed foods account for 75% of sodium consumed
What are the processed foods that are high in sodium?
-Canned meats and soups, condiments, pickled foods and snacks (chips, pretzels, crackers, etc.) are high in added salt;
-Luncheon meats are very high;
-Smoked, processed and cured meats;
-Processed cheeses; and canned fish are HIGH in sodium;
-Instant pasta and rice dishes are exceptionally high in sodium with over 700 mg/serving → frozen dinners are similar
**Found in most PROCESSED foods
What the natural sources of Sodium?
-NATURALLY occurring sources are milk, meat, eggs, and most vegetables → provide only about 10% of the sodium consumed;
-Salt added DURING cooking and at the table represents 15% of sodium intake
What food labels terms relate to Sodium?
1. Free (<140 mg per serving),
4. Reduced or less (at least 25% less sodium per serving compared to an appropriate reference food),
5. Light (food is low in calories and the sodium content has been reduced by at least 50%)
What is the Daily Value for Sodium?
**Daily Value is 2,400 mg;
-Estimated intakes of sodium for Americans range from ~3,000 to 5,000 mg/day
What are the sources of Potassium?
-Potassium is fairly abundant in the diet especially in UNPROCESSED foods (minimally processed or not overly processed);
-These foods provide potassium and also anions phosphate and citrate (a precursor for bicarbonate for acid-base balance)
What foods are HIGH in Potassium?
-Fruits (prune juice, bananas, canteloupe, honeydew melon, mango, and papaya;;
-Some vegetables (avocados, winter squash, leafy green vegetables, and yams);
-Other good sources include fruits (orange juice, grapefruit juice, peaches, pears, kiwi, and nectarines), vegetables (potatoes, asparagus, mushrooms, and okra), legumes, nuts, seeds, and peanut butter
How does potassium relate to high blood pressure?
-Diets HIGH in potassium are associated with lower blood pressure;
-FDA Modernization Act Health Claim that is allowed = Potassium and the Risk of High Blood Pressure and Stroke – health claim notification for potassium containing foods October 31, 2000 (Tropicana);
What was stated in the Tropicana Health Claim of 2000?
1. The combination of a low-sodium, high potassium intake is associated with the lowest blood pressure levels and the lowest frequency of stroke in individuals and populations.
2. Vegetables and fruits are also good sources of potassium. A diet containing approximately 75 mEq (i.e., approximately 3.5g of elemental potassium) daily may contribute to reduced risk of stroke, which is especially common among blacks and older people of all races. Potassium supplements are neither necessary nor recommended for the general population."
What foods "qualified" for the health claim proposed by Tropicana?
-Foods must be a "good source of potassium" (contain 10 percent or more of the Daily Value for potassium) and be "low in sodium.";
-Must have at least 350 mg of potassium per reference amount customarily consumed (RACC), and 140 mg or less of sodium per RACC;
-Must be "low in fat," "low in saturated fat," and "low in cholesterol."
-Must contain 3 g or less of total fat per RACC, 1 g or less of saturated fatty acids per RACC, and not more than 15 percent of calories from saturated fatty acids;
-Must contain 20 mg or less of cholesterol per RACC.
What are the sources of Chloride?
-Almost all chloride is consumed is associated with SODIUM in the form of NaCl (salt);
-High in same processed products high in sodium;
-Salt is ~60% chloride;
-Chloride intake at 50 to 200 mmol/day; DRI book (2005) does not give intakes as meq
How do you calculate Chloride from Salt intake?
Sodium intake is 3,000 to 5,000 mg/day;
-so 3,000 mg is 40% of X, X = 7,500 mg of sodium chloride with 4,500 mg of chloride;
-so 5,000 mg is 40% of X, X = 12,500 mg of sodium chloride with 7,500 mg of chloride
How is SODIUM absorbed in the intestinal brush border?
**95 to 100% of sodium is absorbed and the remainder excreted in feces;
-3 processes =
1. Na+/glucose co-transport → Functions through out the small intestines;
2. Electroneutral Na+ and Cl- absorption;
3. Electrogenenic Na+ absorption → Mainly in the large intestine
**The gradient for absorption by all three mechanisms is maintained by basolateral membrane sodium/ potassium ATPase
How is Sodium absorbed by 1. Na+/glucose co-transport?
*Functions through out the small intestines;
-Carrier on the brush border membrane of the enterocyte cotransports Na+ with a solute such as glucose into the cell;
-Once in the cell, Na+ is pumped across the basolateral membrane by Na+/K—ATPase while glucose exists through the membrane by FACILITATED DIFFUSION
How is Sodium absorbed by 2. Electroneutral Na+ and Cl- absorption?
-The Na+/H+ exchange works in concert with Cl-/HCO- exchange;
-Na+ is then pumped across the basolateral membrane with Cl- DIFFUSING PASSIVELY;
-Proposed because a significant amount of sodium absorption requires the presence of chloride and vice-versa
How is Sodium absorbed by 3. Electrogenenic Na+ absorption?
**Mainly in the large intestine;
-Sodium enter the luminal membrane via a Nat+ channel ;
-Diffusion down concentration gradient of sodium and sodium is accompanied by water and anions
How is Potassium absorbed in the intestine?
-Over 85% absorbed;
-Potassium is absorbed in BOTH small and large intestine;
-Passive diffusion for one mechanism and a K+/H+ ATPase pump;
-May also be potassium channels;
-To cross the basolateral membrane potassium leaves through potassium channels by DIFFUSION
How is Chloride absorbed?
-Chloride is almost COMPLETELY absorbed in the small intestine and follows SODIUM;
-But, the chloride is absorbed PASSIVELY through a paracellular pathway;
-Absorbed sodium creates an electrical gradient to drive chloride absorption ;
-**Chloride is the ONLY ion actively secreted by the epithelium;
-May be active transport
What is mechanism of Chloride into/out of the cell?
1. Chloride is cotransported along w/ Na+ and K+ from circulation across the basolateral membrane in the intestine;
2. Chloride exists cells into lumen through Cl- channe' in apical membrane
3. Driving force from active removal Na+/K+-ATPase pump and recycling potassium through K+ channels in the membrane
How is Sodium transported in the BLOOD?
-FREE ion in blood;
-Serum sodium concentrations are tightly regulated within a fairly narrow range of ~135 to 145 mEq/L
How are Potassium and Chloride concentrations regulated?
-POTASSIUM (ionic, 3.5 to 5 mEq) and CHLORIDE (balances sodium) are also very regulated;
-Regulation is by several hormones including ANTIDIURETIC HORMONE (ADH);
-CHLORIDE is a major secretory product of stomach and rest of GI tract
What are the other names for ADH?
-Atrial natriuretic hormone;
How is Potassium taken into TISSUE cells?
-Uptake of potassium into non-intestinal cells is by ACTIVE transport;
-Intracellular concentrations are also maintained by sodium/potassium ATPase pumps
How is Sodium taken into TISSUE cells?
Same mechanisms as GI tract absorption
What other nutrients does Sodium interact with?
-Calcium = it has been known since before 1940 that high dietary sodium promotes increased CALCIURIA;
-bBut, with the calciuria there is some offset with decreased fecal calcium and increased calcium absorption;
-**Calcuria – presence of calcium in the urine
What other nutrients does Potassium interact with?
-Potassium also interacts with calcium, but has the OPPOSITE effect;
-Addition of potassium citrate can PREVENT calciuria with a high sodium diet;
-REDUCES markers of bone resorption that can be increased with high salt intake in post-menopausal women
What are the functions of Chloride?
-Besides being a major ANION electrolyte;
-Needed for formation of HCl → parietal cells in the stomach;
How does Chloride function as an exchange ion for uptake of HCO3-?
-Chloride also an exchange ion for uptake of HCO3- by RBCs in the “chloride shift”, which requires a protein transporter;
-Waste CO2 from tissues enters RBCs and carbonic anhydrase converts the CO2 to HCO3-;
-Then the lungs can excrete the waste CO2 in the form of plasma HCO3-
How is Sodium EXCRETED?
-Most of dietary sodium is absorbed even on a high sodium diet, a lot of sodium often needs to be excreted;;
-Most excretion is in the URINE, but in high temperatures or when there is sustained vigorous activities and SWEATING increases → There can be significant losses in sweat;
What hormone promotes the retention of Sodium?
-hormone released from the adrenal cortex when sodium DROPS in plasma or increased potassium, promotes the retention (reabsorption) of sodium and excretion of potassium
What is the renin-angiotensin-aldosterone system (RAAS)?
-The cooperation of kidneys, liver, lungs, adrenals, and hypothalamus in this mechanism of fluid homeostasis (Sodium, Potassium, and Chloride);
-Angiotensin II can be converted to angiotensin III, which is more potent than II
What is Angiostensin?
-Peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure;
-Stimulates the release of Aldosterone from the adrenal cortex
What is Aldosterone?
-Potent VASOCONSTRICTOR – narrows the blood vessels;
-the flow of blood is restricted or decreased, thus retaining body heat or increasing vascular resistance → Blood pressure INCREAESED
What chemicals regulate EXCRETION of sodium?
1. Antidiuretic hormone (ADH)
How does ADH regulate Sodium excretion?
-Also called vasopressin;
-Synthesized in the supraoptic nucleus of the hypothalamus, but is stored in and secreted by the posterior pituitary gland;
-ADH promotes water reabsorption, sodium retention and potassium excretion;
-Release of ADH is stimulated by increased extracellular osmolarity or by decreased intravascular volume → Constricts blood vessels to cause retention
What factors stimulate Aldosterone for control of Sodium excretion?
1. increased angiotensin II (interacts with receptors of adrenal cortex)
2. decreased atrial natriuretic peptide (ANP)
3. decreased brain natriuretic peptide (BNP), which is synthesized in the ventricles of the heart and also opposes aldosterone
4. increased potassium concentration in plasma
5. increased adrenocorticotropic hormone (ACTH),
6. decreased sodium
What is ANP (atrial natriuretic peptide)?
-Hormone is synthesized in atrial cells and responds to arteriolar stretch, which indicates high blood pressure;
-This hormone OPPOSES aldosterone in that it inhibits sodium reabsorption in kidney and promotes its excretion,
How does Renin control regulate sodium excretion?
-Secreted in response to decreased renal perfusion pressure in the juxtoglomelular apparatus (near the glomerulus);
-Responds to fall in Na+, Cl-, ECF volume, or blood pressure
What is the mechanism for Renin regulation?
-Renin converts angiotensin to angiotensin I and then angiotensin converting enzyme in lungs converts inactive angiotensin I to active angiotensin II;
-Angiotensin II through receptors leads to hydrolytic products of phospholipids and then increased intracellular calcium
What other proteins are involved with Angiotensin?
-Involves G proteins, phospholipase C, and inositol triphosphate=
1. Phospholipase C increases intracellular calcium by stimulating calcium channels;
2 Inositol triphosphate causes release of calcium from storage in the endoplasmic reticulum;;
3Calmodulin plays a role in stimulating synthetic enzymes and then the production and release of aldosterone
How is Potassium excreted?
-90% of potassium is excreted by the KIDNEYS, the rest in the feces;
-Hormones regulate potassium, but in OPPOSITE direction of sodium;
-Some DIURETICS used to treat HYPERTENSION cause loss of potassium by the kidney and potassium supplements are needed → one of the only times
How is Chloride excreted?
-Chloride excretion follows sodium in URINE and sweat;
-Chloride in feces is usually from chloride not absorbed
What results from Sodium deficiency?
-Deficiencies normally DO NOT OCCUR b/c of the abundance in foods;
-Excessive SWEATING can result in deficiency and symptoms include muscle cramps, nausea, vomiting, dizziness, shock, and coma
What results from Potassium deficiency?
-Dietary deficiencies DO NOT occur;
-Hypokalemia (low blood potassium) usually does occur with large fluid losses with severe vomiting or diarrhea, or use of diuretics;
-Hypokalemia is associated with cardiac arrhythmias, muscular weakness, nervous irritability, hypercalciuria (calcium in the urine), glucose intolerance and mental disorientation
-Can occur with refeeding with increased muscle mass removing potassium from plasma;
-Moderate deficiency can lead to increased blood pressure, increased urinary calcium excretion, and increased bone resorption in relation to bone formation
What results from a Chloride deficiency?
Convulsions are a symptom of chloride deficiency, but deficiency is rare like with sodium and result form GI tract disturbances
What are the recommendations for Sodium?
**AI for = 1,500 mg or 3,800 mg of salt;
-Adequate intake of a variety of nutrients and for losses in sweat in un-acclimatized individuals;
-AI does NOT cover individuals that have excessive sweating such as competitive athletes or workers in high temperatures;
How much Sodium Chloride (salt) relate to sodium intake?
-Sodium chloride accounts for 90% of the consumption of sodium in the US → SALT;
-Other forms include sodium bicarbonate, monosodium glutamate, sodium phosphate, sodium carbonate, sodium citrate, and sodium benzoate;
**Sodium chloride = greatest affect on BP!!
What are the other functions of Sodium Chloride?
-Necessary for yeast bread dough to rise → Functions as a dough conditioner to strengthen the protein in dough (gluten), which allows it to hold air and not collapse;
-Added to frozen foods to preserve texture;
-Decreases the water activity of foods so it helps control the growth of undesirable bacteria; also inhibits growth of molds → preservative in meats;
-Necessary to make fermented products;
-Recommended by FDA to use to preserve foods
What does the DGA say about sodium?
Dietary Guideline 2010 tell us to REDUCE sodium intake to less than 2,300 (UL in 2005 DRI book) or 1,500 for salt sensitive
What are the recommendations for Potassium?
**AI for potassium = 4,700 mg → intake of Americans is BELOW the AI at 3,300 mg;
-Even consumption of DASH diet may not result in meeting AI (10% of people on DASH increase blood pressure)
What is the toxicity of Potassium?
*NO UL from foods, but concern with supplements, should not be done without medical supervision;
-Some drugs inhibit potassium excretion and can lead to hyperkalemia (high blood potassium) ;
-Hyperkalemia is TOXIC with severe cardiac arrhythmias and even cardiac arrest
What are the recommendations for Chloride?
**AI for chloride = 2,300 mg, which is the equivalent of 1,500 mg of sodium for 3,800 mg of salt;
**UL for chloride is 3,600 mg, which is the equivalent of the sodium UL
-Expressed in mmoles sodium and chloride AI and UL would be same
How is Sodium status assessed?
-Sodium in SERUM is often measured;
-Don’t usually see hyponatremia = 135 mmol/L
How is Potassium status assessed?
-Potassium in SERUM is routine measurement;
-Hypokalemia = <3.5 mmol/L
How is Chloride status assessed?
-SERUM chloride measured for status;
-Normal serum level in the range = ~101 to 111 meq/L
Why is Chloride expressed in mEq/L?
-Composition of drug preparations, such as intravenous fluids, is often stated in mmol/l rather than mEq/l;
-Molarity refers to the number of dissolved particles, and does NOT account for the number of available charges;
-For that reason, for an element such as Na+, which has a valence of 1, 1 mmol/l = 1 mEq/l;
-Whereas for a divalent element (i.e. an element having a valence of 2) such as Mg2+ or Ca2+, 1 mmol/l = 2 mEq/l.
Why were microminerals originally called "trace"?
-Initially called “trace” because their concentrations in tissues were below detectability by analytical methods;
-But today there are methods that can detect what used to be a “trace”;
-This is true for contaminants as well what used to be below detectability
What are the various definitions of microminerals?
1. less than 0.01% of body weight
2. the body need is less than 1 part per million (ppm), which is mg/kg
3. body need in amounts less than or equal to the amount of iron needed
4. needed in the body in amounts less than 100 mg
How do MACRO and MICRO minerals in the body compare?
-MACROmineral amounts in the body range from ~35 to 1,400 g;
-MICROmineral range from <1 mg to ~4 g
What are the 9 essential trace minerals?
-6 given an RDA =Iron, zinc, copper, iodine, selenium, and molybdenum = “Trace minerals”
-3 have an AI = fluoride, manganese, and chromium = “Ultra-trace minerals
Other Trace Minerals
iron, zinc, copper, and manganese
Other Ultratrace Minerals
Selenium, iodine, molybdenum, and chromium
How much IRON is found within the body?
-Human body has ~2 to 4g of iron;
-Men = ~50 mg of iron/kg body weight ;
-Women = ~38 mg/kg body weight ;
-Total body iron is NOT just a factor of body weight, but is affected by other physiological conditions such as age, gender, pregnancy, and state of growth
Where in the body is iron found?
-Greater than 65% of iron is in hemoglobin;
-~10% in myoglobin;
-~1 to 5% associated with enzymes;
-Remainder ~20% in blood or mainly in iron stores
What are the FORMS of Iron found within the body?
-Iron can exist in several oxidation states ranging from Fe6+ to Fe2- (inorganic chemistry;
-But in the aqueous environment of the BODY and in FOOD only Fe2+ (ferrous) and Fe3+ (ferric) exist
What type of Iron is in Animal Foods?
Heme iron is iron within a porphyrin ring=
-Porphyrin ring → makes heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−);
-Heme iron comes from iron in hemoglobin and myoglobin and is found in ANIMAL products, basically animal flesh such as meat, fish, and poultry → 50 to 60% is heme
What type of Iron is in Plant Foods?
-Plant foods contain non-heme iron → milk, cheese and eggs would have non-heme iron (poor sources);
-Non-heme iron is BOUND and must be freed by digestion
What foods are high in iron?
-Organ meats, red meats, oysters and clams, beans (lima and navy), dark green leafy vegetables, and dried fruits → also grain products are fortified with iron;
-Several forms of iron compounds are approved for food fortification
What are the Iron Supps?
Iron Supps FERROUS iron is complexed with=
**Iron dextrans can be infused intravenously if oral supplements do not correct iron deficiency
How is Heme Iron digested and absorbed?
1. must be HYDROLYZED from the globin portion of hemoglobin and myoglobin by Proteases in stomach/small intestine;
2. The metalloprophyrin is SOLUBLE and absorbed into the enterocyte by heme carrier protein 1 (hcp1) (mainly in the proximal small intestine, but other parts of small intestine in small amounts)
3. Another possible heme transporter is called proton-coupled folate transporter (PCFT), but is believed not to contribute much to heme absorption
How is Non-heme Iron digested?
-After release from food components, most non-heme iron is FERRIC form that is SOLUBLE in the stomach;
-In the small intestine with ALKALINE (basic) environment ferric forms insoluble compounds → but some ferric is reduced to FERROUS by ferrireductases, such as ferric/cupric duodenal cytochrome b (dcytb);
-Vitamin C appears to be necessary for reductase function and why it promotes non-heme iron absorption
How is the FERROUS (from non-heme) then absorbed?
-FERROUS iron is absorbed by binding to divalent cation (or mineral) transporter 1 (DCT1 or DMT1);
-DMT1 is found primarily in the duodenum;
-DMT1 can transport other minerals as well and transport of minerals is coupled with hydrogen ions (symport –same direction);
-DMT1 amounts increase with low iron stores
What are the steps of Iron absorption?
1. Iron released from food; Some HCl in stomach may reduce Fe3+ to Fe2+;
2. Free heme absorbed by heme carrier pro (hcp) 1, in proximal SI;
3. In intestinal cell, heme catabolized by heme oxygenase to protoporphyrin and Fe2+;
4. Nonheme in SI may react with inhibitors and be fecally excreted;
5. Reductases may reduce Fe3+ to Fe2+;
6. DMT1 carries Fe2+ across brush border into the intestinal cell;
7. Fe2+ may bind to poly rC binding pro from cytosol transport; or absorbed as a part of Ferritin;
8. Ferroportin transports across basolateral membrane; Couple with oxidation to Fe3+ by hephaestin;
9. Fe3+ attaches to transferring for blood transport;
(Converted to Ferric for storage)
What is Integrin?
-Integrin in the brush border membrane binds ferric iron and zinc;
-Integrin is part of the paraferritin complex → which includes mobilferrin and a flavin-dependent ferrireductase;
-Integrin = transmembrane receptor that mediates attachment between cell and surroundings
-Ferric from Non-Heme to enhance absorption
What factors ENHANCE Non-Heme Iron absorption?
1. sugars, especially fructose and sorbitol form chelates;
2. acids, such as ascorbic, citric, lactic, and tartaric act as reducing agents and from chelates with ferric iron;
3. meat, fish, and poultry factors have not been clearly identified → their digestion products (cysteine and histidine) and products such as contractile proteins actin and myosin promote iron absorption, also result in stimulating secretions by the small intestine;
4. gastric mucin (gastroferrin) binds ferric iron in the stomach keeps ferric iron soluble in the alkaline pH in the small intestine; → histidine, ascorbic acid and fructose and more chelators may pass on ferric iron to mucin which can bind multiple ferric ions
What factors INHIBIT Non-heme iron absorption?
1. Polyphenols such as tannin derivatives of gallic acid in tea and coffee;
2. Oxalic acid in spinach, chard, berries, chocolate, and tea;
3. Phytates (corn, whole grains and legumes);
4. Phosvitin, a protein containing phosphorylated serine residues found in egg yolks;
5. Nutrients when ingested in large amounts such as calcium, calcium phosphate and other salts, zinc, manganese
How does Calcium inhibit Non-Heme iron?
-Calcium transiently causes ferroportin to move from basolateral membrane to cytoplasm;
-BUT this affect is transient and iron absorption adapts so iron status NOT negatively impacted → Making it move away from membrane DECREAES absorption;
-Ferroportin – a transmembrane protein that transports iron from the INSIDE of a cell TO the OUTSIDE of it.
What is the overall iron absorption in the body?
-A person with NORMAL iron status will absorb about 10% of dietary iron (0.5 mg/day);
-A person who is iron DEFICIENT can absorb 35% (3 to 6 mg/day)
What can happen to iron in the intestinal cell?
1. transported across the cell and into the circulation;
2. stored in the intestinal cell bound to ferritin for future use or elimination;
3. used in the cell in a functional capacity
**Iron being a pro-oxidant is NEVER FREE in the cell but bound to amino acids and proteins
How is iron stored in the INTESTINAL CELL?
-To store iron in the CELL it binds to Apoferritin → protein capable of storing iron in bodily cells especially of the liver by combining with iron to form FERRITIN ;
-Ferritin – intracellular protein that stores iron and releases it in a controlled manner;
-Intestinal cells are short-lived (2-3 days) and stored iron is lost when cells are sloughed off
What is the regulator of Iron absorption?
-The protein HEPCIDIN → released from the LIVER when body iron stores are adequate or high;
-Hepcidin – regulates transport across the mucosa, preventing excess iron absorption; also inhibits release of transport from macrophages (site of iron storage and transport)
What is the mechanism for Hepcidin to regulate iron?
1. Diferric transferrin binds to transferrin receptor 1(TfR1); → binding releases a high iron protein (HFE) from TfR1;
2. HFE binds to TfR2 → complex acts as an iron sensor and causes hepcidin synthesis through an intracellular signaling pathway;
3 Several other proteins may also play a role in iron sensing;
4. Hepcidin travels in the blood and binds to ferroportin on enterocytes and macrophages so that it is internalized and degraded and thus iron cannot be released from these cells into the blood
What happens to Hepcidin when iron is Low?
-LOW iron status = very little hepcidin made;
-Absence of or reduced hepcidin (genetic defects) leads to toxic iron accumulation;
-Too much hepcidin (genetic defects) leads to iron deficiency
How is Iron stored with the TISSUES?
-Three main sites: liver, bone marrow, and spleen;
1. FERRITIN is the main storage protein and is very large and complex → One ferritin can store 4,500 iron ions
-There is a tissue and a plasma ferritin that are in equilibrium;
2. Hemosiderin is another storage protein and may be a degradation product of ferritin;
-Hemosiderin PREDOMINATES over ferritin at HIGHER levels of iron storage
What is the mechanism of Iron storage in tissues?
1. Transferrin w/ bound Fe3+ atoms attaches to transferrin receptors on the cell membrane; Once attached, complex is endocytosed into the cell cytosol and forms an endosome;
-2. Drop in pH in the endosome helps release Fe3+; Then REDUCED (gain) by steap3 and transported out of the endosome by a transported, DMT1;
-3. Fe2+ released from the endosome may be oxidized and stored in Ferritin;
-4. Fe2+ may be used within cells functionality
How do these the tissues UPTAKE iron?
-Liver and intestinal cells have TfR2 and TfR1 as covered with hepcidin → other cells have TfR1;
-DIFERRIC iron transferrin binds BETTER than monoferric iron transferrin;
-The transferrin and receptor complex is INTERNALIZED by endocytosis
What are the functions of Iron?
-COFACTOR for dozens of enzymes;
-Part of heme (hemoglobin, myoglobin, cytochromes [electron transport chain], monooxygenases, dioxygenases, oxidases);
-Clustered with sulfur and sometimes bridged with oxygen in proteins
What other nutrients interact with Iron?
1. VIt C enhances non-heme iron absorption;
2. Copper for normal release from cells and transport of iron;
3. Supps of non-heme iron can inhibit zinc absorption and zinc can inhibit iron absorption (avoid co-ingestion of these mineral supplements if deficient in one or the other)
4. Retinoic acid promotes gene transcription of a hormone erythropoietin = red blood cell production so low vitamin A causes iron accumulation in spleen and liver;
5. Lead inhibits a zinc-dependent enzyme needed for heme synthesis and another enzyme responsible for putting iron into heme → iron deficiency increases lead absorption, but mechanism unknown, DMT1 may be the answer
How is Iron excreted?
-Iron is very well conserved to meet needs;
-Iron is LOST from the body via the =
1. GI tract,
4. Women in their reproductive years during menses → this loss is significant and thus these women have a higher RDA than men or postmenopausal women
How is iron so greatly conserved?
-Conservation through RECYCING is critical in meeting iron needs;
-Cycles between the Reticuloendothelial cells to Plasma;
-And plasma to Tissues or RBCs;
-RBCs back to Reticuloendothelial cells;
-Ferritin and hemosiderin degraded In liver, spleen and bone marrow;
-Reticuloendothelial cells – Phagocytes in liver, spleen and bone marrow
What is the Iron Reticuloendothelial System?
AKA: Mononuclear Phagocyte System (MPS);
-Part of the immune system that consists of the phagocytic cells located in reticular connective tissue;
-Cells are primarily monocytes and macrophages, and they accumulate in lymph nodes and the spleen;
-The Kupffer cells of the liver and tissue histiocytes are also part of the MPS
What is Reticular Connective Tissue?
-Network of reticular fibers, made of type III collagen;
-Reticular fibers are not unique to reticular connective tissue, but only in this type are they dominant;
-Reticular fibers are synthesized by special fibroblasts called reticular cells → fibers are thin branching structures.
What are tissue Histiocytes?
The histiocyte is a tissue macrophage or a dendritic cell
What are the recommendations for Iron?
-Adult men and postmenopausal women = 8 mg/day based on basal iron losses;
-Women capable of reproducing (menses) = 18 mg/day;
-During pregnancy = 27 mg/day based on increasing blood volume and tissues and storage, as well as iron needed for the fetus
**Median intake for men is 16 to 18 mg/day and 12 mg/day for women
What are the measures used for Iron assessment?
1. HEMOGLOBIN in RBCs per deciliter of blood, and HEMATOCRIT (proportion of total blood volume blood that is RBCs) are most common;
2. Plasma Ferritin;
3. Total iron binding capacity
How do Hemoglobin and Hematocrit show iron status?
-These are among the last to change with deficiency of dietary iron;
-Indicate if there is ANEMIA
How does Plasma Ferritin show iron status?
-May be the BEST indicator of iron stores= <~12 micrograms/L is associated with iron DEFICIENCY;
-But, inflammation or infection can raise serum ferritin unrelated to iron stores
How does Total Iron Binding Capacity (TIBC) show iron status?
-Normally transferrin is 33% saturated with iron and values below 16% indicate deficiency;
-Normal TIBC is ~250 to 400 micrograms/dl and values above 400 indicate deficiency
What measures indicate ANEMIA?
-Hemoglobin levels below 12 g/dL for females and 13 g/dL for males indicate anemia;;
-Hematocrits at <37% for females and 40% for malesalso reflect anemia
**Takes about two weeks to increase blood measures (hemoglobin and hematocrit) after iron deficiency, but building stores back to normal levels may take 6 months to 1 year
What is Iron Deficiency Anemia?
-Characterized by small (microcytic) and pale (hypochromic) red blood cells;
-Mean corpuscular volume represents the size of the red blood cells and is calculated by dividing the hematocrit by the number of red blood cells and then multiplying by 10
What is the formula for Mean Corpuscular Volume?
To calculate the MCV, expressed in femtoliters (fL, or 10-15L), the following formula is used =
10 x hematocrit (%) divided by RBC count (millions/µl);
-The normal range for MCV is: 80-99 fL.
What can cause iron TOXICITY?
-In children with chewable tasty supps;
-Genetic disorder hemochromatosis → homozygotes occur in an estimated 50 people for every 10,000; most often seen in Caucasian males and becomes evident around age 20;
-Gene mutations of low Hepcidin;
-HFE (high iron protein);
-Uptake into enterocyte from plasma down-regulates absorption
What is Hemochromatosis?
-Hemochromatosis is characterized by at least a 2-fold increase in iron absorption;
-One type is associated with a genetic mutation in the HFE gene; one mutation is C282Y (amino acids) with cysteine replaced by a tyrosine;
-Treatment requires frequent withdrawal of blood or organ and joint damage occurs in homozygotes
How do gene mutations causes iron toxicity?
Mutations in one of several genes result in LOW HEPCIDIN so the body does NOT DOWN-regulate iron entry into blood serum
How does HFE causes toxicity?
-HFE (high iron protein) promotes iron uptake into cells by interacting with transferrin receptors;
-Functional HFE is also needed for synthesis of HEPCIDIN in the liver
What is the UL for iron?
UL =45 mg/day based on gastrointestinal distress as an adverse effect
How much IODINE is found in the body?
-Iodine is found in the body and functions as I- (Iodide);
-Iodine is a NONMETAL;
-~ 15 to 20 mg of iodide found in the human body → 70 to 80% in the THYROID gland;
-Iodine is responsible for the synthesis of thyroid hormones!
What affects the Iodine content of foods?
-SOIL in the US is highly variable for Iodine content in different regions and also reflects types of fertilizers used;
-Foods vary in content based on the soil in which they are grown an and animal products based on iodine content of the foods the animals ate;
-Iodide in drinking water is a good reflection of the iodide in soil and correlates with iodine deficiency in the population (not US because of iodized salt);
-Before the 1920s people living in the Great Lakes and Rocky Mountains areas of US had iodine-deficient diets
What are the good food sources of Iodine?
1. Seafood is a good source, but SEAWATER fish are much better sources than freshwater fish ~10 to 100-fold greater;
2. If the soil has iodine then milk, eggs, yogurt and beans are good sources;
3. Breads and grain products made from bread dough are a good source regardless of the soil → dough oxidizers and conditioners have iodates (IO3-) as food additives to improve cross-linking of gluten;
**A ¼ teaspoon of iodized salt supplies about 70 micrograms of iodide
What are the forms of Iodine found in foods?
-Dietary iodine is either attached to amino acids or free as basically two types of iodine species: IO3- or I-
How are Iodine Ions absorbed in the GI tract?
-Iodine ions are absorbed throughout the GI tract including the stomach;
-Iodine can be bound to amino acids, or it can be free, usually in the form of iodate or iodide ions. ;
-IODIDE (iodide ions) is the EASIEST form to absorb, so most of the bound iodine and iodate is converted to iodide by GLUTATHIONE;
-Iodinated amino acids are absorbed to a small extent, broken down in enterocyte;
-Thyroid Hormones absorbed at about 75%, which allows for oral T4 delivery
What forms of Iodine are absorbed in the STOMACH?
-Iodate (IO3-) = Converted to I- for absorption;
-Iodated Amino Acids
What forms of Iodine are absorbed in the Small Intestine?
-All iodine ions;
-Thyroid hormones = Thyroxine (T4) and Triiodothyronine (T3)
What FORM of Iodine is transported in the blood?
-Transported in the BLOOD as the iodide ion → distributed throughout all the extracellular fluids and gets into ALL TISSUES
How is Iodide treated in the Thyroid gland?
-Thyroid gland traps iodide MOST aggressively as iodide selectively concentrates against an iodide gradient by having active transport coupled to SODIUM;
-Concentration is 40 to 50 times the concentration in the plasma;
-The thyroid gland contains 70 to 80% of the iodine in the body;
**Iodine is necessary to synthesize thyroid hormones!
How are Iodide ions (I-) metabolized in the THYROID Gland?
1. I- actively transported into Thyroid gland (coupled with Sodium);
2. I is bound to Tyrosine residue on thyroglobulin-3.5-diodotyrosine;
4. Condenses with another Thg-DIT in the colloid form;
5. Thg-DIT can also condense with Thg-MIT to make Thg-T3 and reverse (r)T3;
6. T4 and T3, active hormones, are released to blood after endocytosis of Thg-T3 and Thg-T4 back into the Thyroid cell and hydrolysis of Thg by proteases
How do the receptors affect the Thyroid Hormones?
-Multiple effects of thyroid hormones are result of their binding to nuclear receptors that affect gene expression (homo- and heterodimers of nuclear receptors);
-Takes much higher levels of T4 to match potency of T3;
What are the physiological effects of thyroid hormones?
-Adipose tissue = enhance lipolysis;
-Muscle = enhance contraction;
-Bone = promotes anabolism (growth);
-Cardio system = Increases heart rate;
-GI Tract = stimulates digestion/absorption;
-Metabolism = stimulates rate and cellular oxygen consumption in metabolically active tissue
How are Thyroid hormones transported in the blood?
-T4 and T3 three transport proteins bind the thyroid hormones:
1. thyroxine-binding globulin
4. a very small percent is FREE (<0.1%) in plasma
-free form is in EQUILIBRIUM with the bound form and it is the active form that binds to receptors on cells
**plasma T4 concentrations are 50X greater than the T3
How is T4 converted to T3 in TISSUES?
-Several tissues have a 5’- and 5-deiodinase so that T4 is converted to T3 or rT3 (reverse);
-Tissues that include: liver, kidney, brain, pituitary, and brown adipose tissue ;
-Most T3 molecules in the BLOOD have been produced from T4 in the LIVER;
-The 5’-deiodinase is a SELENIUM-dependent enzyme and a selenium deficiency impairs conversion of T4 to T3
What others nutrients does Iodine interact with?
-Vegetables of the cabbage family have a goitrogen named GOITRIN;
-Goitrin – REDUCES the production of thyroid hormones such as thyroxine;
-Many vegetables have goitrin, but usually their consumption is not in great enough amounts to produce endemic goiter
What is a Goiter?
-Swelling of the neck or larynx from enlargement of the thyroid gland;
- “Endemic goiter is when goiter in a population exceeds 10% and is an enlargement of the thyroid gland caused by the intake of inadequate amounts of dietary iodine;
-Iodine deprivation leads to diminished production and secretion of thyroid hormone by the gland.
How does the pituitary gland respond to iodine deficiency?
The pituitary gland, operating on a negative feedback system, senses the deficiency and secretes increased amounts of thyroid-stimulating hormone, causing hyperplasia and hypertrophy of the thyroid gland.
How do goiters grow?
-The goiter may grow during the winter months and shrink during the summer months when the person eats more iodine-containing fresh vegetables.;
-Initially the goiter is diffuse and later it becomes multinodular;
-Endemic goiter occurs occasionally in adolescents at puberty and widely in population groups in geographic areas in which limited amounts of iodine are present in soil, water, and food.
How can goiter be prevented?
-The use of iodized salt is a prophylactic (preventative) treatment.;
-Desiccated thyroid given orally may prevent further growth of adult goiters and may reduce the size of diffuse goiters
What can result from a large goiter?
-A LARGE goiter may cause dysphagia, dyspnea, tracheal deviation, and cosmetic problems;
-Also called colloid nodular goiter.
What is a Simple Goiter?
-Simple goiter most often associated with INADEQUATE iodine INATKE;
-Problems with goitrogens would be a secondary deficiency of iodine
What is Cretinism?
-Cretinism in infants has been seen over the years with MATERNAL iodine deficiency;
-Cretinism – a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones (congenital hypothyroidism) usually due to maternal hypothyroidism.
How is Iodine excreted?
-The kidney has NO mechanism to CONSERVE iodide so the urinary output correlates closely with plasma iodide and dietary iodine;
-~ 80 to 90% of iodide excretion is in urine;
-Up to 20% is in feces;
-A little is lost in sweat and if excessive can be important especially if iodine status is marginal
What are the recommendations for Iodine?
-Adult RDA = 150 µg/day;
-Provides a margin of safety for goitrogens in the diet → Inhibitors in veggies;
-RDA is HIGHER for pregnancy and lactation:
1. Pregnancy = 220
2. Lactation = 290 µg/da;
-Aging does NOT increase the requirement;
How was the RDA decided by the DRI committee?
-Used thyroid iodine (96.5 µg/day) accumulation (radioiodine);
-And body turnover of iodine (91.2 µg/day) in euthhyroid (normal) individuals so that EAR was 95 µg/day
How is Iodine status assessed?
-URINARY iodine is a common method in global studies → it REFLECTS INTAKES because kidney does NOT conserve;
-Thyroid size, measured by ultrasonography or palpitation, has been used;
-Note that size takes months to years to shrink to normal after starting iodine supplements
What TOXICITY comes rom Iodine?
*UL = 1,100 µg/day;
-The thyroid gland ENLARGES with too much iodine in the diet;
-Urinary iodine concentration greater than 500 µg/L have been associated with increasing thyroid volume (goiter), which indicates thyroid dysfunction;
-DRI book points out that thyroid dysfunction also has elevated TSH concentrations
What is TSH?
-TSH – thyroid stimulating hormone = stimulates production of T4 and then T3 to stimulate the metabolism of almost every body tissues
How is ZINC found in the body?
-The human body contains ~1.5 to 3.0 g of zinc;
-Found in ALL organs and tissues, primarily INTRACELLULARLY;
-Also in body FLUIDS;
-Zinc is a METAL and thus can exist in several valance states, but biologically encounter it as the divalent cation, Zn2+
How is COPPER found within the body?
-The amount of copper in the human body has a broad range from ~ 50 to 150 mg;
-Found as either cuprous (Cu1+) or cupric (Cu2+)
What are the sources of ZINC?
-Remember zinc fingers in transcription factors/receptor PROTEINS that interact with the DNA so zinc is found in foods with amino acids and nucleic acids → serve primarily to alter the binding specificity of a particular protein.;
-Zinc content of food varies widely, but high in meats and seafood
How id Zinc absorbed?
** PROXIMAL small intestine
1. BOUND zinc is released from food, primarily proteins and AA’s;
2. Most absorbed by Zrt- and Irt-like protein (ZIP) 4 across the brush border membrane;
3. Divalent mineral transporter (DMT) 1 and amino acids may play a minor role in zinc absorption;
4. Some zinc may be directed to feces if bound to inhibitors, or absorption may be ENHANCED by organic acids, low pH, and chelators;
5. With high intakes, zinc may be absorbed between cells → paracellularly;
6. Within cells, zinc may be used functionally or stored in vesicles in the trans-Golgi network;
7. Zinc may be transported across the basolateral membrane by ZnT1;
8. Zinc binds any several proteins for transport in the blood
What are the sources of COPPER?
-Organ meats and shellfish are the RICHEST sources of copper;
-Nuts, seeds, legumes, and dried fruit are good plant sources, but potatoes, whole grains and cocoa are also good sources
What inhibits Zinc absorption?
*Bind Zn and prevent absorption
How is Copper absorbed?
-Some copper absorbed in the stomach (small amounts) and throughout the whole small intestine, mostly duodenum;
1. Cu2+ is releasesd from food
2. REDUCED to Cu1+, mostly likely by cytochrome b ferric./cupric reductase, cytochrome b reductase 1 and/or steap2
3. Cu1+ cross the brush border by high-affinity Ctr1 transporter and to a lesser extent by DMT1. Amino acid transporters may play a minor role.
4. Within the CYTOSOL, copper binds to several chaperonrs from transport/delivery to several target enzymes = Atox1 transports Cu1+ to the basolateral membrane
5. Copper is delivered to enzymes by chaperons to allow use in cells or binds to METALLOTHIONEIN for STORAGE;
6. ATP7A transports Cu1+ across the basolateral membrane
7. Copper attaches to PROTEIN for transport in the BLOOD
What is Metallothionein?
cysteine-rich, low molecular wt. protein that can bind heavy metals
What INHIBITS Copper absorption?
1. Phytate inhibits copper absorption just like it does other minerals iron, zinc, and calcium;
2 Supps of zinc in amounts as low as 18.5 mg, but typically about 40 mg impair absorption;
-Zinc stimulates thionein synthesis and it binds copper stronger than zinc and lost when eneterocytes are sloughed off
3. Iron ingested in large amounts;
4. High dietary calcium or phosphorus increases fecal copper and urinary copper;
5. Antacid ingestion
How is copper transported in the blood?
-Copper is transported in PORTAL BLOOD loosely associated with ALBUMIN (protein carrier);
-OR copper is transported after leaving liver by ceruloplasmin and delivers copper to tissues (not copper in active site)
-Portal blood = Albumin
-From liver = Ceruloplasmin
How is Copper taken up into the Liver?
-Uptake by LIVER and apparently other tissues involves carrier proteins similar to those in the enterocytes (Ctr1 and 2);
-In LIVER copper binds to metallothionein (storage site) first and then is transferred to enzymes that have copper as a COFACTOR
What is Ceruloplasmin?
-Major copper-carrying blood protein and also plays a role in iron metabolism;
-WITHOUT copper it is referred to as APOceruloplasmin;
-Remainder of copper is transported as in the portal blood
How does Ceruloplasmin bind copper?
1. 6 copper ions are attached to apoceruloplasmin post-translational;
2. Attached copper is BOTH cuprous and cupric → WITHOUT sufficeient copper ceruloplasmin’s half life is REDUCED;
3. Ceruloplasmin is released by liver into the systemic circulation and is the main copper carrier protein (60 to 95%)
How is Zinc taken into TISSUES?
-Multiple systems for zinc uptake identified, but mechanism is unclear;
-Several ZIP carriers appear to be involved in UPTAKE→ they are also involved in RELEASE of zinc from intracellular stores;
**ZIP14 functions in hepatocytes (liver cells)
How much Zinc is found in tissues?
-Zinc content of most soft tissue is fairly STABLE;
-Tissue levels DON'T match blood;
-Zinc is part of bone, but is released very slowly;
-When zinc intake is LOW, plasma zinc-containing enzymes and metallothionein (assume stored zinc in tissues) provide zinc
What are the forms of Metallothionein that provide zinc?
-Various forms of metallothionein exist and designated a MT-1 through MT-X;
-MT-1 and MT-2 are the most common;
-Metallothioneins have ~20 of 61 amino acids as CYSTEINE;
-Metallothioneins bind 7 g atoms/molecule, but also bind copper, cadmium, and mercury;
-Metallothioneins have other functions → transfers zinc to other proteins in organelles, scavenge hydroxy radicals
How does Zinc promote Metallothein relate to zinc status?
-Levels of metallothioneins in RBCs and LIVER may reflect zinc status;
-Zinc, and may other minerals, may PROMOTE metallothionein gene expression;
-Zinc or maybe zinc bound to a metal transcription factor (MTF) interacts with metal regulatory elements (MRE) in the promoter region of the thionein gene;
-Interleukin 1, secreted by monocytes and activated macrophages INDUCES thionein gene expression during infection (ties in with lower zinc in plasma during infection)
How is Copper taken into tissues?
-Ceruloplasmin (carrier pro in blood) DELIVERS to tissues;
-Uptake by extrahepatic tissues involves binding of ceruloplasmin to specific receptors;
-Ceruloplasmin also functions as an OXIDASE so COPPERS at the ACTIVE SITE are NOT transferred into the tissues;
-Appears that cupric (Cu2+) is converted to cuprous (Cu1+) (oxidized, loss of e-) involving vitamin C for cellular uptake;
-Copper ions appear to be transferred to hCtr1, 2, or 3 or may move through channels
How is Copper stored?
-Very LITTLE copper is found in the body compared to other trace minerals (<150 mg);
-Liver, kidney, and brain have the most copper per g
-LIVER is the main storage site;
-Metallothionein is the main storage protein
How is Copper Regulated?
-Amount of copper available to extrahepatic tissues is REGULATED by LIVER through synthesis of ceruloplasmin, copper incorporation into metallothionein, and copper put in bile
What are the functions of Zinc?
1. Part of MORE enzyme systems than all of the rest of trace minerals combined (at least 70 and maybe over 200) = Metalloenzymes;
2. Gene expression = Zinc fingers;
3. Membrane/cytoskeleton stabilization;
5. Sexual maturation;
6. Fertility reproduction
How do Zinc fingers work in gene expression?
1. Zn fingers are proteins with a secondary shape like a finger due to zinc-atom linked through cysteinyl or histidyl residues;
2. They are found within many transcription factors, which bindto metal response/regulatory elements (MRE) in the promoter region of genes to enhance/inhibit
What is Polyglutamatehydrolase?
γ-glutamylhydrolase or pteroylglutamate hydrolase) = -Digests FOLATE in the GI tract as polyglutamate folate is converted eventually to monoglutamate folate with the release of glutamates;
-So POOR ZINC status can diminish folate absorption, which would mean a secondary folate deficiency
What are the functions of Copper?
-ENZYME COFACTORS and most of the time function in ELECTRON TRANSFER:
-EX: Ceruloplasmin: iron oxidation and antioxidant → AKA Ferroxidase 1 (iron oxidizer) – may function like Hephaestin
-Hephaestin – transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal enterocytes into the circulatory system
What others nutrients does Zinc interact with?
-Zinc and VIt A interact in a couple of ways:
1. conversion of retinol to retinal by alcohol dhydrogenase a zinc-dependent enzyme,
2. zinc is needed for synthesis of retinol binding protein so zinc deficiency results in lack of release of vitamin A from liver stores;
-Zinc supps REDUCES calcium absorption when calcium is low in the diet
What other nutrients does Copper interact with?
1. DEFICIENCY of copper prevents IRION from leaving enrterocyte (hephaestin = copper-dep.) and efflux from liver and other tissues (ceruloplasmin);
-DO NOT form ferric iron for transport by transferring and leads to ANEMIA;
-But, TOO MUCH iron interferes with mobilization of copper stores;
2. Copper DEFICIENCY appears to DECREASE the activity of selenium-dependent enzymes glutathione peroxidase and 5’deiodinase (would affect iodine)
How is Zinc excreted?
-MOST in the FECES → From secretions and sloughed off enterocytes (old intestinal cells);
-Secretion by enterocytes with proteins ZIP5 and ZnT6;
-Only a small amount of zinc is excreted in the urine→ ZnT1 promotes REABSOPRTION of zinc in the KIDNEYS;
-NON-reabsorbed zinc in kidney may be bound to histidine or cysteine;
-Small amounts are lost with skin or sweat, menses or hair; also semen
How is Copper excreted?
-Copper is excreted primarily in the BILE (>95%);
-LOW DIETARY copper promotes reduced excretion in bile;
-So biliary excretion is REGULATED to maintain copper balance;
-P-type ATPAse (ATP7B) pumps copper into the bile
What is Wilson's Disease?
-Wilson’s disease is a copper ASSUMULATION as biliary copper excretion is impaired;
-Mutations in ATP7B are known to cause the disorder;
-Copper ACCUMULATES mainly in LIVER, but also in the brain, kidney, eye (cornea), and spleen;
-Use zinc supplement to lower copper absorption to help correct excess copper
What is a deficiency of Zinc?
-Delayed sexual maturation;
-Skeletal abnormalities (impairment in connective tissue);
-Poor wound healing;
-Blunting of sense of taste (hypogeusia);
-Hair loss (alopecia);
-Impaired immune function;
-Impaired protein synthesis
What is a deficiency of Copper?
-Includes microcytic hypochromic anemia;
-Leukopenia (specifically neutropenia);
-Hypo- or de-pigmentation of skin and hair;
-Impaired immune function;
-Bone abnormalities (demineralization);
-Cardiovascular and pulmonary dysfunction;
-Sometimes reported increases in cholesterol in plasma
How is Zinc assessed?
-PLASMA zinc is pretty good;
-FASTING amounts <70 µg/dl suggests deficiency
How is Copper assessed?
-PLASMA copper concentration is a reliable indicator of deficiency with lower range of normal 10 micromol/L
What are the Zinc recommendations?
-Adult men = 11 mg/day
-Adult women = 8 mg/day
*Based on zinc balance or better the amount of zinc needed to balance for zinc losses, but the RDAs are lower in 2001 than in 1989
What are the Copper recommendations?
-Adult men and women = 900 µg/day
-The committee in 2001 used several combined factors for the biological markers = Plasma copper, plasma ceruloplasmin concentrations, red blood cell superoxide dismutase activity, and platelet copper concentrations in controlled human depletion/repletion studies
What results from a Zinc toxicity?
UL = 40 mg/day of zinc based on its negative effect with copper;
-Based on the combo of zinc from:
2. Fortified foods
3. Zinc supplements
4. Zinc in water;
**NO toxicity Zn NATURALLY FROM FOODS ;
How does Zinc affect copper?
-the DRI committee states that it is specifically based on the reduction in red blood cell copper-zinc superoxide dismutase activity;
-Zinc stimulates INCREASED intestinal cell metallothionein, which has a higher affinity for copper than for zinc and this “traps” copper in the intestinal cells