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Vitamin C,E,A,K

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Vitamin C - Ascorbic Acid

  • —There are 2 forms of ascorbate

    • —Reduced form

      • Ascorbic acid

    • —Oxidized form

      • Dehydroascorbic acid

  • humans lack the enzyme to synthesize vitamin C, which is why it is essential to us

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Absorption, Transport, Storage and Excretion

  • —No digestion needed prior to absorption

  • —Absorption of ascorbate (the reduced form)

    • —Throughout the small intestine

    • —High absorption rate, >80 - 90%

    • —When get very high doses, % absorbed ¯, but absolute amount absorbed still ­

    • —Ascorbic acid absorbed via active transport 

    • —Transporters: SVCT1, SVCT2 (also help tissues esp adrenals uptake vitamin C from the blood)

  • —Some cells—neutrophils, RBC—cannot uptake ascorbic acid

    • —Use dehydroascorbic acid via GLUTs (glucose transporters)

  • —Distribution differs among tissues

    • —High concentration: adrenals and pituitary gland

    • —Intermediate concentration: liver, spleen, heart, kidneys, lungs leukocytes

    • —Small amounts: muscles, RBC

  • Excreted in urine

    • only water soluble vitamin that is not a B vitamin​

    • too high vitamin C can lower urine pH

study question

  • ​how does vitamin Cs water soluble property play into possible toxicity? Does vitamin C have a UL?

  • explain vitamin Cs role as an antioxidant

Functions

  • —Serves as a reducing agent (antioxidant) to keep Cu and Fe in metalloenzymes in reduced state

  • —Collagen formation

    • —Collagen is a structural protein found in bone, skin, blood vessels, tendons, and cartilage

    • —Vitamin C is cofactor for enzymes that catalyze posttranslational hydroxylation of proline and lysine residues

      • —Hydroxylation of proline and lysine residues helps to stabilize collagen

    • —Ascorbic acid reduces Fe3+ in the enzyme system to Fe2+

  • —Carnitine synthesis

    • —Carnitine is an important compound needed for transporting long-chain fatty acid into mitochondria for β-oxidation

    • —Ascorbic acid is the preferred agent to reduce Fe3+ to Fe2+

    • —Occurs in both first step and last step in carnitine synthesis

  • —Antioxidant

    • —Vitamin C is the primary water-soluble antioxidant

    • —It is present in blood, body fluids, and inside cells and helps to protect again free radicals

  • —Neurotransmitter and hormone synthesis

    • —Cu+ dependent

      • —Norepinephrine

      • —Serotonin

      • —Cholecystokinin (CCK)

  • —Microsomal metabolism

    • —eg. the first step of converting cholesterol to bile acid in liver is a hydroxylation catalyzed cholesterol 7 α-hydroxylase. This step requires vitamin C for an undefined role

Vitamin E - Tocopherols/Tocotrienols

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  • Found dissolved in fat both in plants and animal foods

  • Oil from plants considered the richest

  • In food of animal origin, found in fatty tissues

  • Contents of different tocopherols differ in foods

Digestion, Absorption, and Storage

  • —Tocopherols are found free in foods (no digestion needed)

  • —Tocotrienols are found as esters in foods

  • —Synthetic tocopherols also exist as esters

  • —Enzymes to digest esters

    • —Pancreatic esterase in lumen of small intestine

    • —Duodenal mucosal esterase at brush border

  • —Absorption primarily occurs in jejunum, via passive diffusion

    • —In enterocytes (intestinal mucosal cells), tocopherols are incorporated into chylomicrons (CM)  for transport through the lymph into blood circulation

    • —CM remnants deliver tocopherols to the liver

    • —As being transported by CM, tocopherol can be transferred to HDL and LDL

    • —Liver sends tocopherol to extrahepatic tissues via VLDL

  • —Uptake into cells depends on the vehicle

    • —If carried by LDL, through a receptor-mediated uptake

    • —If carried by CM and VLDL, through LPL (lipoprotein lipase)-mediated hydrolysis

    • —If carried by HDL, through HDL-mediated delivery

  • —Storage

    • —No single storage organ of vitamin E

    • —Largest fraction (>90%) is in the fat droplets in adipose tissue (concentration increases linearly as dosage increases)

    • —Can be found in liver, heart, lung, muscle, etc (concentration relatively stable)

Functions

  • —Principle function is to maintain membrane integrity by preventing the peroxidation of unsaturated fatty acids in membrane phospholipids

  • —As an antioxidant, vitamin E is the first line of defense against peroxidation of polyunsaturated fatty acids (PUFA) in cellular and subcellular membrane phospholipids (mitochondrial membranes; endoplasmic reticulum)

    • Important in protecting cell membranes in brain, lungs, and RBC

    • Vitamin C helps regenerate vitamin E

  • —Second line of defense against PUFA oxidation and formation of lipid peroxides is with antioxidant enzyme glutathione peroxidase which uses selenium as a cofactor

  • —Therefore, vitamin E also has a close relationship with selenium

  • —Also related to its role as an antioxidant, vitamin E can prevent LDL from being oxidized

    • —Oxidized LDL is more readily taken up by macrophages than nonoxidized LDL

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study question

  • explain how vitamin C, vitamin E and Se work together​

Deficiency

  • —Rare in humans

  • —Risk factors

    • —Fat malabsorption (eg as in cystic fibrosis)

    • —Genetic defects in alpha-tocopherol transfer protein or lipoproteins

    • —Newborns due to low vitamin E storage and inefficient absorption

    • —High PUFA intake increases the risk if vitamin E intake is marginal

    • —Vitamin C and selenium deficiency also increases need for vitamin E

  • —Symptoms and Signs

    • —Skeletal muscle pain and weakness

    • —Hemolytic anemia (decrease in membrane integrity of RBCs)

    • —In adults, plasma total tocopherol level relative to lipid  < 5 µg/mL or 8 mg/g

Toxicity

  • —Rare

    • —No evidence of toxicity from vitamin E in foods

    • —Long-term safety of higher doses from supplements has not been tested

    • —Major concern: vitamin E interferes with vitamin K cycle --> impaired blood clotting

    • —UL = 1000 mg/d α-tocopherol for adults

      • —Adverse effects include hemorrhage

      • —Patients on anticoagulant therapy should be monitored (even aspirin)

Assessment

  • —Difficult with current techniques

  • —Serum levels normalized to serum lipids

    • —Low serum  vitamin E may be due to low serum lipids

      •   e.g.   a-tocopherol (mg) /  total serum lipids (g)

  • —Functional assessment:

    • —Erythrocyte hemolysis test (crude assessment)

      • —Incubation with hydrogen peroxide vs water

      • Measure the amount of Hgb released

study question

  • why would low serum vitamin E be due to low serum lipid levels?

Vitamin A - Retinoids

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Digestion and Absorption

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  • —Retinyl esters (RE) from animal products

    • —Hydrolyzed at the brush border

    • —In enterocytes:

      • —Re-esterified and packaged into chylomicrons

      • —Some converted to retinoic acid

  • —Carotenoids from plant sources are absorbed into enterocytes cell intact

    • —Converted to retinal  -->  retinol -->  RE

    • —Or can stay intact and packaged into chylomicrons

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Transport and Storage

  • —Because fat-soluble, retinol must bind to binding proteins whenever in the cytosol of cell, in plasma, or in other aqueous environments

    • —Cellular Retinol Binding Proteins (CRBP)

      • —CRBP I: all tissues, high in liver and kidney

      • —CRBP II: intestine esp jejunum

      • —CRBP III: liver, kidney, skeletal muscle

      • —CRBP IV: heart, kidney, colon

  • —Plasma

    • —RBP and pre-albumin

  • —Stored in liver as retinyl esters (primarily retinyl palmitate)

  • —Travels in blood bound to 2 proteins made in the liver

    • —Retinol Binding Protein (RBP)

    • —Pre-albumin

  • —Protein inadequacy may lead to decrease in plasma levels of RBP and pre-albumin

    • —Vitamin A won’t be delivered to tissues

  • —Would not be enough to just give vitamin A if protein deficient

study question

  • why do you need protein along with adequate vitamin A to cure a deficiency?

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Functions

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VISION

  • —Eye: Dark adaptation

    • —Retina has rods (function in dim light) and cones (function in bright light)

    • —Rhodopsin is the pigmented molecule in rods that absorbs light

      • —Rhodopsin = opsin + 11-cis retinal

        • —Resulting process also uses Ca, Niacin-requiring coenzymes

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DNA

  • —Other functions of vitamin A more or less are related to one form, retinoic acid (RA)

  • —Retinoic acid acts as “Hormone A”

  • —RA travels to nucleus and binds to nuclear receptors, RAR and RXR

  • —These nuclear receptors belong to a supergene family

  • —Binding of RA to these receptors leads to changes in expression of certain genes

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SKIN

  • —Skin epidermis has 4 layers

  • —Skin undergoes terminal differentiation

    • —Basal cells are rapidly dividing, not well-differentiated

    • —As they move upward, they get more differentiated

    • —When reach outer layer, they die and get sloughed off

  • —RA is needed for differentiation of cells

    • —Switch on genes encoding keratin

    • —May help reverse wrinkling due to exposure to sun

  • —Retinol may have the same effects, used in cosmetics

    • —Not regulated by FDA

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IMMUNE SYSTEM

  • Increases resistance to infection by maintaining skin integrity

  • Enhances antibody production by WBC

  • Increase T cell counts and activity

  • Increase activity of natural killer cells (NK cells)

BONE METABOLISM

  • —Vit A deficiency

  • —Stimulates osteoblasts

  • —Inhibits osteoclasts

  • —Excess Vit A

  • —Inhibits osteoblasts

  • —Stimulates osteoclasts

  • —Leads to osteoporosis?

Retinol Function

  • —Retinol gets oxidized to retinoic acid

    • —2 isomers: All-trans RA (t-RA) and 9-cis RA

  • —The retinoic acid (Hormone A) binds to mobile receptors in the nucleus

    • —t-RA binds to Retinoic acid receptor (RAR)

    • —9-cis RA binds to Retinoid X receptor (RXR)

  • —RXR

    • —The “X” was used because for a long time, no one knew what the ligand (compound that binds to the receptor) was

    • —RXR used to be called an “orphan” receptor

    • —After 9-cis RA discovered to be a functioning ligand

      • —RXR = “adopted” receptor

Deficiency

  • —Signs and Symptoms

    • —Dryness of the eye

      • —Conjunctiva and Cornea

  • —Dry, rough, itchy skin with rash

  • —Fatigue

  • —Poor growth

  • —Dry, brittle hair and nails

  • —Inability to adapt and see in dim lights

Toxicity

  • —Hypervitaminosis A

    • —Cause: over consumption of preformed vitamin A, not carotenoids

  • —Signs and symptoms

    • —Bone pain and joint swelling

    • —Dry skin and lips

    • —Enlarged liver and spleen

    • —Headache and blurred vision

  • —Safety in pregnancy

    • —Vitamin A is a teratogen; over consumption of preformed vitamin A is known to cause birth defects

    • —No evidence that beta-carotene can cause birth defects

    • —Pregnant women should avoid supplement that contains more than 1500 µg (5000IU)

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Assessment

  • —Plasma retinol level is measured as a biochemical indicator of vitamin A status

  • —Plasma retinol levels reflect vitamin A status best in

    • —Deficiency: storage (mainly liver) exhausted

    • —Toxicity: storage filled to capacity

  • —Influencing factors

    • —Infection and trauma depress plasma retinol level

    • —Zinc deficiency and protein inadequacy lead to low plasma retinol level due to insufficient synthesis of retinol binding proteins (RBP)

study question

  • why is Zn deficiency relevant?

Vitamin K

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K1 = found in plant foods

K2 = synthesized by colon bacteria

K3 = synthetic

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Phylloquinone (K1)

  • —Absorbed from small intestine, esp jejunum as part of micelles

    • —Enhanced by dietary fat, bile, and pancreatic juice

Menaquinone (K2)

  • Synthesized by bacterial in lower GI and absorbed via passive diffusion from ileum and colon

  • Phylloquinone (K1) is incorporated into chylomicrons (CM) that enter the lymphatic and then blood circulation

  • Eventually, CM remnants deliver vitamin K1 to liver

  • Liver is the major storage site for vitamin K1

  • Liver sends vitamin K1 to extrahepatic tissues via VLDL

Functions

  • —Vitamin K1 and K2 functions by serving as a cofactor of an enzyme that catalyzes posttranslational carboxylation of specific glutamic acid residues in protein: Vitamin K-dependent carboxylation

    • —Enables interactions with calcium and other compounds

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study question

  • explain the relationship between vitamin K and blood clotting/coagulation

Main Function - Coagulation

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VITAMIN K AND BONE

  • —Two vitamin K2-dependant proteins in bone, cartilage, and dentine

  • —Osteocalcin (Bone Gla protein, BPG):

    • —Made by osteoblasts during bone matrix formation

    • —Appears to be involved in bone remodeling or calcium mobilization

  • —Matrix Gla protein (MGP)

    • —Associated with the original matrix and bone mineralization

    • —May prevent calcification of soft tissue and cartilage and help in normal bone growth

  • —Synthesis of both osteocalcin and MGP appears to be stimulated by calcitriol (vitamin D) and retinoic acid (vitamin A)

Vitamin K Cycle

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study questions

  • why does vitamin K need to be recycled?

  • why do we need to eat vitamin K if it gets recycled?

Deficiency

  • —Questionable in healthy adults

    • —Vitamin K1 is widespread in foods

    • —Adults can get vitamin K2 from low GI, generated by bacteria

    • —Vitamin K can be recycled

  • —Risk factors in adults

    • —Liver damage (eg. caused by diseases or alcohol)

      • —Liver is the main storage and recycle site for vitamin K

      • —Body store ~ 100 µg, mainly in liver

  • —Medications

    • —Broad-spectrum antibiotics destroy microflora in the colon

    • —Anticoagulants (eg Warfarin) that disrupt vitamin K recycling

  • —Fat malabsorption

  • —Signs and Symptoms

    • —Prolonged bleeding (detected by lab tests)

    • —Easy bruising, bleeding gum, small amount of blood in stool, urine

    • —Extremely heavy menstrual bleeding

    • —In infants, intracranial hemorrhage (life threatening bleeding within the skull)

  • —Newborns are at a higher risk for vitamin K deficiency

    • —Placenta doesn’t allow vitamin K to pass through efficiently

    • —Breast milk is low in vitamin K

    • —Liver not mature yet

    • —The recycling of vitamin K is not yet efficient enough

    • —Colon is sterile for the first few days after birth

study question

  • how is there no UL if vitamin K is fat soluble?

Toxicity

  • —No UL has been established for vitamin K

  • —Vitamins K1 and K2 have not been reported to cause toxicity even at high dose (eg vitamin K1 at 4000 µg/day)

    • —No tolerable upper intake level established

  • —Vitamin K3 used in the past caused liver damage and anemia if ingested in relatively large amounts

Assessment

  • —Direct measurement

    • —Plasma/Serum level as indicator of recent (within 24 hr) intake

  • —Functional measurement

    • —Whole blood clotting time

    • —Prothrombin time: normal 11-14 seconds, >25 seconds è major risk for bleeding

    • Done prior to surgery

©2023 by Syracuse University Dr.Margaret Voss

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