Vitamins

1
TUMS
Vitamins Coenzymes
Part three
Fat Soluble Vitamins
Azin Nowrouzi, PhD
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Vitamin classification
Name(Letter) RDI
Retinol (A) 5000 IU
Calciferol (D) 400 IU
Tocopherol (E) 30 IU
Phylloquinone (K) 70 ?g
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Fat-soluble Vitamins

• Absorbed with dietary fat in small intestine
• 40-90 absorption efficiency
• Absorption typically regulated by need
• ?need? ?absorption
• Transported away from small intestine in
  chylomicra via blood and lymph (depending on
  size)
• They are not easily excreted through urine.
• Substantial amounts are stored in liver and fat
  tissue.
• Therefore, toxicity is possible.

4
Vitamin A
Compounds with 20-carbon structure. Contain a
methyl substituted cyclohexenyl ring (?-ionone
ring), and an isoprenoid side chain with either
a hydroxyl group, and aldehyde group, a
carboxylic acid group, or an ester group (retinyl
ester) at the terminal C15.

All-trans-retinal
11-cis-retinal

Retinol
Retinoic Acid
Cant be reduced to retinol or retinal in the
body.
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Vitamin A

• Active vitamin A- Preformed vitamin A can be
  obtained either directly from foods that are
  substantial in vitamin A (beef liver, fish liver
  oils, egg yolks and butter)
• The active form of vitamin is retinol, an alcohol
  which can be converted to other forms (e.g.
  vitamin A esters) for storage in liver and
  tissues.
• much the body's vitamin A is stored in the liver
  as retinyl palmitate
• Provitamin A- provitamins, substances that are
  transformed into vitamins in the body
• Beta-carotene is the most abundant and widespread
  provitamin A.
• Beta-carotene comes from a group of compounds
  called the "carotenoids (C40 polyisoprenoids).
• One need to eat approximately six times as much
  beta-carotene to get the same amount of vitamin A
  as in retinol.
• Dark-green leafy vegetables (spinach) and
  yellow-orange fruits (apricots and mango) and
  vegetables (carrots, yellow squash and sweet
  potatoes) are high in beta-carotene and other
  carotenoids (?-carotene, ?-cryptoxathin, etc.)
• Carotenoids are not toxic even at high doses for
  long times.

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Vitamin A Absorption and transport

• Micelle formation
• Inside mucosal cell ?-carotene is cleaved in the
  lumen of the intestine by ?-carotene dioxygenase
  to yield retinal.
• Retinal is reduced to retinol by retinal
  reductase, an NADPH requiring enzyme within the
  intestines.
• Retinol is esterified to palmitic acid and
  delivered to the liver with chylomicrons via
  lymphatic system.
• Carotenoids which escape intestinal conversion to
  retinol can be stored in adipose tissue.
• Species in which this occurs include humans,
  horses and cattle, which have yellow-pigmented
  body fat when carotenoid intake is high.
• Vitamin A absorption efficiency 70-90
  carotenoids 9-22.

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Vitamin A Biological functions

• Role in vision. Vitamin A (retinal) is an
  essential precursor for formation of the visual
  pigment, rhodopsin, in the retina of the eye.
  Retinal plays an important role in vision,
  especially night vision. Lowers cataract
  incidence.
• Role in growth. Helps regulate cell development,
  cell differentiation and cell division.
• Role in Bone and teeth formation. Promotes the
  proper growth of bones and teeth. Bone cells
  (osteoblasts and osteoclasts) depend on vitamin A
  for their normal functioning.
• Is important in the formation and maintenance of
  healthy hair, skin and mucous membranes.
• Role in reproduction. Vitamin A holds an
  important place in sexual reproduction. Adequate
  levels of vitamin A are needed for normal sperm
  production. The female reproductive cycle
  requires sufficient amounts of vitamin A.
• Boosts the body's immune system helping to
  increase body resistance to infectious diseases.

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Role of Vitamin A in Vision(Walds visual cycle)
1. When the rhodopsin is exposed to light it is
bleached releasing the 11-cis-retinal from
opsin. 2. Isomerization of the cis-isomer of
retinal to all-trans-retinal, causes
conformational changes in rhodopsin,
hyperpolarization of the retinal rod cell, and
extremely rapid transmission of electrical
activity to the brain via the optic nerve 3.
Trans-retinal is isomerized to cis-retinal in the
dark, which associates with opsin to regenerate
rhodopsin.
All trans retinol main circulating form of
Vit A
Visual Pigment
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Vitamin A Biological functions (Cell growth and
differentiation)

• Regulation of gene expression by retinoic acid,
  the acid form of vitamin A
• Retinoic acid is formed within the target cell
  from retinol transported in the bloodstream.
• Retinoic acid, combined with protein receptor,
  acts as transcription regulator by binding to
  specific sequences of DNA in the nucleus
• Affected cells include epithelium of numerous
  tissues, including skin and gut, and bone, ovary
  and testis.
• Retinoic acid is an especially important
  regulator of embryonic cell differentiation.

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Problems associated with Vitamin A

• Vit A excess
• Hypervitaminosis A in humans
• Symptoms include dry, pruritic skin with
  excessive itching and increase in intracranial
  pressure.
• is becoming an increasing problem in Western
  countries because of self-medication and
  overprescription.
• has occurred through eating polar bear or seal
  liver by polar explorers.
• Eat polar bear liver sparingly, 30 grams contain
  450,000 IU of retinol! Continued ingestion
  causes peeling of the skin from head to foot.
• It is possible that some early Arctic explorers
  died from eating their sled dogs in an attempt to
  survive.

• Vit. A deficiency
• 1. Night blindness" - lessened ability to see in
  dim light.
• 2. Increased susceptibility to infection and
  cancer and anemia equivalent to iron deficient.
• 3. Prolonged lack of vitamin A
• (keratinization of the cornea, a condition known
  as xerophthalmia).
• 4. Abnormal bone development in fetal and
  neonatal life.
• Skeletal malformations
• spontaneous fractures
• internal hemorrhages
• loss of appetite
• slow growth or weight loss
• 5. Various congenital defects.

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Vitamin A Uses

• Retinol and its precursors are used as dietary
  supplements to prevent deficiency symptoms.
• Retinoic acid is used in dermatology to cure acne
  and psoriasis
• 1. Mild acne (Dariers disease) and aging
• Topical application of tretinoin (all-trans
  retinoic acid), along with benzoyl peroxide and
  antibiotics.
• 2. severe recalcitrant cystic acne
• Oral consumption of isotretinoin (13-cis
  retinoic acid). This drug is teratogenic. Should
  not be prescribed during pregnancy. It may lead
  to hyperlipidemia and increased LDL/HDL ratio
  (increased chance of heart disease) in long term.

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Vitamin D

• Vitamin D is a family of fat-soluble sterol
  compounds
• Vitamin D1 (lamisterol)
• Vitamin D2 (ergocalciferol)
• Vitamin D3 (cholecalciferol)
• Vitamin D4 (dihydroergocalciferol)
• Vitamin D5 (7-dehydrositosterol)

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Vitamin D Types and Sources

• For humans, the two most important forms of
  vitamin D are
• vitamin D2
• vitamin D3.
• Vitamin D2 (ergocalciferol) is derived from
  plants and irradiated yeast and fungi.
• Vitamin D3 is synthesized in the body when skin
  is exposed to sunlight
• Cholesterol sunshine Vitamin D3
• sunshine vitamin UV-B rays (5-10 minutes arms
  and legs, mid-day sun).
• Vitamin D3 can be obtained from foods like milk,
  fortified cereals, tuna, salmon and fish oils.

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Sunlight
Vitamin D2 (Ergocalciferol)
Ergosterol (in plants)
Diet
Sunlight
Vitamin D3 Cholecalciferol)
7-Dehydrocholesterol

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Activation of Vitamin D

• Vitamin D2 and vitamin D3 are biologically
  inactive but can have equal biological activity
• Both can be converted first to calcifediol in the
  liver and then to calcitriol, also known as
  1,25-dihydroxycholecalciferol,
• in the kidneys.
• Calcitriol, which is the most active form of
  vitamin D3, is then transported via a carrier
  protein to the various sites in
• the body where it is needed.

Calcitriol is also called 1,25-dihydroxy vitamin
D3, or (1,25-(OH)2D3.
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1,25-dihydroxyvitamin D3
Conversion of 25-(OH)D3 to its biologically
active form, calcitriol, occurs through the
activity of a specific D3-1-hydroxylase present
in the proximal convoluted tubules of the
kidneys, and in bone and placenta. Cytochrome
P450, O2 and NADPH are needed.
25-hydroxyvitamin D3
In the liver cholecalciferol is hydroxylated at
the 25 position by a specific D3-25-hydroxylase
generating 25-hydroxy-D3 25-(OH)D3 which is the
major circulating form of vitamin D.
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Functions of vitamin D

• Vitamin D regulates the calcium and phosphorus
  levels in the blood by promoting their absorption
  from food in the intestines, and by promoting
  re-absorption of calcium in the kidneys.
• It promotes bone formation and mineralization and
  is essential in the development of an intact and
  strong skeleton.
• It inhibits parathyroid hormone secretion from
  the parathyroid gland.
• Vitamin D affects the immune system by promoting
  immunosupression, phagocytosis, and anti-tumor
  activity.

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Vitamin D Hormone for Calcium and Phosphate
regulation

• Calcium is vital for nerve cell transmissions and
  muscle fiber contractions.
• Calcitriol functions in concert with parathyroid
  hormone (PTH) and calcitonin to regulate serum
  calcium and phosphorous levels by
• Increasing dietary calcium absorption from the
  small intestine.
• Decreasing the urinary calcium excretion
  (increasing renal reabsorption).
• Stimulating resorption of calcium from bone
• Instrumental in the growth, hardening and repair
  of bones.
• Too much vitamin D, however, can increase calcium
  losses from bone
• Vitamin D is essential for normal insulin
  secretion by the pancreas and therefore control
  of blood sugar levels.

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Effects of PTH and Vit D3
Effects of PTH and Vit D3
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When vitamin D goes abnormal

• Too little (northern latitudes) leads to Vit D
  deficiency
• Rickets (bone deformities in children)
• Osteoporosis
• Osteomalacia (weak bones)
• Demineralization of bones
• Too much (5 times the RDA, chronically) It is
  most toxic of the vitamins.
• Nausea, thirst, loss of appetite, stupor
• Hypercalcemia calcium gets deposited in soft
  tissues, arteries and kidneys.

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Diseases caused by deficiency

• Vitamin D malnutrition may also be linked to an
  increased susceptibility to several chronic
  diseases such as
• High blood pressure
• tuberculosis
• cancer
• periodontal disease
• multiple sclerosis
• chronic pain
• depression
• schizophrenia
• several autoimmune diseases
• The American Pediatric Associations advises
  vitamin D supplementation of 200 IU/day (5µg/d)
  from birth onwards.
• Liquid "drops" of vitamin D for infants.

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Vitamin E
A family of eight different molecules. Four of
the eight vitamin E molecules are called
tocopherols (alpha, beta, gamma and delta) also
known as Natural Tocopherols while the
remaining four are called tocotrienols (alpha,
beta, gamma and delta). D-alpha-tocopherol is the
most biologically active in humans.
a-Tocopherol is the most potent of the
tocopherols.
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Functions

• Vitamin E in the form of d-alpha-tocopherol is an
  important fat-soluble antioxidant, scavenging
  oxygen free radicals, lipid peroxy radicals and
  singlet oxygen molecules before these radicals
  can do further harm to cells. Free radicals are
  very reactive atoms or molecules that typically
  possess a single unpaired electron.
• New studies have revealed that the tocotrienol
  forms of vitamin E are even more potent
  antioxidants than the tocopherol isomers.
• Vitamin E helps maintain the structural integrity
  of cell membranes throughout the body.
• d-alpha-tocopherol has been shown to inhibit the
  "clumping" of blood platelets (thus helping to
  avoid blood clots) and enhancing vasodilation
  (the opening of blood vessels).
• d-alpha-tocopherol protects the fat component in
  low-density lipoproteins (LDLs) from oxidation
  and has shown moderate cholesterol-lowering
  capabilities. Studies have shown that gamma- and
  delta-tocotrienols may be better suited than the
  tocopherols at inhibiting the manufacture of
  cholesterol in the liver and hence in
  contributing to a greater cholesterol lowering
  effect.

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Vitamin E (deficiency)

• Deficiency rare in adults usually due to
  impaired fat absorption or transport seen
  usually in children (anemia, edema in infants)
• Muscular dystrophy
• Hemolytic anemia
• Dietary hepatic necrosis
• Excess very safe below 800 IU/day
• Source
• Vitamin E is present in animal fats, meat, green
  vegetables, nuts/seeds.
• Alpha-tocopherol is found in a number of
  vegetable oils, including safflower and
  sunflower. It is also found in wheat germ.
  Soybean and corn oils contain mainly
  gamma-tocopherol.
• Storage of vitamin E is limited. Vitamin E is
  stored in high amounts in the pituitary gland and
  the adrenals. The liver briefly stores vitamin E
  but only in small quantities. Adipose tissue.
• Estimated requirements 5mg/day 0.6mg/day of
  unsaturated fat.
• Uses
• Hemolytic anemia in premature infants,
  unresponsive to B12, Fe and folic acids.
• Macrocytic megaloblastic anemia seen in children
  with severe protein-calorie malnutrition.

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The symptoms of Vitamin E deficiency

• Muscle weakness  
• lethargy                       
• apathy               
• a lack of vitality                      
• indigestion                  
• muscle cramps               
• inability to concentrate
• irritability            
• disinterest in physical activity                  
            
• red blood cell breakage
• anemia
• neurological problems

• An increasing body of evidence is emerging to
  implicate free radical activity in the
  pathogenesis of periodontal breakdown.
• Inadequate antioxidant availability could either
  predispose the host to the disease, or modify the
  progression of a pre-existing disease.

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Free Radicals - the Metabolic Oxidizers
Free radical unpaired electron ?very reactive
.
OH
OH
.
OH
OH
Oxygen radicals Hydroxy (HO) / Peroxy (HOO)
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An antioxidant is a chemical so easily oxidized
itself that it protects others from oxidation.
and / or
Double Bond eg. Vitamin A
Phenol eg. Vitamin E or C
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Antioxidant
The antioxidant neutralizes a free radical by
donating an electron.
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Vitamin K

• The "K" in vitamin K comes from the German word
  "koagulation," which refers to blood clotting
  (coagulation).
• Vitamin K is essential for the functioning of
  several proteins involved in normal blood
  clotting.
• There are several forms K1-K7

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Vitamin K1 (Phylloquinone)

• Naturally occurring vitamin K is absorbed from
  the intestines only in the presence of bile salts
  and other lipids through interaction with
  chylomicrons. Therefore, fat malabsorptive
  diseases can result in vitamin K deficiency.
• Source Present in green leafy vegetables like
  lettuce, parsley, spinach and various greens
  (beet and mustard). Broccoli and certain
  vegetable oils (soybean, cottonseed, and
  olive).are also a good source of vitamin K1.

__                                              
                                                 
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Vitamin K2 (Menaquinone)

• Vitamin K2 is a group of compounds called the
  "menaquinones."
• Synthesized by intestinal bacteria "n" can be 6,
  7 or 9 isoprenoid groups.
• The number of isoprene residues in the side chain
  of the vitamin K2 molecule designate the
  individual menaquinone compounds, e.g.,
  menaquinone-4 (MK-4) has four isoprene units in
  the side chain of vitamin K2 menaquinone-7
  (MK-7) has seven isoprene units in the side
  chain.
• Source Vitamin K2, which is the most
  biologically active form of vitamin K, is found
  in egg yolks, butter, liver, cheddar cheese and
  yogurt.
• It has been suggested that products like yogurt,
  may help to increase the functioning of these
  useful bacteria.

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Vitamin K3 (Menadione)

• The synthetic (man-made)
• vitamin K3 is water soluble
• and absorbed irrespective
• of the presence of
• intestinal lipids and bile.

Uses essential cofactor in blood clotting.
Excess Dangerous if taking anti-coagulants. He
molytic anemia, jaundice in infants.
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Functions

• Blood coagulation
• Post-translational carboxylation of some
  glutamate residues in blood factors.
• Vitamin K is needed for the body to make four of
  the blood's coagulation factors, including
  prothrombin (also known as factor II),
  proconvertin (factor VII), Christmas factor
  (factor IX) and the Stuart-Power factor (factor
  X).
• It occurs in the liver
• Vitamin K has to change to Hydroquinoine to
  function as coenzyme for carboxylase.
• Calcium binding proteins
• Carboxylation of specific glutamate residues in
  calcium binding proteins.
• Role in oxidative phosphorylation

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Prothrombin ?-Carboxylation
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Vitamin K role in ?-Carboxylation
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Causes of Deficiency

• Prolonged use of antibiotics
• Malabsorption and biliary tract obstruction
• Spoilt sweet-clover hay
• Contains dicumarol (vit K antagonist)
• Short circuiting of the bowel
• In immediate post-natal infants
• (bruising/bleeding in infants).
• Sterile bowels (no intestinal microflora)
• Low Vit K in mothers milk
• Hemorrhagic disease of the newborn.

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Too Much Broccoli !
Two women with diseases characterized by abnormal
blood clotting did not improve when they were
given Warfarin. When questioned about their
diets, one woman reported that she ate at least a
pound of broccoli every day, and the other ate
broccoli soup and a broccoli salad every day.
When broccoli was removed from their diets,
warfarin became effective in preventing the
abnormal clotting of their blood. Because
broccoli is high in vitamin K, these patients had
been getting enough dietary vitamin K to compete
with the drug, thereby making the drug
ineffective.
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What do vitamins do?

• Metabolically they have diverse functions as
• Coenzymes (B vitamins, vitamin K)
• Hormones (retinoic acid, vitamin D)
• Modulators or regulators of growth and
  development (retinoic acid, folic acid)
• (apparently non-specific) antioxidants (Vitamins
  C and E)

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• Vitamin C
• Bleeding gums
• Loose teeth
• Poor healing

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Cofactors and coenzymes
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Other coenzymes
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Coenzyme Q Ubiquinone

• A lipid in inner membrane of mitochondria.
• Moves freely within membrane.
• Carries electrons.
• Coenzyme Q10 (CoQ 10) or ubiquinone is
  essentially a vitamin or vitamin-like substance.
• (1) fish (2) organ meats, including liver,
  kidney and heart and (3) the germs of whole
  grains
• It is synthesized in all tissues.
• The biosynthesis of CoQ10 from the amino acid
  tyrosine requires at least eight vitamins and
  several trace elements.
• Coenzyme Q10 is the coenzyme for at least three
  mitochondrial enzymes (complexes I, II and III)
  as well as enzymes in other parts of the cell.
• CoQ10 has been studied in its reduced form as a
  potent antioxidant.

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Coenzyme Q - 'promoted' to a Vitamin?
A vital 'transport agent' in the use of oxygen to
generate energy, especially in the heart muscle.
Supplements do aid in many forms of heart
disease, gum disease, BUT gtgt slows
Parkinsons/Alzheimers/ aging, relieves allergies,
boosts athletic performance and immunity, aids
weight loss ?!
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Causes of Deficiency

• Significantly decreased levels of CoQ10 have been
  noted in a wide variety of diseases in both
  animal and human studies.
• CoQ10 deficiency may be caused by
• Insufficient dietary CoQ10.
• Impairment in CoQ10 biosynthesis.
• Excessive utilization of CoQ10 by the body
• excessive exertion
• hypermetabolism
• acute shock states
• or any combination of the three.
• Drugs can cause CoQ deficiency
• HMG-CoA reductase inhibitors used to treat
  elevated blood cholesterol levels by blocking
  cholesterol biosynthesis also block CoQ10
  biosynthesis.
• The resulting lowering of blood CoQ10 level is
  due to the partially shared biosynthetic pathway
  of CoQ10 and cholesterol.

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Phytochemicals
Non-nutrient compound Found in plant-derived
foods and have biological activity in the
body. Some categories Antioxidants
(anti-aging/cancer/heart disease?) -
catechins (berries, green/black tea), lycopene
(tomatoes,watermelon), bioflavanoids
(citrus fruit, grapes), coenzyme Q
(nuts,oils). Estrogen mimics (?cancer
inhibitors?) - indoles (broccoli,
cauliflower), isoflavones (legumes),
lignans omega-3- fatty acids
(canola, flaxseed), genistein (soy).
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Lycopene red pigment in tomatoes, red
grapefruit, watermelon
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Plant Pigments Potent Antioxidants
Almost 2000 known plant pigments. gt800
flavonoids, 450 carotenoids and 150
anthocyanins. Red (lycopene) tomatoes, pink/red
grapefruit, watermelon,
guava, red peppers. Red/Blue/Purple
(anthocyanins) red/blue grapes,
blue-/straw-/raspberries, beets, cherries,
egg plant, plums, red
cabbage. Orange (carotene) squash, pumpkin,
yams, carrots, mango,
cantaloupe.
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Plant Pigments Phytochemicals
Orange/Yellow (cryptoxanthin) peach, orange,
nectarine, papaya. Yellow/Gree
n (lutein), zeaxanthin
especially good for health
of eyes) corn, cucumber
skins, yellow/green
peppers, green beans/peas, spinach,
honeydew melon, kiwi, romaine lettuce,
50
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