Transcript Retinoic acid

Perspectives in Nutrition
5th ed.
Gordon M.Wardlaw, PhD, RD, LD, CNSD
PowerPoint Presentation by
Dana Wu Wassmer, MS, RD
Chapter 9: The Fat-Soluble
Vitamins
Vitamins
• Essential organic substances
• Yield no energy, but facilitate energyyielding chemical reactions
• If absent from a diet, it will produce
deficiency signs and symptoms
• Fat-soluble vitamins
• Water-soluble vitamins
• Preservation of vitamins in foods
– exposure to light, heat, air, water, and alkaline
Fat-Soluble Vitamins Overview
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Dissolve in organic solvents
Not readily excreted; can cause toxicity
Absorbed along with fat
Concern for people with fat malabsorption
Transported like fat in chylomicrons,
VLDL, LDL
Vitamin A
• Most common cause of non-accidental blindness
• Preformed
– Retinoids (retinal, retinol, retinoic acid)
– Found in animal products
• Proformed
– Carotenoids (beta-carotene, alpha carotene,lutien, lycopene,
zeaxanthin)
– Must be converted to retinoid form
– Intestinal cells can split carotene in two (molecules of
retinoids)
– Found in plant products
Terminal Ends of Retinoids
H
C OH
H
Retinol
H
C O
O
C O H
Retinal
Retinoic Acid
Conversion of Carotenoids to
Retinoids
-Carotene
Enzymes in the small
intestine or liver cells
2 molecules of retinol
Oxidation
retinal
retinoic acid
Absorption of Vitamin A
• Requires bile, digestive enzymes,
integration into micelles
• Dependent on the fat in the diet
• 90% of retinoids can be absorbed
• Only ~3% of carotenoids are absorbed
• Intestinal cells can convert carotenoids to
retinoids
Transport and Storage of
Vitamin A
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Liver stores 90% of vitamin A in the body
Reserve is adequate for several months
Transported via chylomicrons to the liver
Transported from the liver as retinol via
retinol-binding protein to target tissue
• Carotenoids can be transported via VLDL
• Target cells contain intracellular retinolbinding proteins
• RAR, RXR receptors on the nucleus
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Nuclear Retinoid Receptors (Fig. 9-2)
Functions of Vitamin A
• Retinol is needed for reproduction
• Retinoic acid supports growth and cell
maturation
• Retinal is needed for night and color vision
The Visual Cycle
• Cones in the retina
– Responsible for vision under bright lights
– Translate objects to color vision
• Rods in the retina
– Responsible for vision in dim lights
– Translate objects to black and white vision
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The Visual Cycle (Fig. 9-3)
Growth and Development
• Retinoic acid is necessary for cellular
differentiation
• Retinoic acid triggers specific RAR and
RXR receptors on the DNA for
differentiation
• Important for embryo development, gene
expression
• Synthesis of bone protein and enlargement
of bone
Cell Health and Maintenance
• Epithelial cells line the outside (skin) and
external passages (mucus forming cells)
within the body
• Retinoic acid influences how epithelial
cells differentiate and mature
• Without vitamin A, cells will deteriorate
• Leads to xerophthalmia (major cause of
blindness)
• Leads to follicular hyperkeratosis (skin
disorder)
The Anti-Infection Vitamin
• Uncertain of the action of vitamin A and
resistance to disease
• Deficiency leads to poor mucus formation
• Deficiency reduces activity of some
immune-system cells
• High-dose therapy of vitamin A increase
immune response
Cancer and Carotenoids
• Role in cell development and immunesystem
• Role as an antioxidant
• Lower risk of breast cancer with vitamin A
supplements
• Megadose is not advise
• Mixed results in cancer/vitamin A studies
• Foods rich in vitamin A and other
phytochemicals are advised
Deficiency of Vitamin A
• Night blindness
• Decrease mucus production
• Leading to bacterial invasion in the eye
– Conjunctival xerosis
– Bitot’s spots
– xerophthalmia
• Irreversible blindness
Deficiency of Vitamin A
• Follicular hyperkeratosis
• Keratin protects the inner layers of skin and
maintains moisture
• Kertinized cells replaces the normal
epithelial cells in the underlying skin layers
• Hair follicles become plugged
• Bumpy, rough, and dry skin
Prevention of Deficiency
• Establish an adequate liver store in weaned
infants
• Deficiency occurs most often after baby has
been weaned
• Providing a megadose of vitamin A to at
risk population may be helpful
Cancer Prevention
• Some studies report positive benefit from
taking vitamin A (retinoids)
• No longer-term studies on human has been
done
• Role in cell differentiation
• Role in inhibition of proliferation
• Possible role in programmed cell death
• Carotenoid lycopene may protect against
prostate cancer
Cardiovascular Prevention
• Carotenoids’ antioxidant capacity
• No definitive conclusions
• Many recommend 5-A-Day
Age-Related Macular
Degeneration
• Leading cause of legal blindness among
Americans over the age of 65
• Changes in the macula (for detail vision)
• Carotenoids lutein and zeaxanthin found in
high amounts in healthy macula
• Risk lowered with high intakes of
carotenoids
Vitamin A and Your Skin
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Topical treatment and oral drug
Decreases sebum secretion
Accutane (oral) and Retin-A (topical)
Can induce toxicity symptoms
Must limit sun exposure
Not recommended for pregnant women
Use only under supervision of a physician
Sources of Vitamin A
• Preformed
– Liver, fish oils, fortified milk, eggs
– Contributes to half of all the vitamin A intake
• Proformed
– Dark leafy green , yellow-orange
vegetables/fruits
– Contributes to half of all the vitamin A intake
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Vitamin A from the Food Guide
Pyramid (Fig. 9-5)
Measuring Vitamin A
• International unit (IU)-crude method of
measurement
• Retinol activity equivalent (RAE) current, more precise method of
measurement
1 ug of retinol = 1 RAE = 3.3 IU =12
ug beta-carotene = 24 ug of other
provitamin A
RDA for Vitamin A for Adults
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900 REA for men
700 REA for women
Average intake meets RDA
Much stored in the liver
Vitamin A supplements are unnecessary
No separate RDA for carotenoids
Who is at Risk For Deficiency
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Breast fed infants
Preschooler with poor vegetable intake
Urban poor
Elderly
Alcoholics and people with liver disease
Individual with fat malabsorption
HIV, AIDS
Toxicity of Vitamin A
Hypervitaminosis A
• Result of long-term supplement use (3-10x
>RDA)
Acute
• Ingestion of LARGE dose(s) of vitamin A
(within a short period)
• Result in intestinal upset, headache, blurred
vision, muscular incoordination
• Symptoms disappear when supplements are
stopped
Toxicity of Vitamin A
Chronic
Large intake of vitamin A over a long period
Bone/muscle pain, loss of appetite, skin
disorders, headache, dry skin, hair loss,
increased liver size, vomiting
Discontinue supplement is recommended
Possible permanent damage
Toxicity of Vitamin A
Teratogenic
• Tends to produce physical defect on
developing fetus as a result of excess vitamin
A intake
• Spontaneous abortion, birth defects
• May occur with as little as 3 x RDA of
preformed vitamin A
Upper Level for Vitamin A
• 3000ug for adults
Fatal dose -12 g of vitamin A can be fatal
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Effects of Vitamin A (Fig. 9-6)
Toxicity of Carotenoids
Hypercarotenemia
• High amounts of carotenoids in the
bloodstream
• Excessive consumption of
carrots/squash/beta-carotene supplements
• Skin turns a yellow-orange color
Vitamin D
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Prohormone
Derived from cholesterol
Synthesis from sun exposure
Insufficient sun exposure makes this a
vitamin
• Activated by enzymes in liver and kidneys
• Deficiency can cause diseases
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Vitamin D Synthesis (Fig. 9-7)
Absorption of Vitamin D
• ~80% of vitamin D consumed is
incorporated into micelles
• Absorbed in the small intestine and
transported via chylomicrons
• Transported through the lymphatic system
Metabolism and Storage of
Vitamin D
• Activation by the liver and the kidneys
• Stored in fat tissue
• Activate vitamin D when calcium is
inadequate
• Excretion of vitamin D mainly via bile
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Functions of Vitamin D
• Regulate blood calcium level (Fig. 9-8)
Vitamin D and Cell
Differentiation
• Calcitriol is able to influence
differentiation and function of the
some cells
• Linked to reduction of breast, colon,
and prostate cancer development
Role in Bone Formation
• Calcitriol creates a supersaturated Ca +
Phos solution
• Causes Ca + Phos to deposit in the bones
• Strengthen bones
• Rickets is the result of low vitamin D
• Osteomalacia (soft bone) is rickets in the
adult
Food Sources of Vitamin D
• Fatty fish (salmon, herring)
• Fortified milk
• Some fortified cereal
The Adequate Intake (AI) for
Vitamin D
• 5 ug/d (200 IU/day) for adults under age 51
• 10-15 ug/day (400 - 600 IU/day) for older
Americans
• Light skinned individuals can produce
enough vitamin D to meet the AI from
casual sun exposure
• Infant are born with enough vitamin D to
last ~9 months of age.
Who is at Risk for Deficiency?
• Elderly (staying indoors)
• People living in the northern climate
• People with fat malabsorption need sun
exposure
• Vitamin D resistance
– Resistance to the action of vitamin D
– May be due to lack of calcitriol synthesis
or inability to bind to nuclear receptor
– Requires large doses of calcitriol
Vitamin D as a Medicine
Type II (age-related) osteoporosis
• Loss of bone mass
• Limited ability to absorb vitamin D or
produce calcitriol
• 10-20 ug vitamin D/ day plus calcium
decrease bone fracture
• Risk for hypercalcemia
Psoriasis
• Skin disorder
• Topical treatment
Toxicity Warning
• Vitamin D can be very toxic
• Regular intake of 5-10x the AI can be toxic
• Result from excess supplementation (not
from sun exposure or milk consumption)
• Sign and symptoms: over absorption of
calcium (hypercalcemia), increase calcium
excretion
• Calcium deposits in kidneys, heart, and
blood vessels
• Mental retardation in infants
Vitamin E
• Tocopherols and tocotrienols
• Amount absorbed is dependent on fat intake
– Incorporated into micelles
– Requires bile and fat digesting enzymes
• Transported via chylomicrons to the liver
• Transported via VLDL, LDL, HDL from the
liver
• Found concentrated in areas where fat is found
• Excreted via bile and urine (much in feces due
to limited absorption)
Redox Agent
• Vitamin E is able to donate electron to
oxidizing agent
• Protect the cell from attack by free radicals
• Peroxyl-radical scavenger
• Protects PUFAs within the cell membrane
and plasma lipoproteins
• Prevents the alteration of cell’s DNA and
risk for cancer development
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Vitamin E, An Antioxidant (Fig. 9-10)
Free Radicals
• Production is normal result of cell
metabolism and immune function
• Destructive to cells; set off a chain reaction
• Lipid peroxidation
• More vitamin E is found in the lungs
• Smoking causes significant oxidative
damage
Protection From Oxidative
Damage
• Glutathione peroxidase
– A selenium containing enzyme
– Helps breakdown peroxidized fatty acids
(that tends to form free radical)
– Lessen the burden of vitamin E
• Superoxide dismutase and catalase
– Reacts with peroxide and single oxygen
(free radicals)
– Reduce free radical activity
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The Antioxidant System (Fig. 9-11)
The More The Better?
• Vitamin E is only one of many antioxidant
• It is likely that the combination of
antioxidant is more effective
• Diversify your antioxidant intake with a
balanced and varied diet
• Megadose of one antioxidant may interfere
with the action of another
Other Functions of Vitamin E
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Protects the double bonds in saturated fat
Role in iron metabolism
Inhibits LDL oxidation
Inhibits protein kinase C activity
Enhance release of prostacyclin
Maintenance of nervous tissue and immune
function
• No specific role in metabolic reaction
Food Sources of Vitamin E
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Plant oils
Wheat germ
Asparagus
Peanuts
Margarine
Nuts and seeds
Actual amount is dependent on harvesting,
processing, storage and cooking
RDA for Vitamin E
• 15 mg/day for women and men
• (=22 IU of natural source or 33 IU of
synthetic form)
• Average intake meets RDA
1 mg d--tocopherol = 0.45 IU (synthetic
source)
1 mg d--tocopherol = 0.67 IU (natural
sources)
Deficiency of Vitamin E
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Hemolytic anemia
Peripheral neuropathy
Maldigestion of fat
Insufficient bile production
Rare
Who is at Risk for Deficiency?
• Premature infants
• People with fat malabsorption
– Cystic fibrosis, celiac disease, liver disease
• Low selenium intake
Toxicity of Vitamin E
• Supplements up to 800 IU is probably
harmless
• Upper Level is 1,000 mg/day of any form of
supplementary alpha-tocopherol
• Upper Level is 1500 IU (natural sources) or
1100 IU (synthetic forms)
• Inhibit vitamin K metabolism and
anticoagulants
Vitamin K (“Koagulation”)
• Phylloquinone (K1) and menaquinones (K2)
• 40%-80% of dietary vitamin K is absorbed
• Absorption requires bile and pancreatic
enzymes
• Menaquinones are synthesized by the
bacteria in the colon and are absorbed
• Role in the coagulation process
• Calcium-binding potential
• Formation of osteocalcin
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Vitamin K and the Coagulation
Process (Fig. 9-13)
Drugs and Vitamin K
• Anticoagulant
– Lessens vitamin K reactivation
– Lessens blood clotting process
– Monitor vitamin K intake
• Antibiotics
– Destroy intestinal bacteria
– Inhibits vitamin K synthesis and absorption
– Potential for excessive bleeding
Food Sources of Vitamin K
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Liver
Green leafy vegetables
Broccoli
Peas
Green beans
Resistant to cooking losses
Limited vitamin K stored in the body
Adequate Intake for Vitamin K
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90 ug/day for women
120 ug/day for men
RDA met by most
Excess vitamins A and E interferes with
vitamin K
• Newborns are injected with vitamin
K(breast milk is a poor source)
• Toxicity unlikely; readily excreted