Post on 03-Mar-2016
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10/1/2015
VITAMIN A (RETINOL)
A/Prof Rozanne Kruger
Learning objectivesInvestigate vitamin A and all its compounds through
the following objectives:
To describe the chemistry, digestion, absorption, transport and metabolism.
To define the term vitamin precursor and to list and describe its various precursors
To identify all the sources
To establish the requirements
To discuss the functions
To determine the effect of deficiency and excess.
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Vitamin A / Retinoids
Fat-soluble vitamin
Discovered 1909, involved with growth (retinol)
and 1928 (carotene)
Vitamin A is found in the body in compounds
known as retinoids: retinol, retinal, and retinoic
acid.
These have functional roles in vision, healthy
epithelial cells, and growth.
Vitamin A deficiency is a major health problem in
the world.
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Vitamin A / Retinoids
Plant foods provide carotenoids e.g. beta-carotene
which may have vitamin A activity
Animal foods provide compounds that are easily
converted to retinol.
Retinol binding protein (RBP) allows vitamin A to
be transported throughout the body.
Toxicity is often associated with abuse of
supplements.
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Vitamin A / RetinoidsTwo forms:
Preformed vitamin A (active form)(retinyl esters) Retinoids
Retinol alcohol form (OH group)
Retinal aldehyde form
retinoic acid acid form
Found in animal products (liver)
Provitamin form (inactive form)(-carotene) Carotenoids and related compounds (-carotene,
-cryptoxanthine)
Can be converted to vitamin A (retinaldehyde)
Found in plant products (orange / green fr & veg)
Storage form = retinyl esters retinol + organic acid (palmithic acid)
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Carotenoids
Only 50 of 600+ found are converted into vitamin A
e.g. -carotene, -carotene, -carotene and -cryptoxanthine
(Lycopene is an example of a carotenoid without vit A activity)
Also act as antioxidants
Bioavailability of carotenoids varies from
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Forms of Vitamin A
Retinol, the alcohol form
Beta-carotene, a precursor
Cleavage at this point canyield two molecules of vitamin A*
Retinoic acid, the acid formRetinal, the aldehyde form
*Sometimes cleavage occurs at other points as well, so that one molecule of beta-carotenemay yield only one molecule of vitamin A. Furthermore, not all beta-carotene is convertedto vitamin A, and absorption of beta-carotene is not as efficient as that of vitamin A. Forthese reasons, 12 g of beta-carotene are equivalent to 1 g of vitamin A. Conversion ofother carotenoids to vitamin A is even less efficient.
Units of vitamin A Vitamin A intakes or requirements are expressed in terms of retinol
activity equivalents (RAE)
Old units = RE or IU (labels or articles)
Conversions can be done as follows:
1g RAE = 1 g retinol
= 2 g -carotene (supplement)
= 12 g (dietary)
= 24 g other vitamin A precursor carotenoids
= 3.3 IU
1 IU retinol = 0.3 g retinol or 0.3 g RAE 1 IU -carotene (supplement) = 0.5 IU retinol or 0.15 g RAE 1 IU -carotene (dietary) = 0.165 IU retinol or 0.05 g RAE 1 IU other vitamin A precursor carotenoids = 0.025g RAE
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Nomenclature
Retinol (parent compound) also from Retinyl ester-compounds (retinol + fattyacid)(animal)
Retinal (aldehyde form) also from Beta-carotene (plants) & retinol
Retinoic acid (acid form) also from Retinal and retinol
11-cis retinal (form active in vision)
13-cis retinoic acid (used therapeutically)
Retinyl palmitate (major storage form)
-carotene (major provitamin A)10/1/2015
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Conversion of Vitamin A Compounds
IN FOODS:
Notice that the conversion from retinol to retinal is reversible,whereas the pathway from retinal to retinoic acid is not.
IN THE BODY:
Betacarotene(in plant foods)
Retinyl esters(in animalfoods)
Retinoic acid(regulatesgrowth)
Retinal(participatesin vision)
Retinol(supportsreproduction)
Absorption, transport & storage:general
Dietary retinyl esters are hydrolysed by
intestinal lipases (70-90% absorbed) leaving
retinol in its free form
Free retinol uptake into enterocytes (wall of
small intestine) by facilitated diffusion from lipid
micelles
Attach to free fatty acids to form new retinyl
ester-compounds (re-esterification)
Compounds packaged into chylomicrons and
enter lymphatic system
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Absorption, transport & storage:specific
Preformed Vit A (animal foods) occur as retinylesters in association with membrane-bound cellular lipid and fat storage cells.
Pro-vitamin A (plant sources carotenoids)embedded in complex cellular structures ie in the matrix of chloroplasts or in the pigments of chromoplasts.
Digestive processes free vit A & carotenoids from their food matrices (more efficiently from animal products / retinol)
Dietary retinyl esters & retinol & carotenoids incorporated into micelles in small intest.
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Absorption, transport & storage:specific
Pass into the membrane of the enterocytes (intestinal mucosal cells).
Retinol is trapped intracellularly by re-esterification or binding to specific intracellular binding proteins.
Retinyl esters incorporated into chylomicrons and excreted into lymphatic channels and delivered to the blood.
Released: into circulation in chylomicrons when needed (function)
into liver to be stored
Storage: 90% of vit A absorbed stored in liver (as retinyl palmitate) (100-
1000 IU/g in liver tissue, total = 500 000 IU )
Remainder stored in adipose tissue, kidneys, lungs10/1/2015
Absorption, transport & storage:specific
Carotene is absorbed dissolved in lipid micelles (5-
60%)
-carotene is cleaved by carotene dioxygenase to retinal reduced to retinol in the intestinal cells esterified and secreted in chylomicrons with retinyl
esters from retinol
But -carotene does not 2 x retinol Activity of intestinal carotene dioxygenase is low
Other carotenoids inhibit carotene dioxygenase
Asymmetrical cleavage also occurs
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Storage and transport Vitamin A from chylomicron remnants is taken up by
cells of the liver, where it is stored as retinyl esters
Retinyl esters are stripped from chylomicrons, hydrolysed and taken up by liver cells
If not required retinol is re-esterified and stored in liver cells (stellate cells )
When released to circulation for functioning, the esters are re-hydrolysed to retinol, which is bound to retinol binding protein (RBP).
Vitamin E enhances absorption and storage
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Storage and transport
Apo-RBP + retinol holo-RBP
This complex holo-RBP secreted into blood, associates with a larger protein (pre-albumin / transthyretin) which circulates in the blood delivering retinol to tissues
Holo-RBP transiently associates with target-tissue membrane and specific intracellular binding proteins extract the retinol Required due to fat-solubility cannot dissolve in blood
require proteins to bind with and transport them to storage sites or target tissues and cells (RBPs)
Zn is also required to mobilise vit A from its stores
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Retinoid binding proteins
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Abbrev. Name Binds LocationRBP Retinol binding
proteinRetinol Plasma
CRBP Cellular retinol binding protein
Retinol/ retinal
I CellsII Intestine
CRALBP Cellular retinal binding protein
Retinal Eye
CRABP Cellular retinoic acid binding protein
Retinoic acid
Cells
IRBP Interstitial binding protein
Retinol/ retinal
Interphoto-receptor space
Recycling of vitamin A
Vitamin A is recycled between tissues and reserves
at quite a high rate, but is usually well conserved.
Movement of holo-RBP into urine as blood flows
through the kidney is usually small, but may
increase during severe infection, so that dietary
need for vitamin A increases.
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FUNCTIONS OF VITAMIN A
1. Vision
2. Cell differentiation (embryogenesis)
3. Reproduction & growth (spermatogenesis;
bone growth)
4. Acts as an antioxidant
5. Immune response
6. Other functions (taste, hearing, appetite)
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major
Vitamin As Role in Vision
Helps to maintain the cornea
Conversion of light energy into nerve impulses at the retina
Retinal + opsin (prot.) rhodopsin (visual purple) rods of retina (b & w images)
Light on rods bleached
Rhodopsin opsin + retinal nerve impulse optical nerve (brain) vision retinal (cis to trans) retinol
Cycle repeats! end of each cycle a little vit A is lost needs replenishment
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Bleaching & replenishing process
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As light enters the eye,pigments within the cellsof the retina absorb thelight.
Lightenergy
As rhodopsin absorbs light, retinal changes fromcis to trans, which triggers a nerve impulse thatcarries visual information to the brain.
Cornea
Eye Nerve impulsesto the brain
Retinacells(rods andcones)
cis-Retinal trans-Retinal
The cells of the retina contain rhodopsin, amolecule composed of opsin (a protein) andcis-retinal (vitamin A).
Vitamin As Role in Vision
Vitamin As Role in Vision
[Blood retinol] regulates tempo of rhodopsin regeneration If slow poor vision - dim light
Dark adaptation = adapt to dim light after light flash exposure
If long time night blind
Cones colour perception of vision (interprets wavelengths) Contains less vit A (pigment = iodopsin)
0.01% of total
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Cellular differentiation
Retinoic acid binds to retinoic acid receptors sites on a cells DNA (RAR & RXR) and forms transcription factors that bind to DNA and regulate gene expression and the type of cell the stem cells become
This in turn regulates processes such as cellular differentiation and embryonic development (healthy organs & effectively functioning systems)
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Cellular differentiation
Example epithelial cells of the skin (outer lining) and mucus producing cells (inner lining) of the skin Keratinisation of epithelial cells dry out hardening
due to keratin deposition (skin, eye, GIT lining, respiratory cells)
Cilia on normal cells prevent accumulation of infectious agents
ANTI-INFECTIVE VITAMIN (keratinisation + cilia loss infections)
constant peeling constant vit A need (tissues, skin, trachea, salivary glands, cornea, testes
cornea keratinisation ulceration destruction blindness
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10/1/2015 Fig. 11-4, p. 372
Vitamin A maintains healthy cells in the mucous membranes.
Without vitamin A, the normal structure and function of the cells in the mucous membranes are impaired.
Mucus Goblet cells
Stepped Art
Protein synthesis & Cell differentiation
Reproduction and growth
Sperm development in men Foetus development in women Growth in children
First symptom = poor appetite growth failure
(plato) weight loss death
Vit A critical for normal bone growth, deficiency poor quality, thicker bone
Larger cavities in skull & spinal column not for CNS growth
Specific role immature bone cells osteoclasts
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Reproduction and growth
Normal foetal development
Both vitamin A excess and deficiency are known to
cause birth defects.
During fetal development, RA functions in limb
development and formation of the heart, eyes, and
ears.
Additionally, RA has been found to regulate
expression of the gene for growth hormone.
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Immune function
Deficiency in animals and humans: rates of infection.
Both specific and non-specific defence mechanisms are impaired: humoral responses to bacterial, parasitic and viral
infection, cell- mediated immunity, natural killer cell activity and
phagocytosis.
The T-helper cell is a major site of vitamin A activity, and the active form appears to be 14-hydroxy-retroretinol (HRR).
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Immune function - Infection
Retinoids play an important role in immunity
Even mild vitamin A deficiency leads to a higher risk of serious infection and even death from diseases like measles and diarrhoea.
However the immunity enhancing effects of vitamin A vary with the type of infection, and vitamin A decreases the severity but not the incidence of the disease.
HIV infected adults have a significantly higher mortality rate if they have low serum vit A levels
Women with low vit A status and HIV are also more likely to pass on the virus to their children
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Vitamin A Deficiency
Preschool children developing countries (20-40M) Often vit A intakes OK, but low fat intakes (
Vitamin A Deficiency
Visual Manifestations Night blindness (too little vit A to replace rhodopsin)
Kornea (outer transparant layer) affected early
Tear gland does not form any tears drying out keratinization peeling non-transparant cornea infections & eye bleeds
XEROPHTHALMIA (stages)1. Bitots spots - in conjunctiva [light degree] (corneal
ulceration)
2. Xerosis conjunctiva conjunctiva dry + rough [moderate degree]
3. Keratomalasia irreversable scars in cornea blindness [serious degree]
Xerophthalmia (dry eyes, mucus, scratches, infection and blindness) 10/1/2015
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Vitamin A deficiency- Night Blindness
In dim light, you can make out thedetails in this room. You are usingyour rods for vision.
A flash of bright light momentarily blindsyou as the pigment in the rods is bleached.
With inadequate vitamin A, you do notrecover but remain blinded for manyseconds.
You quickly recover and can seethe details again in a few seconds.
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Hypovitaminosis - Vitamin A
In the eye:
Xerosis (drying)
Keratomalacia (softening)
Xeropthhalmia (thickening, irreversible blindness)
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Bitots spots in children and other
eye signs (corneal ulceration)
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Xerophthalmia
Blindness
Xerosis is the first stage where the cornea
becomes dry and hard.
Keratomalacia is the softening of the cornea.
Xerophthalmia is blindness due to Vitamin A
deficiency.
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Corneal degeneration / scarring
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2010
retinopathy of prematurity (ROP)
Vitamin A Deficiency
Total blindness children (
Vitamin A Deficiency
Non-visual manifestations
Epithelial changes (e.g. follicular hyperkeratosis or
folliculosis)
Skin dry, flaky, scales peeling
Scales block sweat glands chicken skin on arms and
legs
Infection (respiratory / diarrhoea)
Anaemia
Morbidity & mortality
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Vitamin ADeficiency SymptomThe Rough Skin of Keratinization
In vitamin A deficiency, the epithelial cells secrete the proteinkeratin in a process known as keratinization.
Skin lesions
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Risk for deficiency
Breast-fed infants; Lactating women
Preschoolers with poor vegetable intake
Urban poor, Elderly, Alcoholics
People with febrile diseases or liver disease
Protein-energy malnutrition
Low fat intake
Individuals with fat malabsorption
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Vitamin A toxicity
Concept of optimum intake
Toxic only by supplements & drugs, not food
Vit A is toxic but not carotene (hypercarotenosis)
Acute effects: N&V, headache, vertigo, blurred
vision, in-coordination, malaise . anorexia, skin
exfoliation
Chronic effects: headache, alopecia, dry itchy skin,
hepatomegaly, bone and joint pain
Teratogenic effects: fetal resorption, abortion, birth
defects (hydrocephaly), learning disability
Vitamin A toxicity
High carotene intakes = not toxic
Stored in subcutaneous fat yellow colour hand palms + soles of feet
Not harmful only poor appearance
Carotenodermia
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Dietary sources
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Pre-formed vitamin A (~ 50% intake):Animal sources, e.g. liver, dairy products, milk, cheese, butter, ice cream, eggs, fish oils (e.g. cod, halibut, shark).
Pro-vitamin A carotenoids:Carrots, squash, pumpkin, green vegetables, corn, tomatoes, oranges etc.(Note that not all orange/red colours are due to provitamin A compounds.)
Dietary sources
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10/1/2015Copyright 2005 Wadsworth Group, a division of Thomson Learning
Requirements
Estimated Average Requirement A daily nutrient level estimated to meet the requirements of half the
healthy individuals in a particular life stage and gender group.
RDI Recommended Dietary Intake The average daily dietary intake level that is sufficient to meet the nutrient
requirements of nearly all (9798 %) healthy individuals in a particular life stage and gender group.
AI Adequate Intake (used when an RDI cannot be determined) The average daily nutrient intake level based on observed or
experimentally-determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate.
UL Upper Level of Intake The highest average daily nutrient intake level likely to pose no adverse
health effects to almost all individuals in the general population. As intake increases above the UL, the potential risk of adverse effects increases.
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Vitamin A: requirements
Multivitamin supplements usually provide:
750 g RAE / 2500 IU
1500 g RAE / 5000 IU
Infants
RDA
06 months 400 g RAE/d
7-12 months 500 g RAE/d
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Upper level
0-12 months 600
g RAE/d
Vitamin A: requirements
Children & adolescents
RDA
13 yr 300 g RAE/day
48 yr 400 RAE/day
Boys
913 yr 600 RAE/day
1418 yr 900 RAE/day
Girls
913 yr 600 RAE/day
1418 yr 700 RAE/day
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Upper levels 13 yr 600 RAE/day
48 yr 900 RAE/day
913 yr 1 700 RAE/day
1418 yr 2 800 RAE/day
Vitamin A: requirements
Adults
RDA Vitamin A as RAE
Men 900 RAE/day
Women 700 RAE/day
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Upper levels
Adults 19+ yr
Men 3000 RAE/day
Women 3,000 g/day
Pregnancy & Lactation
1418 yr 2,800 g/day
1950 yr 3,000 g/day
Nutrient interactions - zinc
Zinc deficiency results in decreased synthesis of
retinol binding protein (RBP).
Zinc deficiency results in decreased activity of
the enzyme that releases retinol from its storage
form, retinyl palmitate, in the liver.
Zinc is required for the enzyme that converts
retinol into retinal.
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Nutrient interactions - iron
Red blood cells, like all blood cells, are derived from
precursor cells called stem cells.
These stem cells are dependent on retinoids for
normal differentiation into red blood cells.
Additionally, vitamin A appears to facilitate the
mobilization of iron from storage sites to the
developing red blood cell for incorporation into
haemoglobin, the oxygen carrier in red blood cells.
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