151232 Vit a 2015 Full Slides

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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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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


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).



[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 (


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)


Total blindness children (


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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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


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


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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Documents

151232 Vit a 2015 Full Slides