Vitamin A Flashcards
3 forms of Vit A in the body
retinol
retinal
retinoic acid
what is preformed vit A
animal origin foods
retinol, found as retinyl ester
4 forms of vit A
- Retinol
- Retinal
- Retinoic acid
- Retinyl ester
Provitamin A =
carotenes in plant-based foods (about 10% of carotenes are provitamin A)
basic chemical structure of All-trans retinol:
- alcohol at carbon 15
- OH site of ester bond retinyl palmitate
basic chemical structure of retinal:
- Aldehyde (CHO) at carbon 15
basic chemical structure of retinoic acid
carboxylic acid (COOH) carbon 15
basic chemical structure of retinyl ester
usually palmitate, liver stores
basic chemical structure of beta-carotene
- Provitamin A with greater ability to make retinol
- Split at carbon 15 = 2 retinals = 2 retinols
- Hydration
basic chemical structure of alpha-carotene
1 retinol
basic chemical structure of cryptoxanthin
- Provitamin A carotene
- = 1 retinol
carotenoids that ARE NOT provitamin A
- Lycopene, canthaxanthin, lutein
- No retinol
during digestion what is retinol bound to
retinyl esters bound to fatty acids
during digestion what are carotenoids bound to
bound to proteins
what is the role of the stomach during digestion of Vitamin A
pepsin hydrolyzes carotenoids and retinyl esters
- formation of fat globules
what is the role of the duodenum during digestion
- Bile emulsifies fat globules into smaller droplets
- Pancreatic enzymes hydrolyze remaining esters
what’s a mixed micelle
- Formation from bile, lipids, retinol, and carotenoids
- Diffusion through lumen
general Vitamin A absorption process
passive diffusion and facilitated
receptors involved in Vit A absorption
- Role of SR-B1 receptors: absorb carotenoids in small intestine
o Deficiency: SR-B1 increases (upregulated)
o Normal: Decrease (downregulated)
regulation of Vitamin A absorption
ISX transcription factor depending on A levels in tissue
o inhibits enzyme that converts beta-carotene into retinol
Conversion of vitamin A inside the cell step 1.
- Provitamin A carotenes to retinal = retinol
- Some retinoic acid formed
- Not all provitamin A carotenes converted in GI, can be converted later in other tissues
- Conversion factor for beta-carotene is overall in body not just GI
o Beta-carotene conversion efficiency is 50%
o Alpha-carotene conversion efficiency is 25%
- Remaining carotenes are added to chylomicron
Conversion of Vit A inside cell step 2.
- Retinol to retinyl ester
- Preformed retinol is absorbed
- Other source of retinol from carotene conversion
- Both these are re-esterified and palmitate is preferred fatty acid
- Retinyl ester is added to growing chylomicron
What does CRBP 2 do
cellular retinol binding protein
-stabilize and protect retinol and retinal in cell
-prevent degradation and other interactions
1 RAE = mcg retinol
1 mcg retinol
During absorption of Vit A, what happens after retinol leaves enterocyte
leave cell, lymph, blood, liver
exception: retinoic acid enters blood bc more water soluble
1 RAE = mcg beta-carotene from FOOD
12mcg beta-carotene
1 RAE = mcg other provitamin carotenes
24mch other provitamin carotenes
1 RAE = mcg beta-carotene from SUPPLEMENTS
2mcg beta-carotene
why do beta-carotene RAE differ from supplements and foods
- Higher bioavailability and efficiency
- In body, only 50% of beta-carotene is converted to retinol
- Why body needs double the supplements to make same amount of retinol
Carotenes in food are poorly absorbed, plant cell walls (why it takes 6 times more food beta-carotene to make 1 RAE than supplemented beta-carotene)
4 Major steps of Vit A metabolism (Step 1)
- Retinyl esters are taken up into liver cells via chylomicron and the retinol and fatty acids are released by retinyl ester hydrolase
4 Major steps of Vit A metabolism (Step 2)
retinyl esters are stored in hepatic stellate cells (liver cells) with lipids until needed
4 Major steps of Vit A metabolism (Step 3)
CRBP-retinol can be:
1. converted to CRBP-retinal, then converted to retinoic acid or;
2. it can be attached to retinol-binding protein for release into blood or;
3. it can be conjugated with glucuronic acid to form retinyl beta-glucuronide for excretion in bile
4 Major steps of Vit A metabolism (Step 4)
retinol attached to retinol-binding protein in liver. Holo-retinol-RBP then release into blood, binds transthyretin and thyroxine to form trimolecular complex
transport of retinol to tissues
- After a meal, Vit A appears in portal blood as retinyl ester in chylomicron -> liver
o Stored as retinyl ester in liver
o Release from storage as retinol or -> retinoic acid
o Liver: also put retinol or retinoic acid in bile - Exit liver only if there is RPB to bind retinol
o Need zinc and amino acids to make and release RBP (apo-RBP = nothing binded/free) Apo-RBP + retinol = holo-RBP - Retinol exits cell as holo-RBP
- Loosely binds TTR in plasma -> transport in blood to tissues
food sources of Vitamin A
liver
fatty fish (herring, sardines, salmon, tuna)
fortified margarin + milk
cheese
food sources of beta-carotene
spinach, carrots, collards, kale, squash, cantaloupe
what form of Vitamin A functions in vision
retinol/retinal
what form of Vitamin A functions in cell differentiation
reinol/retinal indirect
retinoic acid binds RXR + RAR
what form of Vitamin A functions in growth and bone health
retinol/retinal and retinoic acid
Rhodopsin/vision cycle
trans-retinol -> trans retinyl esters -> CRALBP-11-cis-retinal -> 11-cis-retinal+opsin = rhodopsin
+light
-> all-trans-retinal (opsin breaks away) -> all-trans-retinol
RAR receptor
retinoid acid receptor
RXR receptor
retinoid X receptor for 9-cis-retinoic acid
cell differentiation process
- all-trans or 9-cis retinoic acid moves to nucleus and binds to binding proteins
- all-trans retinoic acid binds to RAR, 9-cis binds to RXR
- this binding to nuclear receptors and interaction with retinoic acid response element (RARE) on the DNA enhances transcription of selected genes. Absence of bound vit A usually results in repression of gene transcription
- changes mRNA = change protein synthesis
importance of cell differentiation
epithelial cells (skin, GI, respiratory)
explains severe deficiency symptoms (blindness)
inability to resist infection, poor immunity
Function of Vit A in Growth
- Mechanism unclear
- Involved in control of cell growth and embryo development
- Bone development and maintenance
- Retinol is active form of Vitamin A for bone formation (regulates bone cells)
- Excess retinol can damage bone, stimulate osteoclasts (bone formation), inhibits osteoblasts (breakdown for blood stream)
early symptoms of Vit A deficiency
- Night blindness (less rhodopsin)
- Hyperkeratosis = obstruction and enlargements of hair follicles (appears the same as vit C deficiency)
- Children most at risk: show poor growth, anorexia, infections, iron deficiency
later/irreversible Vit A deficiency symptoms
- Keratomalacia = eye covered in soft opaque keratin, results in blindness
- Infections (measles), poor growth, death in children
Vit A: initial deficiency vision
- Lack of retinol = less rhodopsin
o “Night blindness” showing poor adaptation to dark
o Measured as how long it takes to see in dark after shining a bright light into the eye
Vit A: later deficiency vision
- Structure of eye is compromised:
o Xerophthalmia
o Bitot’s spots (white spots)
o Keratomalacia
assessment of Vit A status
- plasma retinol below standard = liver stores depleted = “static indicator”
- change in plasma retinol after dose = relative dose response (RDR), over 20% means liver stores are low
- functional impairment: dark adaptation: time to recover from light shone in eyes -> assesses stores in eye = liver stores
EAR is set to maintain ?
adequate liver stores
Factor A
EAR factorial summation (losses + minimum stores)
Loss of vit A per day (determined on a vitamin A free diet = 0.5% of body weight = turnover rate
Factor B
EAR factorial summation (losses + minimum stores)
minimum acceptable reserve of vitamin A = 20mcg/g in liver
Factor C
EAR factorial summation (losses + minimum stores)
liver:body weight ratio = 1.33 = 0.33
Factor D
EAR factorial summation (losses + minimum stores)
reference weight (adult men = 76kg, adult women = 61kg)
Factor E
EAR factorial summation (losses + minimum stores)
E: Ration of body:liver reserves of Vit A = 10:9 = 1.1
Factor F:
EAR factorial summation (losses + minimum stores)
Efficiency of storage of ingested Vit A = 40% 2.5 more
Vit A EAR men
625mcg RAE/day
Vit A EAR women
500mcg RAE/day
Vit A SD of EAR
20%
Vit A RDA men
900mcg RAE
Vit A RDA women
700mcg RAE
Vitamin A deficiency as a world issue
- children at greater risk of dying from childhood diseases (measles)
- 350 000 children go blind each year
- 3 million children die from diseases that are preventable with one capsule of Vit A twice a year $1/dose
Vit A secondary deficiency causes
Fat malabsorption: A and E affected most out of fat-soluble Vits
Protein deficiency: needed to make RBP
Zinc deficiency: needed to make RBP in liver
Measles and other infectious diseases
Vit A toxicity acute
hypervitaminosis A
- polar bear liver = dead
- 100 000 RAE all at once
Vit A Chronic toxicity (levels + symptoms)
3 000mcg retinol daily over time
- dry skin, alopecia, bone pain, liver damage
level for women - teratogenic effects –> birth defects
- accutane = 13-cis-retinoic acid
NOAEL
no observable adverse effects level
- at this level or lower, no effect of chronic intake
LOAEL
lowest observable effects level
- effect is seen at this level or higher
UF
uncertainty factor
- lowers LOAEL to NOAEL
- accounts for gaps and variability in individuals (metab)
- protects public health
how do LOAEL and NOAEL help set UL
“safe range” RDA to UL
then NOAEL then LOAEL
ensures UL is below harm/toxic levels
UL Vitamin A
3 000mcg retinol
IU to RAE retinol
10 000IU retinol / 3.33 = 3 000mcg RAE = UL
IU to RAE beta-carotene
20 000IU beta-carotene / 3.33= mcg beta-carotene, THEN / 2 = 3 000mcg RAE
*no UL
carotene and lycopene chemical properties and colour
hydrocarbon
yellow and orange F&V
non oxygenated
lutein and zeaxanthin chem properties and colour
oxygenated
dark leafy green V (spinach and kale)
eye health and AMD
provitamin A: alpha, beta, gamma- carotenes and cryptoxanthin
convert retinol in body
immune, vision, skin
examples of sources of beta-carotene
carrots, peaches, apricots, mango, papya, sweet potatoes, spinach, collars, pumpkin, cantaloupe, broccoli
examples of sources of alpha-carotene
pumpkin, carrots
example of sources of beta-cryptoxanthin
citrus
examples of sources of lutein/zeaxanthin
kale, collards, spinach, swiss chard, mustard greens, red peppers, okra, romaine lettuce, corn
examples of sources of lycopene
tomato, watermelon, pink grapefruit, guava, red peppers
carotenoderma
yellowing of skin with increased consumption of carrots, not toxic
role of carotenoid in single oxygen quench reactions
light and or chems convert normal oxygen to reactive singlet oxygen
electron excited to higher energy
UV + O2 = 1O2
carotenoid + 1O2 = O2 + carotenoid + heat
studies on carotenoids and CV disease
- Decrease LDL oxidation, decrease plaque formation
- Studies unclear on decreased CVD risk
o No positive evidence in intervention studies
o Cohort studies show protective effect in some populations - Whole food diet interactions are best for disease prevention!!
studies on carotenoids and cancer
- Some models show benefits in cancer initiation, progression, and proliferation
o Cell culture, epidemiology, blood levels = decreased risk - Possible protectors for DNA damage
- Source of vitamin A inhibits proliferation and induces differentiation
- BUT, intervention trials mostly negative results (patients with previous cancer)
- Food is more than single nutrients!!
studies on carotenoids, cancer, and smokers or asbestos exposure
- Possible negative effect in smokers and asbestos workers:
o Studies showed increased lung cancer with beta-carotene supplementation
o However, only with high dose beta-carotene supplementation (not physiological levels or dietary intake)
o Because vitamin A stimulates cell differentiation and cell growth, it may have encourage the cancer cell growth
studies on lycopene and prostate cancer
o Some positive evidence
Decrease risk with high tomato/lycopene consumption
Increase blood lycopene = decrease risk
Intervention studies (lycopene or tomatoes) -> decrease prostate cancer growth
AMD + carotenoids role
Age-Related Macular Degeneration:
- Progressive retinal disease, no cure or treatment
- 20% of age over 65 years have clinical evidence
- Lutein and zeaxanthin in macula lutea of retina (other carotenoids not present in this area of retina)
- Lutein and zeaxanthin may help prevent AMD by:
o Acting as optical filters to prevent photochemical damage
o Antioxidant
- Supported by epidemiology and some intervention trials
carotenoids and skin protection
- UV-irradiation -> photooxidative damage (-> erythema, skin aging, photodermatoses (rash), skin cancer)
- Carotenoids lost from sun in UV exposure (especially lycopene)
- Several intervention studies show protection against UV induced erythema
o Carotenoid supplements
o Tomato paste (rich in lycopene)
