Transcript Chapter 9 The Fat Soluble Vitamins

Chapter 9
The Fat Soluble Vitamins
“If a little is good, then more must be better”
→Χ
*$17 billion/yr in mineral & vit. Supplements
in the USA
*↑↑↑Vit. → Extra energy, protection from DZ.,
& prolonged youth?
*Plants syn. all the vit. they need.
*Animals vary in their ability to syn. vit.
I. Vitamins: Vital Dietary Components
*Definition: Essential organic substances
needed in small amounts in the diet
for normal function, growth &
maintenance of body tissues.
*Vitamins→ no energy, but some can
facilitate energy-yielding chemical
reactions.
*Fat-soluble vit.: A, D, E, K
*Water-soluble vit.: B vitamins & C
*Indispensable in human diets, Exception:
Vit. D, Niacin, Vit. K & biotin.
*Substance to be classified as a Vitamin:
1. The body is unable to synthesize enough
of the compound to maintain health.
2. absence →deficient signs & symptoms,
quickly cured when the substance is resupplied.
*As pharmacological agents(1) Megadose of niacin → ↓blood Chol.
(selected individuals)
(2) Vitamin D analogs→ psoriasis
*Isolated from food or synthetic → vitamins
same chemical compounds & work equally
well in the body.
Exceptions:
1.Vit. E, Folate.
2. Some vit. exist in several related forms
that differ in chemical or physical properties.
A. Historical perspective on the vitamin
1. Treated night blindness with topical
applications of liver extracts.
2. Scurvy was common among sailors
3. Identification of various vitamins →
related deficiencies were dramatically
cured
4. Vitamins were named alphabetically: A,
B, C, D………..
5. It took some time to uncover the true
nature of the various vitamins.
6. We can be relatively confident that
the vitamins needed by humans have
been discovered. Ex.TPN (iv)
B. Storage of Vitamins in the Body
1. The fat-soluble vitamins are not
readily excreted from the body.
(Exception: Vit. K)
2. The water-soluble vitamins are
generally lost from the body quite
rapidly. (Exceptions: Vit. B6 &12)
C. Vitamin Toxicity
1. Some fat-soluble vitamins can easily
accumulate in the body and cause toxic
effects. (Ex. Toxicities of vitamin A & D are
the most frequently observed.)
2. Megadose of water-soluble vitamins
are also toxic
D. Malabsorption of Vitamins
- If absorption of a vitamin is defective, a
person must consume larger amounts
of it or likely to develop def.
- Fat malabsorption is associated
with malabsorption of the fat- soluble
vitamins
- Alcohol abuse & GI diseases/B vitamins
E. Preservation of Vitamins in Foods
*Improper storage and excessive cooking
→↓Vit. B-1, Vit. C
*Heat, light, exposure to the air, cooking
in water, and alkalinity are all factors that
can destroy vitamins.
*If the food is not eaten within a few days,
freezing is the best way to retain
nutrients
II. Fat-Soluble Vitamins
A. Absorption of the Fat-soluble Vitamins
1. Fat-soluble vitamins → lipid like mol.
∴absorbed along with dietary fat, and
depends on fat digestion (bile salts & lipase)
~ 40-90 % vitamin ingested (in a typical
amounts) are absorbed. (Fig 9-1)
2. Absorption efficiency ↓with intake ↑
B. Distribution of the Fat-soluble Vitamins
Fat abs.→chylomicron →TG
↘remnant.
fat-sol. Vitamins →
liver→→ →→ →→ →→cells & tissues
blood lipoprot.
- DZs. or medications (Ex. orlistat ) ↓fat
absorption → ↓fat-soluble vitamin
absorption
III. Vitamin A
1. Vitamin A def. constitutes one of the major
public health problems in developing
countries.
2. Vitamin A def. is the leading cause of nonaccidental blindness. (worldwide)
*Children in Africa, Asia and South America
3. Vit. A structure: Ring + F.A. tail (p.301)
4. Preformed Vit. A: Retinoids: retinal (CHO),
retinol (- CH2OH) and retinoic acid (- COOH),
cis or trans form (p.300)
5. Provitamin A: Carotinoids –, Ex.: βcarotene, α-carotene, lutein, lycopene,
zeaxanthin, β-cryptoxanthin
(converted to retinol or retinal)
A. Absorption, transport and metabolism
1. Absorption of preformed vit. A or
provitamin A varies from 90% - 3%.
depending on the amount of fat.
Vitamin A in foods
(1) Animal foods - retinol or retinyl ester
(retinol + F.A.)
(2) Plant foods – carotenoids
Fig 9-1 Digestion and absorption of vitamins
- retinyl ester (thru bile and lipase) → retinol
+ F.A., 90% retinol then absorbed. Form
new retinyl ester in the intestinal cells.
- Carotenoids are absorbed intact →
enzymatically split to retinal in intestinal
cell → retinol → retinyl ester
- or, absorbed intact carotenoids→ blood
stream.
2. Storage and Transport of Vitamin A
(1) Storage:
a. Retinoids: Liver
Cartenoids: Liver & adipose tissue
liver contains >90 % Vit. A of body
b. Adequate for several months
(2) Transport: liver to target cells
a. Retinoids: Retinol-binding protein
b. Provitamin (carotenoids): VLDL
(3) Excretion: only some is lost in the urine.
B. Cellular Retinoid-Binding Proteins (CRBP)
- CRBP take up retinoids and hold
retinoids and direct them to functional
sites within the cell. (transport)
- CRBP protect the vitamin from oxidation
and enzymatic reactions
C. Retinoid Receptors in the Nucleus
- within cell nucleus: RAR and RXR
- retinoid/RAR or RXR complex bind to
DNA to regulate the activity of retinoidresponsive genes on DNA
regulate gene expression → formation
mRNA → protein synthesis (Fig. 9-3)
C. Functions of Vitamin A
1. Vision
a. Fig. 9-4 vision cycle
Retina:
(1) Cones – bright light, color images
(2) Rods – dim light, black-white images
b. Various cell types in the retina, cornea,
and epithelium of the eye depend on the
presence of retinoic acid for maintaining
structural integrity.
2. Growth and Differentiation of Cells
- all-trans retinoic acid and 9-cis-retionic
acid → activate RAR and RXR →code for
a variety of structural proteins (Fig. 9-2)
- Retinoic acid is also necessary for the
production, the structure, and the normal
function of epithelial cells. R.A. is also
essential in the formation and
maintenance of mucus-forming cells.
- Retinoic Acid – used for wrinkle
3. Immunity
- Vit. A def. →vulnerable to infections
- Specific immunity: cell-mediated and
antibody-mediated response, such as
macrophage and natural killer cell activity
and growth and differentiation of Blymphocytes
- Non-Specific immunity: insufficient mucus
production in the eyes, intestinal tract, and
lungs, deterioration of many types of cells.
D. Vitamin A Analogs for Acne
*Tretinoin (Retin-A): Analog form
of vitamin A, acne medication,
topical treatment, ↓sebum
secretion.
*Accutane (13-cis retinoic acid)acne medication, oral
*Acintretin – treat severe psosiasis
*** fetal malformations (use during
Prg.
E. Possible Carotenoid functions
1. Heart Disease Prevention
*Carotenoids: antioxidants
*Recommendation: at least 5 servings fruits
and veg./day
2. Cancer Prevention
- ↓ various cancers in animal studies, but not
shown in human study.
- Retinoids influence cell differentiation,
inhibition cell proliferation & ↑apoptosis
3. Lycopene protects against prostate cancer
(antioxidant )
4. Age-related macular degeneration (Fig. 9-5):
macular contains lutein and zeaxanthin
(carotenoids) (↑er carotenoids in the diets ↓ er
incidence of macular degeneration)
*Megadose vitamin A supplements to ↓cancer
risk is currently not advised (∵toxicity)
F. Vitamin A in Foods (p.305)
- Preformed vit. A: liver, fish oils, fortified milk,
and eggs
- Provitamin A: carotenoids in dark green &
yellow-orange vegetables & some fruit
1. *Retinol Activity Equivalent (RAE)
1 RAE
= 1μg all-trans retinol
= 12μg all-trans β-carotene
= 24μg other carotenoids
Table 9-1 (p.306)
2. Calculating Retinol activity equivalents
1 RE (or 3.3 IU) = 1RAE
Waiting for all the food tables to be updated
G. Vitamin A Needs
•
•
•
•
•
•
*RDA for Vitamin A
Adult: ♂: 900 RAE
♀: 700 RAE
- Actual intake: meet RDAs
- Liver reserves of vitamin A are
3 – 5X >needed for good health
H. Vitamin A Deficiency Diseases
- Preschool children who do not eat
enough veg.
- Urban poor, the elderly, people w/ alcoholism
or liver disease, children and adult w/ severe
fat malabsorption syndromes, cystic
fibrosis, AIDS etc.
*Night Blindness
*Conjunctival xerosis: abnormal dryness
of the conjunctiva of the eye
*Bitot’s spot: dry out of the eye and
appearance of hardened epithelial cells
*Xerophthalmia: → blindness
*Follicular hyperkeratosis: keratin
accumulates around hair follicles
Fig 9-6
I. Upper Level for Vitamin A
* Vitamin A Toxicity
“ Hypervitaminosis A”: long-term
supplement 2 – 4X RDA
Fig 9-7
UL: 3000 μg
- 3 kinds of Vitamin A toxicity:
a. Acute – GI upset, headache,
blurred vision, muscular
in-coordination, death
b. Chronic – wide range of signs
and symptoms
• c. Teratogenic – birth defect
• * animal study: Accutane causes
spontaneous abortion and birth
defects
• * Pregnant women taking Accutane:
offspring show congenital
malformations of the head.
*Consuming huge amount of
carotenoids – relatively non-toxic,
∵conversion and absorption
*Hypercarotenemia: yellow orange
color skin (appears to have
jaundice, but sclerae are white
and liver is not enlarged)
*Lycopenodermia: excessive
intake of foods rich in lycopene,
A deep orange discoloration.
*Expert Opinion
Carotinoids and Human Health: Beyond
Conversion to Vitamin A
a. Antioxidants:
In vitro: trap free radicals
In vivo: unknow
b. Carotenoids may decrease the risk of
cataracts and macular degeneration in
the eye, some cancers, some CVD.
Clinical trials?
*Hundreds of studies show that diets
rich in fruits and vegetables are ass.
w/↓ risk of cancer and other chronic
diseases.
*Supplement β-carotene→ X↓lung
cancer or heart DZ.
*Many researchers are now
convinced that β- carotene
supplement offer no protection
against cancer
c. Eyesight
- Age-related macular degeneration is
the leading cause of blindness in
American over 65.
- Study of 876 subjects: ↑carotenoids
(β- carotene, lutein and zeaxanthine)
intake, ↓macular degeneration
d. Pharmacological use of Vitamin A
*Tretinoin (Retin-A):
acne medication, topical treatment,
↓sebum secretion.
*Accutane (13-cis retinoic acid)- acne
medication, oral
*Acintretin – treat severe psosiasis
*** fetal malformations (use during Prg.)
*All trans retinoic acid for leukemia →
side effects
VI. Vitamin D
• *Prohormone – converted to active
form by enzymes in the liver &
kidney
• *Amount of sun exposure needed to
produce vit. D depends on – skin
color, age, time of day, season, and
location
• *Def. – rickets in children
- osteomalacia in adults
A. Vitamin D Formation in the Skin
(p.309)
Cholesterol → 7-dehydrocholesterol
(skin)
(Provitamin D)
UV ↘(290-315 nm)
→→→→→→→→→ →→ cholecalciferol
lumisterol↗
B. Absorption and Formation of Vitamin D
from Food
• - 80% of Vit. D - micelles
• - Absorbed vit. D w/ chylomicron →liver
• - Def. occurred in persons with fat malabsorption syndromes.
c. Metabolism, Transport, storage, and
Excretion of Vitamin D
Fig. 9-8
• - Stored : liver & adipose tissue
(25(OH)cholecalciferol)
Shortage of Ca →↑PTH →↑
1, 25(OH)2cholecalciferol
• - Activated in liver & kidney
Conversion of Provit. to Active Vitamin D
liver
cholecalciferol→→25(OH)cholecalciferol
→→1,25(OH)2 cholecalciferol (Calcitriol)
kidney
• Animal foods – cholecalciferol (D3)
• Plant foods –
liver
ergosterol (D2)→→25(OH) ergocalciferol
→→→1,25(OH)2 ergocalciferol
kidney
d. Functions of Vitamin D
* Regulation of Blood Calcium (Fig 9-9)
Blood Ca↓or Vit. D ↓→↑PTH →Sti. Kidney
to syn. active Vit. D →
1. Vitamin D → Intestine→↑abs. Ca
2. PTH & Vit. D →↑ Bone resorption
3. PTH & Vit. D →↑kidney
reabsorption，↓Ca loss
*Intestinal Calcitriol→Intestinal→
(1)↑Syn. Ca-transport proteins (Cacarrier)
(2) Alters the memb. permeability of
intestinal cells
1,25(OH)2D
• *Stem cell monocytes →→→→→mature
•
osteoclasts
• *Human epidermal cells (nuclear receptors)
for 1,25(OH)2D → effects proliferation and
differentiation of skin cells
*Influence differentiation and function
in cells of the intestine, skin, immune
system, and bones, also cancer cells
(skin, bone and breast cancer cells)
*Rickets and Osteomalacia (Fig 9-10)
Children – rickets, associated with fat
malabsorption (Ex. Cystic fibrosis)
Adults – osteomalacia (soft bone), occur
in people w/ kidney, stomach,
gallbladder, or intestinal disease or
liver cirrhosis
*Treatment – combination of sun
exposure and vit. D supplement
e. Vitamin D in Foods
- Fatty fish (Sardine, salmon),
fortified milk and some fortified
breakfast cereals
f. Vitamin D Needs
• Adequate Intake (AI) for vitamin D
• <51 years old – 5 μg/day (200 IU/day)
• 51-70 years old – 10 μg/day
• > 70 years old - 15μg/day
• Infant born w/ a sufficient supply of vit. D–
last about 9 months
g. Vitamin D deficiency
• a. Elderly people
• b. Anyone stays indoors most of the
day and ingests little or no vit. D.
* Vitamin D Resistance
a. Lack of calcitriol synthesis in the
kidney
b. an inability of calcitriol to bind to
nuclear receptors (VDR) thru body
*Vitamin D supplements
a. Pt’s w/ age-related osteoporosis
treated w/ vit. D & Ca (close medical
supervision is needed)
b. 10μg/day from a multivitamin/ mineral
supplement
h. Pharmacologic Use of Vit. D Analags
Topically treat Psoriasis (a skin
disorder – a failure in differentiation
of keratinocytes) with Vit. D analogs: safe
and effective
I. Upper level for Vit. D
- UL: 50 μg/day
*Vitamin Toxicity
- Intake of 5X AI can be toxic (infant)
Adult: 10X AI for 6 months
(only from excess supplement, not from
sun exposure or milk consumption)
- Symptoms: over absorption of Ca, ↑Ca
deposits in the kidneys, heart, and blood
vessels etc. → cell death
V. VITAMIN E
• Many benefits of vit. E have been claimed,
only some have been supported by
scientific invest.
*Vitamin E supplements >$300 million /year in
the U.S.A.
*Lab. Animal – Vit. E deficiency – muscular
dystrophy, inability to produce viable
offspring, and impotence.
a. Natural and Synthetic Vitamin E
*Chemical name: tocopherol (p:317)
*Vitamin E: 1. tocopherols (α, β,γ,δ)
2. tocotrienols (α, β,γ,δ)
Most active form: d-α-tocopherol
b. Absorption, Transport storage, and
Excretion of Vitamin E
*Absorption
1. Depends on the total abs. Of dietary fat
2. Precise degree of absorption is unknown
* Transport: Chylomicron & other
lipoprotein
*Most conc. in body structures containing
an abundance of F.A. (liver, adipose
tissues and skeletal muscle. cell
membrane (PL))
*Excretion: urine and bile
c. Function of Vitamin E (T. 9-3)
“ Protecting cell membranes from
oxidative destruction”(Fig. 9-11)
1. Stopping Free Radical Chain
Reactions
ROO． + Vit. E-OH → ROOH + Vit. E-O．
* Free Radicals: Highly reactive
molecules containing an unpaired
electron, seeking electrons by
attacking other compounds (cell
membrane, DNA etc.)
*Cell metabolism and immune-system
function→ Free radical (Ex. White
blood cells generate free radicals as
part of their action to stop infection)
*Oxidizing agents: singlet oxygen,
hydrogen peroxide, hydroxyl
radical, superoxide, ozone, nitrooxide etc.
** Free Radicals set off a chain reaction
→ generate thousands of free
radicals→ destruction of cell
membranes
*Vitamin E interrupting free radical
chain reactions→ becomes free
radical itself (not very active one)
→ excreted or recycled
*Smoker: low vitamin E conc. in the
lung
• Numerous enzymes convert reactive
oxidizing agents to less reactive
compounds:
1. Glutathione peroxidase (GPX): A Secontaining enzyme that can destroy
peroxides
2. Superoxide dismutase (SOD):
Enzymes containing Mn, Cu or
Zn that destroy superoxides.
3. Catalase: destroy superoxides.
4. Uric acid and bilirubin: interfere w/
oxidizing processes
5. Certain protein bind metals (Fe, Cu)
preventing the metals from
catalyzing free radical production
(Fig. 9-11)
*Other Roles for Vitamin E
1. Protect the C=C double bonds in
dietary UFA
2. Protect other lipid-soluble nutrients
3. Needed for Fe metabolism in the
cells
4. Maintenance of nervous tissues
and immune function
“ Anti-aging vitamin”: No clear
evidence that supplementation w/
vitamin E and other antioxidants
slows the aging process, but an
inadequate intake likely promotes
this oxidative damage
d. Vitamin E in Food
*Plant oils (Corn, soybean, safflower,
and wheat germ oils), wheat germ,
asparagus, peanuts, and margarine.
(p.320)
*Get from Foods: Balance
*Actual vitamin E content of food
depends on harvesting, processing,
storage, and cooking (highly
susceptible to destruction by
oxygen, metals, light, and deep-fat
frying)
e. Vitamin E Needs
• RDA for Vitamin E
• Women: 15 mg/day
• Men: 15 mg/day
(22 IU of natural form, 33 IU of
synthetic form)
• *The Need for vitamin E varies w/ the
amount of PUFA in the diet.
• Plant oils: high in PUFA, often high
in vitamin E, exception: fish oil
f. Vitamin E Deficiency Diseases
*PUFA in the RBC membrane are
very sensitive to attack by free
radicals→ Vit. E helps prevent
oxidative damage to RBC membrane
1. Preterm infants are particularly
susceptible to hemolysis:
(1) born w/ limited tissue stores of
vitamin E and inefficiently absorb
vitamin E from the intestinal tract
(2) The rapid growth of preterm
infants exhausts what little vit. E
supplies exist.
2. Fat malabsorption ass. W/ cystic
fibrosis or GI dz.
g. Upper Level for Vitamin E
>19 yr. old, UL: 1,000 mg/day of any
form of supplementary αtocopherol
• Large dose of Vitamin E →
inhibiting vitamin K metabolism,
Hemorrhaging.
*Large-scale studies are needed to
study
1. Vit. E requirement
2. Vit. E reduce the risk or prevent a
whole range of chronic diseases.
VI. VITAMIN K
• *Essential for blood clotting
• Phylloquinone (K1): Plants
• Menaquinones (K2): Fish oils ,
meats and bacteria in the human
intestine.
• Absorption and Transport of
Vitamin K
1. Absorption: 40% - 80% of dietary
vitamin K in the small intestine
2. Transport: Chylomicron→ liver
→other lipoproteins→ various
tissues
• *Functions of Vitamin K
(1) Blood clotting (Fig 9-13)
Intrinsic
extrinsic
Preprothrombin
↘ Vit. K ↙
Ca ↘ Vit. K***
↘ ↙Vit. K
Prothrombin →→→→ Thrombin
↙
Fibrinogen →→→ Fibrin
↙
Clotting
CO2↘
A. A.-Glutamic acid-A.A.→→→→
Ca, Vit. K
A. A.-γCarboxyl Glutamic acid-A.A
(2) Adding to glutamic acid found in proteins
present in bone, muscle, and kidneys.
• *Dietary Sources of Vitamin
- Liver, green leafy vegetables,
broccoli, peas, and green beans
- Vit. K is quite resistant to cooking
losses
•
Vitamin k Needs
(1) AI: ♀ 90 μg/day
♂120 μg/day
(2) ↑Vitamin A & E→↓Vitamin K
absorption and ↑bleeding time
• *Deficiency : Antibiotics user and fat
malabsorption.
• *Deficiency can occur in newborns:
• ∵1. GI tract is relative sterile. 2. Vit.
K in human milk is low. ∴Inject
Vitamin K to newborn at birth
• *Toxicity: unlikely, ∵readily excreted.
• *Symptoms: jaundice and hemolytic
anemia in infants
• (Table 9-4)