chapter 9 the fat soluble vitamins. “if a little is good, then more must be better” →Χ *$17...

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 re-supplied.

*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 A1. Vitamin A def. constitutes one of the major

public health problems in developing countries.

2. Vitamin A def. is the leading cause of non-accidental 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.: β- carotene, 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 retinoid-responsive 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 B-lymphocytes

- 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

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

*Bitot’s spot

*Xerophthalmia

*Follicular hyperkeratosis

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 mal-absorption 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 (Ca-

carrier)

(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, nitro-oxide 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 Se-containing 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 α-tocopherol

• 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)