Vitamin A and Carotenoids

Ancient Egyptians recognized that night blindness could be treated by consumption of liver.

In the late 1920’s through the efforts of a Swiss scientist named Karrer and his colleagues, the fat-soluble compound in liver was isolated and termed vitamin A.

Vitamin A is Fat-soluble alcohol, most abundant in fatty fish and especially in fish-liver oils.

It is not found in plants, but many vegetables and fruits contain β-carotene which is readily converted in the body to vitamin A (Provitamin).

CH2OH

Vit.A1: all-trans-Retinol CH3

CH3

CHO

1

2

3

4

5

6

7

8

9

10

11

12

1315

14

all-trans- Retinal

CH3

CH3

CH2OH

1

2

3

4

5

6

7

8

9

10

11

12

1315

14

Vit. A2: All - trans- 3-DehydroRetinol

CH3

CH3

CH3

CH3

H3C

CHO11-cis-Retinal

11

Light cause isomerization of 11-cis to all-trans isomer resulting in activation of the

photoreceptor molecule.

SourcesSources Vitamin AVitamin A11: :

A yellow crystalline compound found in:A yellow crystalline compound found in:

Egg yolks, Milk, and Cod-liver oil. Egg yolks, Milk, and Cod-liver oil.

Vitamin AVitamin A22 : :

A golden yellow oil Found in:A golden yellow oil Found in:

Livers of fresh water fish Livers of fresh water fish (40 % of the biological activity of vitamin A(40 % of the biological activity of vitamin A11).).

CarotenoidsCarotenoids They are known as Provitamin A as they They are known as Provitamin A as they

converted in the body to vitamin A. They converted in the body to vitamin A. They are mostly found in plants.are mostly found in plants.

Plant Carotenoids are found in: Carrots, Apricots, Asparagus, Broccoli, and

Green leafy vegetables.Special strain of rice “Golden Rice are rich in -carotene.

Role of Vit. ARole of Vit. A Vision: Vitamin A is the chromophore of rhodopsin (vertebrate

photoreceptor molecule) used in low light levels. Rhodopsin is a complex of Vit. A and Opsin protein present in the retina.

Epithelial Cells: Vitamin A is essential for the epithelial cells. In Vitamin A

deficiency, mucus-secreting cells are replaced by keratin producing cells, leading to xerosis.

Glycoprotein synthesis: Glycoprotein synthesis requires Vitamin A. In severe

Vitamin A deficiency, lack of glycoproteins may lead to corneal ulcers or liquefaction.

Immune System:Vitamin A is essential to maintain intact epithelial tissues as a physical barrier to infection, maintaining a number of immune cell types. These include the lymphocytes (B-cells, T-cells, and natural killer cells), as well as many myelocytes (neutrophils, macrophages, and myeloid dendritic cells).

Formation of red blood cells: Vitamin A may be needed for normal haematopoiesis; deficiency causes abnormalities in iron metabolism.

Growth:Vitamin A affects the production of human growth hormone (GH).

Recommended Daily Amount (RDA)

900 micrograms/day, or 3,000 IU for a 25-year old male.

1 IU of retinol is equivalent to 0.3 μg.

DeficiencyDeficiency Night blindness: Is one of the first signs of vitamin A

deficiency. Vitamin A deficiency contributes to blindness by making the cornea very dry and damaging the retina and cornea.

Impaired Immunity: Vitamin A deficiency also diminishes the ability to fight infections causing frequent infections (especially respiratory). In countries where children are not immunized, infectious disease like measles have relatively higher fatality rates.

Symptoms of deficiency may include, loss of appetite, hair loss, rashes, dry skin and eyes, poor growth, and fatigue.

UsesUses Treatment of Treatment of Night blindness. Skin Diseases:

Psoriasis acne vulgaris Keratosis pilaris

Cosmetics: vitamin A derivatives are used as so-called antiaging chemicals- vitamin A is absorbed through the skin and increases the rate of skin turnover, and gives a temporary increase in collagen giving a more youthful appearance.

promote development of bones and soft tissues and sperm production.

protects against bladder cancer, lung cancer (aerosol form ).

ProductsProducts

Tretinoin : Retinoic acid: Retin-A: Retinoic acid Isotretinoin: Accutane Etretinate: Tegison

Risk Factors for DeficiencyUnder certain circumstances some individuals may require higher doses of vitamin A as following:

1- Those who consume alcoholic beverages may be more liable to vitamin A deficiency.

2- People taking some medications, including birth control pills, methotrexate, cholestyramine, colestipol, and drugs that act to sequester bile acids.

3- Those who are chronically ill, recovering from surgery or other injuries.

4- Patients undergoing treatments for cancer (radiation and chemotherapy).

5- Other conditions that may impair vitamin A balance including chronic diarrhea, cystic fibrosis, and kidney or liver disease.

6- Diabetics persons are often deficient in vitamin A.

Vitamin A Toxicity

1- High level of carotenoid ( β-carotene) was associated with an increase risk of lung cancer in male smokers. In non-smokers, the opposite effect has been noted.

2- Excess vitamin A during early pregnancy has also been associated with an increase in birth defects (Terratogenic effects). No more than 5,000 IU per day.

3- Tingling and itchy feeling due storage of excessive amounts of vitamin A in fat cells.

Symptoms of Vit. A toxicity include:

Dry lips and skin. Bone and joint pain. Blurred or double vision. Confusion and fatigue.liver and spleen enlargement.Diarrhea, vomiting, headaches. Soft spot on the head in infants.Very high levels of vitamin A may also create deficiencies of vitamins C, E, and K.

Drug Interactions

Vitamin A supplements should not be taken in conjunction with any retinoid medications, due to higher risk of toxicity.

Using of mineral oil impairs absorption of all the fat-soluble vitamins, including A.

Aluminum-containing antacids and cholesterol-lowering drugs (cholestyramine and colestipol) may inhibit absorption vitamin A

Alcohol, barbiturates, caffeine, cortisone, tobacco, and very high levels of vitamin E deplete the body of Vitamin A.

Overuse of alcohol and vitamin A together may increase the possibility of liver damage.

Vitamin C, vitamin E, Zinc, and Selenium optimizes absorption and use of vitamin A and carotenoids.

Iron deficiency anemia is better treated with a combination of iron supplements and vitamin A than with iron alone.

Vitamin D

Vitamin D is a generic description of a group of Vitamin D is a generic description of a group of compounds have equivalent activity.compounds have equivalent activity.

On of the fat soluble vitamins.On of the fat soluble vitamins. Know as Sunshine vitamin as it is formed by Know as Sunshine vitamin as it is formed by

the effect of UV rays during the midday from the effect of UV rays during the midday from sterols.sterols.

Forms of Vitamin DForms of Vitamin D Vitamin D1: Mixture of ergocalciferol with

lumisterol 1:1 Vitamin D2: ergocalciferol or calciferol (made

from ergosterol) Vitamin D3: cholecalciferol (made from

7-dehydrocholesterol) Vitamin D4: 22,23-dihydroergocalciferol

Vitamin D5: sitocalciferol (made from 7-dehydrositosterol)

DD22 D D33Vitamin DVitamin D22 = Ergocalciferol = Ergocalciferol (Deltalin®)(Deltalin®) Vitamin DVitamin D

33 = Cholecalciferol = Cholecalciferol

SourcesSources

Code liver oilCode liver oil TunaTuna SardinesSardines

BiosynthesisBiosynthesis

HO HO

UV Light

HOHO OH

OH

7-dehydrocholesterol pre-vitamin D3

Vitamin D3 (cholecalciferol)

25-hydroxycholecalciferol (calcidiol)formed and stored in the liver

The main biologically active form 1,25-dihydroxycholecalciferol

(calcitriol) formed in the Kidney.

Isomerization

Calcitriol

Role of Vit DVitamin D has the net effect of increasing the serum calcium and phosphate concentrations by:

1- By increasing intestinal calcium and phosphate absorption and reabsorption from the kidney.

2- increasing the effect of parathyroid hormone (PTH) on bone.

Controls parathyroid gland growth and production of the parathyroid hormone.Treatment of rickets and osteomalacia. It is an immunomodulator. Regulation of insulin production. It is required for female reproduction.

Recommended Daily Amount (RDA)

10 10 g Cholecalcifrol = 400 IU.g Cholecalcifrol = 400 IU.

Materno-fetal transfer of vitamin D is mostly in the form of calcidiol (25-OH vitamin D), which readily crosses the placenta. The half-life of calcidiol is approximately three to four weeks. Thus, the serum concentration of vitamin D falls rapidly after birth unless additional sources are available.

Causes of deficiencyCauses of deficiencyVitamin D deficiency can occur as a result of:

Decreased intake or absorption, Reduced sun exposure, Increased hepatic catabolism, Decreased endogenous synthesis (via 25-

hydroxylation in the liver and subsequent 1-hydroxylation in the kidney).

End-organ resistance to vitamin D .

Diseases caused by deficiency Vitamin D deficiency is known to cause several

bone diseases including: Rickets: a childhood disease characterized by failure of

growth and deformity of long bones. Osteoporosis: a condition characterized by fragile bones. Osteomalacia: a bone-thinning disorder in adults that is

characterised by proximal muscle weakness and bone fragility. Osteomalacia can only occur in a mature skeleton.

Vitamin D malnutrition may be linked to chronic diseases such as cancer (breast, ovarian, colon, prostate, lung and skin cancer

), chronic pain, several autoimmune diseases, high blood pressure, depression, and seasonal affective disorder

RicketsRickets RicketsRickets is a softening of the bones in children is a softening of the bones in children

potentially leading to fractures and deformity. Rickets is potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many among the most frequent childhood diseases in many developing countries. The predominant cause is a developing countries. The predominant cause is a vitamin Dvitamin D deficiency, but lack of adequate deficiency, but lack of adequate calciumcalcium in in the diet may also lead to rickets. the diet may also lead to rickets.

OsteoporosisOsteoporosis

OsteoporosisOsteoporosis is a disease in which bones is a disease in which bones become fragile and more likely to break. If not become fragile and more likely to break. If not prevented or if left untreated, osteoporosis can prevented or if left untreated, osteoporosis can progress painlessly until a bone breaks. These progress painlessly until a bone breaks. These broken bones, also known as fractures, occur broken bones, also known as fractures, occur typically in the hip, spine, and wrist typically in the hip, spine, and wrist

OsteomalaciaOsteomalacia

OsteomalaciaOsteomalacia is a softening of the bones, is a softening of the bones, resulting from defective resulting from defective bone mineralizationbone mineralization. It . It may show signs as pain, weakness, and fragility may show signs as pain, weakness, and fragility of the bones. This is caused from the lack of of the bones. This is caused from the lack of Vitamin DVitamin D in adults, or in adults, or RicketsRickets in children in children

Groups at greater risk

Older people (age 50 and over) have a higher risk of developing vitamin D deficiency because: a- The ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 is decreased in older individuals.

b- The kidneys, which help convert calcidiol to its active form, sometimes do not work well.

Newborn infants who are exclusively breastfed require vitamin D supplements. Breast milk does not contain significant levels of the vitamin. Infant formula is generally fortified with vitamin D. so this requirement only applies to breastfed infants.

Those who avoid or are not exposed to summer midday sunshine may also require vitamin D supplements.

Dark-skinned individuals may require extra vitamin

D because melanin acts like a sun-block, prolonging the time required to generate vitamin D.

Obese people have lower levels of the circulating form of vitamin D, probably because it is deposited in body fat compartments and is less bioavailable.

Patients with chronic liver disease or intestinal malabsorption , parathyroid glands removed

General Use of Vitamin D

1- Prevent and treat osteoporosis as a result of calcium depletion. Treatment require taking both calcium and vitamin D. fractures.

2- Osteomalacia and rickets are also effectively prevented and treated through adequate vitamin D supplementation.

3- Vitamin D also has a role in cancer prevention (colon cancer, breast and prostate cancer). The action of Tamoxifen (Chemotherapeutic agent) appears to be improved with small added doses of vitamin D.

4- Treatment of hearing loss resulted from vitamin D deficiency that affect the function of small bones in the ear responsible sound transmition.

5- In combination with phosphate to treat some metabolic diseases as Fanconi syndrome and familial hypophosphatemia.

Fanconi syndrome: is a disorder in which the proximal tubular function of the kidney is impaired, resulting in decreased reabsorption of electrolytes and nutrients back into the bloodstream. Compounds involved include glucose, amino acids, uric acid, phosphate and bicarbonate.

Familial hypophosphatemia: is a rare inherited disorder characterized by impaired transport of phosphate and altered vitamin-D metabolism in the kidneys. In addition, calcium and phosphate are not absorbed properly in the intestines, which can lead to softening of bones.

6- A topical form of vitamin D can be helpful in the treatment of plaque-type psoriasis (Oral doses of vitamin D are not effective).

Side Effects

Minor side effects are poor appetite, constipation, dry mouth, increased thirst, metallic taste, or fatigue.

Other reactions are headache, nausea, vomiting, diarrhea, or confusion.

1- The absorption of vitamin D is improved by calcium, choline, fats, phosphorus, and vitamins A and C.

2- Rifampin, H2 blockers, barbiturates, heparin, isoniazid, colestipol, cholestyramine, carbamazepine, phenytoin, fosphenytoin, and phenobarbital reduce serum levels of vitamin D and increase its metabolism.

3- Overuse of mineral oil and stimulant laxatives may deplete vitamin D. 4- Osteoporosis and hypocalcemia can result from prolonged use of corticosteroids. It is necessary to take of calcium and vitamin D together with corticosteroid drugs.

Interactions

5- The use of thiazide diuretics with vitamin D can cause hypercalcemia in individuals with hypoparathyroidism.

6- Concomitant use of digoxin or other cardiac glycosides with vitamin D may lead to hypercalcemia and heart irregularities.

Vitamin E A group of compounds (α, β, γ, and δ-tocopherols)

with a chromanol ring and phytyl side chain. They have the activity equivalent to d--tocopherol.

OCH3

CH3 CH3 CH3 CH3

CH3

HO

H3CCH3

Chromanol group

Phytyl side chain

6

SourcesSources Natural sources: Natural vitamin E (RRR-Natural sources: Natural vitamin E (RRR--tocopherol)-tocopherol)

present in plants only mainly the leaves of green vegetables.present in plants only mainly the leaves of green vegetables. Vegetable oils Vegetable oils (wheat germ, sunflower, cottonseed, safflower,

soybean, and corn oil) . . Unprocessed grains, nuts.

Synthetic sources all racemic-tochopherol.Synthetic sources all racemic-tochopherol.

Gastrointestinal absorption of all forms of vitamin E is equivalent. the subsequent physiological steps are sharply in favor of the RRR form. The cellular liver transfer protein that maintains the plasma level is specific for the RRR form of α -tocopherol. It selectively choosing the RRR form and bind it into plasma lipoproteins for distribution of the vitamin to every tissue and organ in the body.

Recommended Daily Amount (RDA)

d--tocopherol Equivalent (TE):

1 TE = 1 mg = 1.5 IU

30 IU commercial products, however it is safe so larger doses are allowed.

Role of Vitamin ERole of Vitamin E

Vitamin E has a very important role in normal cells Vitamin E has a very important role in normal cells metabolism. It protects with other nutrient (Vitamin C metabolism. It protects with other nutrient (Vitamin C and Selenium) against he damaging free radicals and Selenium) against he damaging free radicals formed during metabolism of fatty acids.formed during metabolism of fatty acids.

Causes of deficiencyCauses of deficiency

Insufficient dietary intake.Insufficient dietary intake. Impaired absorption.Impaired absorption. Other factors:Other factors:

Deficiency of Riboflavin and cystein.Deficiency of Riboflavin and cystein. Deficiency of minerals like Cu, Zn and Mg.Deficiency of minerals like Cu, Zn and Mg.

UsesUses Cancer prevention and treatment: Vitamin E is a known

antioxidant reduces risk of Cancer. High doses of dietary antioxidants may increase the efficacy of the radiation treatment and protects healthy cells against damage.

Immune system stimulation: Especially in elderly patients, boosts immune system function. It also slow disease

progression in HIV-positive patients. Eye disease prevention: Reduces the risk for

cataracts and for macular degeneration, particularly among women.

Macular degeneration:Macular degeneration: is a medical condition predominantly is a medical condition predominantly found in elderly adults in which the center of the inner lining found in elderly adults in which the center of the inner lining of the eye, known as the of the eye, known as the maculamacula area of the area of the retinaretina, suffers , suffers

thinning, atrophy, and in some cases bleeding.thinning, atrophy, and in some cases bleeding.

A cataract is a condition of clouding lens of the eye. A patient who is blind from cataracts might have white not clear corneas. Lens clarity was better in regular users and higher blood levels of vitamin E.

Memory loss prevention.

Alzheimer's disease (AD) treatment: Alzheimer's patients who took daily vitamin E maintained normal functioning longer than patients who took a placebo. High dietary intake of vitamin E lowers the risk of developing AD.

Diabetes treatment: Vitamin E reduces the symptoms of

diabetic neuropathy and to improve the speed of transmission of nerve impulses.

Pain relief: Vitamin E acts as both an anti-inflammatory and analgesic. It may be useful in arthritis pain in some individuals.

Vitamin E may protect the liver against disease.

Parkinson's disease prevention: High doses of vitamin E lowered risk of developing Parkinson's disease.

Heart disease prevention:Vitamin E may prevent heart disease by lowering total blood cholesterol levels and preventing oxidation of LDL cholesterol.

Skin care: Vitamin E is thought to increase an individual's tolerance to UV rays when taken with vitamin C and to promote faster healing of wounds.

Side Effects

Vitamin E is well-tolerated, and side effects are rare. However, in some individuals who are vitamin K deficient, vitamin E may increase the risk for hemorrhage or bleeding.

Vitamin E ointments, oils, or creams may trigger an allergic reaction known as contact dermatitis.

InteractionsVitamin E can alter the efficacy of anticoagulant or anticonvulsant drugs.

Vitamin E increase bleeding time in patient taking herbal preparations as Feverfew or Gingko Biloba.

Inorganic iron supplements destroy vitamin E, so individuals taking iron supplements should space out their doses (e.g., iron in the morning and vitamin E in the evening).

Large doses of vitamin A can decrease the absorption of vitamin E.

Alcohol and mineral oil can also reduce vitamin E absorption, and these substances should be avoided in vitamin E deficient individuals.

Vitamin KVitamin K ((Antihemorrhagic factor)

A group of compounds derived from 2-methyl-1,4-naphthoquinone that prevent bleeding in mammals and birds.

Forms of Vitamin K: Vitamin K1 (Phylloquinones, Phytonadione) is produced by

green plants. Vitamin K2 (Menaquinones, MK) is produced by intestinal

bacteria. Vitamin K3 (Menadione) is a synthetic compound.

SourcesSources

Rich Food in Vitamin K:Rich Food in Vitamin K: Kale, Spinach, Turnip, Parsley and Mustard.Kale, Spinach, Turnip, Parsley and Mustard.

Food Moderate in Vitamin k:Food Moderate in Vitamin k: Lettuce and Broccoli.Lettuce and Broccoli.

O

O

1

4

Vitamin K1 = Phytonadione

O

O

1

4

2

Vitamin K2(30) = Menaquinone-6 n = 4Vitamin K2(35) = Menaquinone-7 n = 5

n

[ ]n

[ ]

O

O

1

4

Menadione

Role of Vitamin KRole of Vitamin K

Vitamin K (hydroquinone , the active form) is involved as a cofactor in the carboxylation of certain glutamate residues in proteins to form γ-carboxyglutamate residues (Gla-residues). Gla-residues are usually involved in binding calcium. The Gla-residues are essential for the biological activity of :

Blood coagulation: (factors II (prothrombin), IX, X , VII anticoagulant proteins C and S, and the thrombin-targeting protein Z ) must be convered to γ-carboxyglutamate and bind to Ca to form clot. This is the most important role of Vitamin K.

Bone metabolism: Bone Gla-protein Osteocalcin: Regulate incorporation of Calcium

Phosphate into bones. Matrix Gla protein (MGP)]: Clearance of extracellular Calcium to

protect against soft tissue calcification.

Vascular biology.

Recommended Daily Amount (RDA)

Male: 80 g/day Female: 65 g/day New Born: 500- 1000 g/day (Sterile intestine) 0- 6 Months: 5 g/day 6- 12 Months: 15 g/day

Commercial infant formula contain 50- 125 g/day

AbsorptionAbsorption

Vitamin KVitamin K11 is absorbed through Active is absorbed through Active

transport mechanism.transport mechanism.

Vitamins KVitamins K22 and K and K33 are absorbed through are absorbed through

passive diffusion.passive diffusion.

MetabolismMetabolism

70% of Vit K70% of Vit K33 excreted in urine in 24 hr in the excreted in urine in 24 hr in the

form of sulphate, phosphate and glucuronic acid form of sulphate, phosphate and glucuronic acid conjugate.conjugate.

Small % excreted in faces as glucuronic acid Small % excreted in faces as glucuronic acid conjugate.conjugate.

Vit KVit K22 and K and K33 undergo slower metabolism to undergo slower metabolism to

shorten the side chain to 5- 7 carbons carboxylate.shorten the side chain to 5- 7 carbons carboxylate.

Causes of DeficiencyCauses of Deficiency

Disturbed intestinal uptake (a bile duct obstruction).

Therapeutic or accidental intake of vitamin K-antagonists.

Nutritional vitamin K-deficiency.

DeficiencyDeficiency

Uncontrolled internal bleeding.

Cartilage calcification and malformation of developing bone.

Deposition of insoluble calcium salts in the arterial vessel walls.

Structure Activity Relationship (SAR)Structure Activity Relationship (SAR)

Increase activity:Increase activity: Ring A : a- Aromatic or hydro- aromatic. b- Not substituted. Ring B is aromatic or hydro- aromatic.

Decrease Activity: Alkyl group larger than Methyl at C-2. Hydroxyl group at C-3 or hydroxtlation of the side chain.

CH3

O

O

1

4

A B

Activity not affected if positions 1 and 4 are:Activity not affected if positions 1 and 4 are: OHOH O-AcO-Ac OCHOCH33

OCOC22HH55

C=OC=O

CH3

O

O

1

4

A B

ToxicityToxicity

Vitamins KVitamins K11 and K and K22 are non-toxic in large doses. are non-toxic in large doses.

Vitamin KVitamin K33 is toxic in doses tree time more than the is toxic in doses tree time more than the

usual dose.usual dose.

Toxicity cause:Toxicity cause: Hyperbilirubinemia.Hyperbilirubinemia. Sever Jaundice.Sever Jaundice. Anemia.Anemia.

InteractionInteraction Some interactions may increase the need for Some interactions may increase the need for

vitamin K:vitamin K: Antibiotics: Prevent absorption and kill normal bacterial Antibiotics: Prevent absorption and kill normal bacterial

folra. folra. Anticonvulsants: Affect the body ability to use Vit K. Anticonvulsants: Affect the body ability to use Vit K. Bile Acid Sequestrants (Cholestyramine) and Aspirin: Bile Acid Sequestrants (Cholestyramine) and Aspirin:

Affect absorption. Affect absorption. Mineral oil laxatives: Affect absorption.Mineral oil laxatives: Affect absorption. Weight Loss Products (Weight Loss Products (Orlistat and olestra): Orlistat and olestra): Affect Affect

absorption as they prevent absorption of fats.absorption as they prevent absorption of fats. X-rays and Radiation: Deplete vitamin K levels and raise X-rays and Radiation: Deplete vitamin K levels and raise

vitamin K requirements.vitamin K requirements. Avoid high doses of vitamin K and food rich in Avoid high doses of vitamin K and food rich in

vitamin K when anticoagulants are used.vitamin K when anticoagulants are used.