1. FAT SOLUBLE VITAMINS Element 5 - Lecture 31 Ms. K. Rohini 04.05.2012

2. OBJECTIVES Classification of vitamins. Chemistry, Source, Daily requirements. Biochemical role and deficiency disorders of fat-soluble vitamins.

3. Introduction A vitamin is an organic compound required as a nutrient in tiny amount by an organism for normal growth and maintenance of good health. A vitamin is an organic compound required as a nutrient in tiny amount by an organism for normal growth and maintenance of good health. The term ‘vitamin’ was derived from the term ‘vitamine’ a combination word from vital and amine. The term ‘vitamin’ was derived from the term ‘vitamine’ a combination word from vital and amine.

4. Classification

5. Properties of fat soluble vitamins Insoluble in water, soluble in organic solvents Insoluble in water, soluble in organic solvents Require bile for absorption Require bile for absorption Require a transport protein in blood Require a transport protein in blood Stored in liver Stored in liver Not excreted in urine, therefore excess intake causes hypervitaminosis Not excreted in urine, therefore excess intake causes hypervitaminosis

6. Properties of water soluble vitamins Soluble in water, insoluble in organic solvents Soluble in water, insoluble in organic solvents Do not require bile for absorption Do not require bile for absorption Require a transport protein in blood Require a transport protein in blood No storage in body No storage in body Excreted in urine, therefore no hypervitaminosis Excreted in urine, therefore no hypervitaminosis

7. Vitamin A Chemistry: All compounds with vitamin A activity are called retinoids, they are isoprenoid compounds with beta ionone ring A. In animals,3 compounds with vitamin A activity - Retinol (alcohol) - Retinal (aldehyde) - Retinoic acid (carboxylic acid) B. In plants, the provitamin beta carotene – can give rise to 2 molecules of vitamin A

8. Interconversion of vitamin A molecules Retinol (alcohol) Retinol (aldehyde) reductase NAD + NADH + H + Retinoic acid

10. Food Source Preformed Vitamin A Liver Fish Liver oils, Kidney, Dairy produce, eggs, fortified margarine. β carotene carrots, red palm oil, apricots, melon, pumpkin, dark green leafy vegetables (spinach, brocolli,sprouts etc)

11. Recommended dietary allowance (RDA)  400-600  g -for children  700  g - for women  900  g - men  1000  g -during pregnancy  1200  g -during lactation

12. FUNCTIONS OF VITAMIN A 1. Role in vision (Wald’s visual cycle) Rhodopsin is the visual pigment present in the retina of eye. It is made of opsin and retinal (11-cis retinal) Rhodopsin Lumi Rhodopsin Light Meta Rhodopsin All trans retinal + Opsin Opsin + 11 cis retinal Isomerase dark Retinal reductase NADH + H + NAD + Retinal reductase NADH + H + NAD + 11 – cis retinol All trans retinol Isomerase Liver Retina Night vision

13. 2.Retinoic acid is essential for the maintenance of normal epithelium and skin 3.Retinoic acid is implicated in growth and differentiation of tissues 4.Retinol is essential for normal reproduction. It acts like a steroid hormone in controlling expression of certain genes. 5.Carotenoids act as antioxidants

14. Vit A deficiency diseases The earliest sign of deficiency is impairment to adapt to dim light, followed by night blindness. Vitamin A deficiency is the most important preventable cause of blindness.

15. Deficiency manifestations 1. Ocular manifestations a. Night blindness or nyctalopia – diminished visual acuity in dim light b. Xerophthalmia – Dry, thick, wrinkled, keratinised conjunctiva c. Bitot’s spots – greyish white triangular plaques on conjunctiva d. Keratomalacia – degeneration & vascularisation of corneal epithelium leading to ulceration, perforation & blindness

16. Deficiency manifestations 2. Non-ocular manifestations a. Follicular hyperkeratosis – hyperkeratinisation of epithelium lining the follicles, keratinisation of epithelia lining the respiratory tract, GIT, genitourinary tract b. Increased infections and acne on skin

17. Hypervitaminosis Anorexia Anorexia Irritability Irritability Headache Headache Peeling of skin Peeling of skin Drowsiness Drowsiness Vomiting Vomiting Bony exostosis & pain Bony exostosis & pain Hepatomegaly Hepatomegaly Release of lysosomal enzymes leading to cell death Release of lysosomal enzymes leading to cell death

18. VITAMIN D Chemistry: Has a secosterol ring In plants: Vitamin D 2 or ergocalciferol In animals: Vitamin D 3 or cholecalciferol Active form: 1,25 dihydroxycholecalciferol or Calcitriol Calcitriol Precursor in humans: 7-dehydrocholesterol in the skin

19. Distribution and requirement of vitamin D Vitamin D occurs naturally in fatty fish, liver, and egg yolk. Milk, unless it is artificially fortified, is not a good source of the vitamin. The RDA for adults is 5 micrograms of cholecalciferol, or 200 international units (IU) of vitamin D

20. Biosynthesis of vitamin D Cyt.P 450, NADPH, O 2 In chylomicrons

21. When there is decrease in plasma calcium Vit D maintains adequate plasma levels of calcium by 1,25-(OH) 2 -D 3 stimulates intestinal absorption of calcium and phosphate. Minimizing loss of calcium by the kidney 1,25-(OH) 2 -D 3 stimulates the mobilization of calcium and phosphate from bone. The result is an increase in plasma calcium and phosphate.

22. Functions In the intestine: Promotes absorption of calcium & phosphate Promotes absorption of calcium & phosphate In the bone: Increases bone mineralisation if plasma calcium is high Increases bone mineralisation if plasma calcium is high Increases bone demineralisation if plasma calcium is low Increases bone demineralisation if plasma calcium is low In the kidney: Increases reabsorption of calcium and phosphate by renal tubules Increases reabsorption of calcium and phosphate by renal tubules

23. Vitamin D Deficiency

24. Rickets Rickets is deficient mineralisation at the growth plate of long bones results in growth retardation. If the underlying condition is not treated, bone deformity occurs, typically causing bowed legs and thickening of the ends of long bones. Only occurs in growing children before fusion of the epiphyses, typically affecting wrists, knees and costochondral junctions. Dental Enamel hypoplasia

25. Vitamin D deficiency In children: Rickets In children: Rickets –Inadequate mineralization of bones; soft pliable bones –Pot belly, bow legs, knock-knee, pigeon chest, rickety rosary (bead like appearance of ribs) In adults: Osteomalacia In adults: Osteomalacia –Inadequate mineralization of bones, osteoporosis, more prone for fractures –Low serum Ca2+ & phosphate, high serum ALP (bone isoenzyme)

26. Hypervitaminosis D Hypervitaminosis D is a state of vitamin D toxicity Hypervitaminosis D is a state of vitamin D toxicity Toxicity symptoms Toxicity symptoms –Elevated blood calcium –Calcifications of soft tissues –Damage the kidney and produce kidney stones

27. VITAMIN E Chemistry: Compounds with vitamin E activity are called tocopherols. They have a chromane ring with isoprenoid side chain α tocopherol has the maximum vitamin E activity RDA : Males: 10 mg/day Females: 8 mg/day Pregnancy: 10 mg/day Lactation: 12 mg/day

28. Food sources of vitamin E vegetable oils—wheat germ oil the richest margarines, mayonnaise nuts and seeds Small amounts in wholegrain cereals, eggs, butter,some vegetables, and some fruits. RDA : 15 mg alpha tocopherol RDA : 15 mg alpha tocopherol

29. Sources Vegetable oils like palm oil, wheat germ oil, sunflower oil, cottonseed oil Absorption, transport & storage Absorbed and transported as chylomicrons, stored in adipose tissue

30. Functions Most powerful natural antioxidant to scavenge free radicals generated in living systems Most powerful natural antioxidant to scavenge free radicals generated in living systems Prevents peroxidative damage of membranes, protects the structural integrity of RBCs and all cells Prevents peroxidative damage of membranes, protects the structural integrity of RBCs and all cells Boosts immune response Boosts immune response Reduces LDL oxidation, reduces risk of atherosclerosis Reduces LDL oxidation, reduces risk of atherosclerosis

31. Vitamin E is present in all cell membranes where, being an antioxidant, it reduces peroxidation of unsaturated fatty acids by free oxygen radicals

32. Deficiency manifestations Not reported so far in human beings Not reported so far in human beings Increased fragility of RBCs, muscle weakness and creatinuria has been seen in volunteers Increased fragility of RBCs, muscle weakness and creatinuria has been seen in volunteers Vitamin E is better known as ‘the vitamin in search of a disease’ Vitamin E is better known as ‘the vitamin in search of a disease’ Hypervitaminosis Tendency to hemorrhage (since vit.E is a mild anticoagulant) Tendency to hemorrhage (since vit.E is a mild anticoagulant)

33. Vitamin K Chemistry: They are naphthaquinone derivatives with long isoprenoid side chains In plants: Vitamin K 1 or phylloquinone In animals: Vitamin K 2 or menaquinone Synthetic form: Menadione RDA 50-100 μg

34. Absorption, transport and storage Absorbed as chylomicrons, transported in plasma in LDL, stored in liver Sources: Green leafy vegetables, liver, intestinal bacteria (enough to meet daily requirements; hence vitamin K supplements are given during antibiotic therapy)

35. Functions Necessary for blood coagulation Necessary for blood coagulation – Clotting factors II, VII, IX & X which are secreted as inactive zymogens, are activated by post translational modification – Post translational modification involves gamma-carboxylation of glutamate residues in the proteins (clotting factors) – Vitamin K is a cofactor for gamma carboxylation reaction

36. γ Carboxyglutamate chelates calcium ions, and so permits the binding of the blood clotting proteins to membranes. Vitamin K Is Required for Synthesis of Blood Clotting Proteins

37. Functions (contd.) Vitamin K dependent gamma carboxylation is necessary for the functional activity of osteocalcin (to bind tightly to hydroxyapatite crystals of bone) Vitamin K dependent gamma carboxylation is necessary for the functional activity of osteocalcin (to bind tightly to hydroxyapatite crystals of bone) Vitamin K dependent gamma carboxylation is necessary for the functional activity of structural proteins of kidney, lungs & spleen Vitamin K dependent gamma carboxylation is necessary for the functional activity of structural proteins of kidney, lungs & spleen

38. Vitamin K and bone growth Osteocalcin is a noncollagenous protein found in bone and dentin. Osteocalcin is secreted solely by osteoblasts and is pro-osteoblastic, or bone-building. Vitamin K  carboxylating glutamic acid (Glu) to gamma- carboxyglutamic acid (Gla), in and a role in bone growth and the maintenance of bone density. Vitamin K  carboxylating glutamic acid (Glu) to gamma- carboxyglutamic acid (Gla), in Matrix gla protein and osteocalcin  a role in bone growth and the maintenance of bone density.

39. Clinical correlation :Vitamin K metabolism and the effect of warfarin. Warfarin is an anticoagulant. It is a vitamin K antagonist. Decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII.

40. Deficiency manifestations Hemmorhagic disease of the newborn (in newborns - no liver stores, sterile intestine, very low levels in breast milk) – preterm infants are given prophylactic doses of vitamin K Hemmorhagic disease of the newborn (in newborns - no liver stores, sterile intestine, very low levels in breast milk) – preterm infants are given prophylactic doses of vitamin K Bruising tendency, echymotic patches, mucous membrane hemorrhage, post traumatic bleeding, internal bleeding in chidren and adults Bruising tendency, echymotic patches, mucous membrane hemorrhage, post traumatic bleeding, internal bleeding in chidren and adults Prolonged prothrombin time, delayed clotting time Prolonged prothrombin time, delayed clotting time

41. Toxicity Symptoms include RBC hemolysis, jaundice and brain damage Symptoms include RBC hemolysis, jaundice and brain damage High intake of vitamin k can reduce the effect of anticoagulant medication used to prevent the blood from clotting High intake of vitamin k can reduce the effect of anticoagulant medication used to prevent the blood from clotting

42. Anti vitamins (vitamin antagonists) An antivitamin or vitamin antagonist is "a substance that makes a vitamin ineffective." Vitamin A Antagonists: Blood-thinning medications and other drugs, including aspirin, phenobarbitol, arsenicals and dicumarol (a drug used medically to retard blood clotting), destroy vitamin A in the body. Mineral oil used as a laxative absorbs vitamin A and carotene (a naturally-occurring substance in foods which is used by the body to make vitamin A), thereby destroying it.

43. Anti vitamins and vitamin antagonist Vitamin K antagonists (VKA): are a class of anticoagulants which, as their name indicates, act by inhibiting the action of vitamin K. Vitamin K antagonists (VKA): are a class of anticoagulants which, as their name indicates, act by inhibiting the action of vitamin K. Eg. warfarin or coumadin, dicoumarol etc Birth control pills are antivitamins, especially of the B vitamins riboflavin, vitamin B6, vitamin B12. These contraceptives are especially damaging to vitamin B12 and folic acid. (The estrogen in oral contraceptives is also an antagonist of vitamin E.) Birth control pills are antivitamins, especially of the B vitamins riboflavin, vitamin B6, vitamin B12. These contraceptives are especially damaging to vitamin B12 and folic acid. (The estrogen in oral contraceptives is also an antagonist of vitamin E.)

44. LEARNING OUTCOMES At the end of the lecture, you should be able to: At the end of the lecture, you should be able to: Classify vitamins and list the various sources of all fat soluble vitamins and their recommended dietary intakes. Classify vitamins and list the various sources of all fat soluble vitamins and their recommended dietary intakes. Describe the various metabolic roles of Vitamin A in vision, Vitamin D in Ca homeostasis, Vitamin E as an antioxidant and Vitamin K as an important cofactor in clotting. Describe the various metabolic roles of Vitamin A in vision, Vitamin D in Ca homeostasis, Vitamin E as an antioxidant and Vitamin K as an important cofactor in clotting. Describe the various disorders caused due to deficiency and the signs and symptoms of hypervitaminosis A and D. Describe the various disorders caused due to deficiency and the signs and symptoms of hypervitaminosis A and D. List the various vitamin antagonists in preventing cancer and ageing. List the various vitamin antagonists in preventing cancer and ageing.