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Fat Soluble Vitamins Vitamin A Vitamin E Vitamin D Vitamin K

Fat Soluble Vitamins Vitamin A Vitamin E Vitamin D Vitamin K. Vitamin A. RETINOIDS. The retinoids : a family of molecules that are related to retinol (vitamin A) ------------------------------------- The term retinoids includes

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Fat Soluble Vitamins Vitamin A Vitamin E Vitamin D Vitamin K

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  1. Fat Soluble Vitamins Vitamin A Vitamin E Vitamin D Vitamin K

  2. Vitamin A

  3. RETINOIDS The retinoids: a family of molecules that are related to retinol (vitamin A) ------------------------------------- The term retinoids includes natural & synthetic forms of vitamin Athat may or may not show vitamin A activity

  4. Retinoids 1- Retinol A primary alchol containing b-ionone ring with an unsaturated side chain. It is found in animaltissues as a retinyl ester with long-chain fatty acids. 2- Retinal The aldhyde derived from the oxidation of retinol. Retinol and retinal canbeinterconverted.

  5. 3-Retinoic acid The acid derived from oxidation of retinal. It can not be reduced in the body, and therefore, can not give rise to either retinal or retinol 4-b-carotene Plantfoods contain b-carotene, which can be oxidatively cleaved in the intestine to yield two moleculesofretinal In humans, the conversion is insufficient, and vitamin A activity of b-carotene is only about one sixth of that of retinol

  6. Absorption & Transport of vitamin A Transport to the Liver I- Retinol is derived from (DIET SOURCES) 1-DIET Retinyl esters (animal source) which are hydrolyzed in the intestinal mucosa, releasing retinol and free fatty acids 2- DIET b-carotenes(plant source) which is cleaved 2 retinal retinol II- Retinol is esterified with fatty acids to give retinyl esters III-Retinyl esters are collected by the chylomicrons into the lymphatic system. IV- Retinyl esters contained in the chylomicrons are taken up and stored by the liver

  7. Release from the Liver • When needed, retinol is released from the liver and transported to extra hepatic tissue by plasmaretinol binding protein(RBP) • Theretinol - RBP complex attaches to specific receptors on the surface of the cells of peripheral tissues permitting retinol to enter

  8. Mechanism of Action of vitamin A • Retinol is oxidized to retinoic acid inside cells. • Retinoic acid binds with high-affinity to specific receptor proteins present in the nucleus of target tissue, such as epithelial cell. • The activated retinoic acid - receptor complex interacts with nuclear chromatin (genes) to stimulate retinoid-specific mRNA synthesis, resulting in the production of specific proteins that mediate several physiological functions. e.g. retinoids control the expression of keratin gene in most epithelial tissues.

  9. Functions of Vitamin A • Vision • Growth • Reproduction • Epithelial cells maintenance

  10. Functions of Vitamin A 1-Vision • Vitamin A is a component of the visual pigments of rodand cone cells. • Rhodopsin, the visual pigment of the rod cells in the retina, (for vision in dim light) consists of 11-cis retinal specially bound to the protein opsin. • When rhodopsin is exposed to light, a series of photochemical isomerization occurs, which results in release of all trans retinal and opsin (with bleaching of the visual pigment). • This process triggers a nerve impulse that is transmitted by the optic nerve to the brain. • Regeneration of rhodopsin requires isomerization of all trans retinal back to 11-cis retinal, which spontaneously combines with opsin to form rhodopsin.

  11. 2- Growth • Vitamin A is essential for normal growth of cells (by synthesis of important proteins) • bone growth is slow in vitamin A deficiency. • Animals deprived of vitamin A suffers keratinzation of taste buds leading to losing of their appetites.

  12. 3-Reproduction • Retinol & retinalare essential for normal reproduction 1- supporting spermatogenesis in males 2- preventing fetal resorption in females • Retinoic acid is inactive in maintaining reproduction & the visual cycle, BUT promotes growth. Thus, retinoic acids given only since birth to animals, leads to blindness & sterility. 4-Epithelial cells maintenance • Vitamin A is essential for normal differentiation of epithelial tissues and mucus secretion.

  13. Distribution of Vitamin A • Sources of retinol(retinyl esters) : animal source Liver, kidney, cream, butter & egg yolk • Sources of carotenes(precursors of vitamin A) : plant source Yellow & dark green vegetables & fruits Requirement for Vitamin A • One RE (retinol equivalents) = 1mg of retinol 6mg of b-carotene 12mg of other carotenoids • RDA for adults 1000 RE for males 800RE for females

  14. Clinical indications 1-Dietary deficiency Vitamin A, administered asretinolor retinyl esters, is used to treat patients deficient in the vitamin (not retinoic acid) Night blindness One of the earliest signs of vitamin A deficiency Difficulty in seeing in dim light. Prolonged deficiency leads to irreversible loss of visual cell. (affection of rods of retina) Xerophthalmia Severe deficiency of vitamin A Pathological dryness of the epithelium conjunctiva & cornea. It may end in corneal ulcerations and blindness.

  15. 2-Acne & Psoriasis Dermatologic problems of acne and psoriasis are effectively treated with retinoic acid or its derivatives. • Mild cases of acne is treated by topical application of tretinoin (All trans retinoic acid) which is too toxic for systemic administration. • Severe recalcitrant cystic acne unresponsive to conventional therapies, isotretinoin(13-cis retinoic acid) is administered orally

  16. 3-Prevention of chronic diseases • Populations consuming diets high in b-carotene show decreased incidence of heart diseases & lung & skin cancer • Consumption of foods rich in b-carotene is associated with reduced risk of cataracts and macular degeneration

  17. Toxicity of Retinoids I. Vitamin A excess(hypervitaminosis A syndrome) Amounts exceeding 7.5 mg/day of retinol 1- Excessive intake of vitamin A may cause the followings: • dry skin & pruiritis are early signs • liver enlarged, cirrhotic • increased intracranial pressure (mimic symptoms of brain tumours e.g. headache etc…) 2-Pregnant females should not ingest excessive amounts of vitamin A because of its potential for causing congenital malformations in developing fetus.

  18. II. Isotretinoin drug(13-cis retinoic acid) 1-Teratogenic • So, absolutely contraindicated in women with childbearing potential. • Pregnancy should be excluded before initiation of treatment & adequate contraceptive (birth control) must be used 2-Risk of coronary heart diseases Prolonged treatment with 13-cis retinoic acid leads to hyperlipidemia & increase in LDL/HDL ratio with increased risk of coronary heart diseases.

  19. Vitamin E

  20. Vitamin E • E vitamins consist of 8 naturally occurring tocopherols, of which - tocopherol is the most active. • The primary function of vitamin E is an antioxidantin prevention of the nonenzymic oxidation of cell components as polyunsaturated fatty acids by molecular O2 & free radicals.

  21. Distribution & requirements of vitamin E • Vegetable oils are rich sources (plant sources) • Liver& eggs contain moderate amounts (animal sources) • RDA for a-tocopherol is 10 mg for men 8 mg for women • Requirement is increased with increased intake of polyunsaturated fatty acids.

  22. Deficiency of vitamin E • Deficiency of vitamin E is almost entirely restricted to premature infants. • In adults, it is usually associated with defective lipid absorption or transport. • Signs of vitamin E deficiency include sensitivity of RBCs to peroxide & appearance of abnormal cellular membrane.

  23. Clinical indications Vitamin E is notrecommended for the prevention of chronic disease, such as coronary heart disease or cancer. Subjects in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study trial who received high doses of vitamin E, not only lack cardiovascular benefit but also had an increased incidence of stroke. Toxicity of vitamin E:no toxicity at 300mg / day dose

  24. Vitamin D

  25. Vitamin D • The D vitamins are a group of sterols that have a hormone-like function. • The active molecule, 1,25-dihydroxycholecalciferol (1,25-di OH D3 ), binds to intracellular receptor protein. • The 1,25-diOH D3 - receptor complex interacts with DNA in the nucleus of target cells, and either stimulates gene expression, or represses gene transcription. • The main actions of 1,25-diOH D3 are to regulate plasma levels of calcium & phosphorous.

  26. Distribution of vitamin D: (Sources) 1- Diet • Ergocalceferol (vitamin D2) is found in plants • Cholecalceferol (vitamin D3) is found in animaltissues. 2- Endogenous vitamin precursors 7-Dehydrocholesterol, is converted tocholecalceferol (vitamin D3) in the dermis and epidermis of human skin exposed to sunlight. Individuals with limited exposure to sunlight require performed vitamin D

  27. Metabolism of vitamin D 1- Formation of 1, 25 dihydroxycholecalceferol (1,25-diOH D3) • Vitamin D2 & D3 are not biologically active • but are converted in vivo to the active form of D vitamin by two sequential hydroxylation reactions (two hydroxylases) that require monooxygenase, molecular oxygen and NADPH. The two hydroxylases uses cytochrome P450

  28. First Hydroxylation • occurs at the position 25 • catalyzed by a specific hydroxylase in the liver • to give 25 hydroxycholecalceferol (25-OH D3) - the predominant form of vitamin D in plasma - the major storage form of the vitamin

  29. Second Hydroxylation • 25-OH D3 is further hydroxylated at position 1 • by the enzyme specific 25-hydroxycholecalceferol 1-hydroxylase • found primarily in the kidney • resulting in the formation of 1, 25 dihydroxycholecalceferol(1,25 diOH D3) is the most active vitamin D metabolite

  30. 2-Regulation of 1-hydroxylase • Its formation is regulated by the level of plasma calcium and phosphate levels in plasma. • 1-hydroxylase activity is increased: • DIRECTLY by low phosphate • INDIRECTELY by low calcium levels (hypocalcemia) release of Parathyroid Hormone (PTH) activation of 1 hydroxylase increased production of 1,25-di(OH) D3

  31. Function of Vitamin D The overall function of 1,25-diOH D3 is to maintain adequate plasma levels of calcium. It performs this function by • increasing uptake of calcium by the intestine • minimizing loss of calcium by the kidney • stimulating resorption of bone (when necessary)

  32. 1-Effect of vitamin D on INTESTINE: • 1, 25-diOH D3stimulates intestinal absorption of calcium & phosphate. • 1,25-diOH D3 enters intestinal cell and binds to cytosolic receptor 1,25-diOH D3 – receptor complex to nucleus selectively interacts with DNA increased synthesis of specific calcium-binding protein enhanced Calcium Uptake

  33. 2-Effect of vitamin D on BONE: 1,25-diOH D3 stimulates the mobilization of calcium and phosphate from bone by a process that requires PTH increase inplasma calcium & phosphate

  34. Distribution & Requirement of vitamin D • Vitamin D(Cholecalcerferol) occurs naturally in fatty fish, liver, and egg yolk. • Milk is not a good source for vitamin D (unless if fortified). • The RDA for adults is 200 IUvitamin D [available in 5 mgcholecalceferol (vitamin D3)]

  35. Clinical indications 1- Nutritional Rickets Vitamin D deficiency net demineralizationof bone Rickets(in children)Osteomalacia(in adults)

  36. Rickets thecontinued formation of the collagen matrix BUT incomplete mineralization softbones deformity Osteomalacia demineralization of preexisting bones susceptibility tofracture

  37. Causes of vitamin D deficiency (one or bothof the following causes) 1- Insufficient exposure to daylight(sunlight). 2- Deficiencies in vitamin D consumption In areas where sunlight is not sufficient RDA should be increased up to 800 IU/day instead of 200 IU/day (5 mg cholecalceferol) to reduce the incidence of osteoprotic fractures

  38. 2- Renal Rickets(renal osteodystrophy) The disorder results from chronic renal failure (with activity of 1-hydroxylase) decreased ability to form the active form of the vitamin (1,25-diOH D3) Treatment: 1,25-diOH D3 (calcitriol)

  39. 3- Hypoparathyroidism ( PTH) Deficiency or absence of parathyroid hormone (PTH) causes hypocalcemia and hyperphosphatemia. Treatment: any form ofvitamin D+ PTH

  40. Toxicity of vitamin D • Vitamin D is the most toxic of all vitamins. • Vitamin D can be stored in the body and is only slowly metabolized • High doses (100,000 IU for weeks or months) can cause: loss of appetite, nausea, thirst and stupor • Enhanced calcium absorption and bone resorption results in hypercalcemia, which can lead to deposition of calcium in many organs, particularly the arteries and kidneys

  41. Vitamin K

  42. Vitamin K Some forms of vitamin K: 1- in plants as phylloquinone (vitamin K1) 2- in intestinal bacterial floras as menaquinone (vitaminK2) 3-syntheticderivative of vitamin K (menadione )

  43. Function of vitamin K 1-Formation of gamma carboxyglutamate • Vitamin K is required in the hepatic synthesis of prothrombin and blood clotting factors II, VII, IXand X. • These proteins are synthesized as inactive precursor molecules. • Formation of clotting factors requires the vitamin K-dependentcarboxylation of glutamic acid residues • This forms a mature clotting factor that contains g carboxyglutamate (Gla), which are active clotting factors.

  44. The action of vitamin K can beinhibitedby the following anticoagulants: • Dicumarol: natural, available in some plants • Warfaryn:a synthetic analog of vitamin K

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