Vitamin A and Vitamin E

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Biochemical and Clinical Aspect of Vitamin A and Vitamin E

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  • A small percentage of dietary retinoids is converted to retinoic acid in the intestinal cell. In addition, the intestine actively synthesizes retinoyl β-glucuronide that is hydrolyzed to retinoic acid by β-glucuronidases (Barua and Olson, 1989). The efficiency of absorption of preformed vitamin A is generally high, in the range of 70 to 90 percent (Sivakumar and Reddy, 1972). A specific retinol transport protein within the brush border of the enterocyte facilitates retinol uptake by the mucosal cells (Dew and Ong, 1994). At physiological concentrations, retinol absorption is carrier mediated and saturable, whereas at high pharmacological doses, the absorption of retinol is nonsaturable (Hollander and Muralidhara, 1977). As the amount of ingested preformed vitamin A increases, its absorbability remains high (Olson, 1972).The hydrolysis of retinyl ester to retinol is catalyzed by retinyl ester hydrolase following endocytosis. To meet tissue needs for retinoids, retinol binds to retinol-binding protein (RBP) for release into the circulation. In the blood, holo-RBP associates with transthyretin (a transport protein) to form a trimolecular complex with retinol in a 1:1:1 molar ratio. Retinol is transported in this trimolecular complex to various tissues, including the eye. The mechanism through which retinol is taken up from the circulation by peripheral cells has not been conclusively established.The liver, lung, adipose, and other tissues possess carotene 15, 15′-dioxygenase activity (Goodman and Blaner, 1984; Olson and Hayaishi, 1965), and thus it is presumed that carotenes may be converted to vitamin A as they are delivered to tissues.
  • The average concentration of vitamin A in postmortem livers of American and Canadian adults is reported to range from 10 to as high as 1,400 μg/g liverIn developing countries where vitamin A deficiency is prevalent, the vitamin A concentration in liver biopsy samples is much lower (17 to 141 μg/g) A concentration of at least 20 μg retinol/g of liver in adults is suggested to be the minimal acceptable reserve
  • When light falls on retina, 11cis-retinal isomerizes to all trans retinal.Single photon can excite rod cell.The photon produces immediate conformational change.Unstable intermediates produced are –After dissociation, opsin remains in retina.٭Trans retinal enters blood circulation.٭Later cis retinal generated reaches retina.٭The reattachment of 11 cis-retinal to opsin is critical for shutting off pigments catalytic activity.
  • Retinoic acid, through the activation of retinoic acid (RAR) and retinoid X (RXR) receptors in the nucleus, regulates the expression of various genes that encode for structural proteins (e.g., skin keratins), enzymes (e.g., alcohol dehydrogenase), extracellular matrix proteins (e.g., laminin), and retinol binding proteins and receptors.Retinoic acid, as well as RAR, RXR, cellular retinol-binding protein (CRBP), and cellular retinoic acid-binding proteins (CRABP-I and CRABP-II), is present in temporally specific patterns in the embryonic regions known to be involved in the development of structures posterior to the hindbrain (e.g., the vertebrae and spinal cord) (Morriss-Kay and Sokolova, 1996). Retinoic acid is also involved in the development of the limbs, heart, eyes, and ears (Dickman and Smith, 1996; Hofmann and Eichele, 1994; McCaffery and Drager, 1995).
  • Deficiency of vitamin A impairs vitamin D function because of lack of 9-cis -retinoic acid to form receptor dimers, while excessive vitamin A also impairs vitamin D function, because of formation of RXR-homodimers, meaning that there are not enough RXR available to form heterodimers with the vitamin D receptor.
  • The epithelium is characterized by keratinization, a prominent granular cell layer, and distended squamous cells with large, open nuclei and prominent nucleoli.Characteristic changes of keratomalacia in autopsy specimen from a severely marasmic 1-year-old Indonesian boy with bilateral corneal ulceration, a serum vitamin A level of only 10 μg/dl, and a holo retinol binding protein of only 2 μg/ml. The sharply demarcated area of stromal necrosis is covered by keratinized epithelium. There is little inflammatory infiltrate and no bacteria in the area of collagen dissolution.
  • Age Related eye Disease Study.
  • Vitamin A and Vitamin E

    1. 1. Vitamin A and Vitamin E D . Abhi shek R r oy Email: mail@abhishek.ro Junior Resident, Dept. of Biochemistry, Grant Govt. Medical College & Sir J.J. Group of Hospitals, Mumbai.
    2. 2. Categories: • Brief History • Chemistry • Functions • Deficiency Disorders • Treatment of Def. Disorders. • Clinical Importance in Modern Medicine • Hypervitaminosis
    3. 3. Definition • Vitamins are organic bio-molecules which are required by a living organism in micro quantities and is to be derived from food sources as they cant be synthesized in the body (with the exception of Vitamin D and Niacin). Classification Fat Soluble Water Soluble
    4. 4. Fat Soluble Vitamins • Vitamin A • Vitamin D • Vitamin E • Vitamin K
    5. 5. WATER SOLUBLE • Vitamin B Complex • Vitamin C
    6. 6. WHY DOES DEFICIENCY OCCUR?  Reduced Intake  Impaired Absorption  Impaired Metabolism  Additional Requirements  Increased Losses
    7. 7. Vitamin A
    8. 8. Brief History • François Magendie (1816) • Nicolai Lunin (1880s) • Carl Socin • Frederick Gowland Hopkins (1906) • Wilhelm Stepp (1911)
    9. 9. • In 1913, Elmer McCollum and Marguerite Davis at Wisconsin and Thomas Osborne and Lafayette Mendel at Yale showed butter and egg yolk were not equivalent to lard and olive oil in supporting the growth and survival of rats. • The growth-supporting 'accessory factor' became known as 'fat-soluble A' in 1918 and then ‘Vitamin A' in 1920. • Paul Karrer described the chemical structure of vitamin A in 1932. • Harry Holmes and Ruth Corbet isolated and crystallized vitamin A in 1937. • Methods for the synthesis of vitamin A came with the work of David Adriaan van Dorp and Jozef Ferdinand Arens in 1946 and Otto Isler and colleagues in 1947. (Source: http://www.ncbi.nlm.nih.gov/pubmed/23183288)
    10. 10. Chemistry Of Vitamin A • Fat Soluble Vitamin • Active form is present only in Animal Tissue • 20 carbon structure with a methyl substituted cyclohexenyl ring (β-ionone ring) and a tetraene side chain with a – OH(retinol), -CHO(retinal), -COOH (retinoic acid), COOR(retinyl ester) at carbon-15. • Pro-vitamin is documented in food sources - (α-carotene, βcarotene, β-Cryptoxanthin)- only in plants. • β-carotene has two β ionone rings connected by a polyprenoid chain.
    11. 11. Active Forms • Consists of 3 biologically active forms collectively called Retinoids. 1. Retinol (Alcohol) 2. Retinal (Aldehyde) 3. Retinoic Acid (Acid)
    12. 12. Absorption And Transport • Dietary retinyl esters are hydrolysed by pancreatic/intestinal hydrolases in intestine releasing retinol & free fatty acids. • Carotenes are hydrolysed by β-carotene 15-15’ dioxygenase of intestinal cells to release 2 moles of retinal which is reduced to retinol. • In intestinal mucosal cells, retinol is re-esterified to LCFA incorporated into chylomicrons & transferred to lymph. • Retinol esters of chylomicrons are taken up by liver & stored. • When required Vitamin A is released from liver as free retinol.
    13. 13. • Retinol is transported in circulation by Plasma Retinol Binding Protein in association with albumin(transthyretin). • Retinol-RBP complex binds to specific receptors on cell membrane of peripheral tissues & enters cells. • Carry retinol by Cellular Retinol Binding Protein(CRBP)and Cellular Retinoic Acid Binding Protein(CRABP-I, CRABP-II) to nucleus & binds to chromatin(DNA).
    14. 14. WALD’S VISUAL CYCLE • G. Wald was awarded Nobel Prize in 1967 • Studied role of vitamin A in vision. • 1) Generation of nerve impulse • 2) Regeneration of 11-cis-retinal
    15. 15. Generation Of Nerve Impulse • RHODOPSIN  Pivotal Role in the visual cycle. Membrane protein in photoreceptor of retina. Protein opsin and 11 cis-retinal.
    16. 16. • Visual pigments are G-protein coupled receptors. • 11cis retinal locks opsin(receptor protein) in its inactive form. • The isomerization & photoexcitation leads to activation of G-protein & regeneration of cyclic GMP. 5’ GMP (Na + Channel Closed) cGMP(Na + Channel Open) Inactive Phosphodiesterase GDP Active Phosphodiesterase Transducin-GTP Pi Metarhodopsin GTP Transducin-GDP
    17. 17. • Cyclic GMP acts as the gate for cation specific channels. • TRANSDUCIN is the G-protein in retina. • The nerve impulse thus generated in retina is transmitted to visual centers in brain. • The signal is terminated by phosphorylation of serine residue of activated rhodopsin. • Enzyme- Rhodopsin Kinase. • Inhibitory protein β-arrestin binds & inactivates rhodopsin.
    18. 18. Dark Adaptation • Torsten Wiesel -1981 Nobel prize. • Bright light depletes stores of rhodopsin in rods. • After few minutes rhodopsin is resynthesised & vision improved. • This period called -Dark Adaptation Time. • Increased in vitamin A deficiency.
    19. 19. Photosensitive Cells In Retina • Rods Dim Light Contains Rhodopsin (opsin+11cis-retinal) Def. of 11cis-retinal - Increased Dark Adaptation Time (Night Blindness) In humans:  1 eye =120 million rods =120 million molecules of rhodopsin
    20. 20. • CONES • Bright Light & Color Vision • Contains conopsin(photosensitive protein) • 3 types of cones – characterised by different conopsin that is maximally sensitive to: • Blue – Cyanopsin • Green – Iodopsin • Red – Porphyropsin 1 eye has 6 million cones.
    21. 21. FUNCTIONS • The 11-cis-retinaldehyde (retinal) form of vitamin A is required by the eye for the transduction of light into neural signals necessary for vision (Saari, 1994). • The Retinoic Acid form is required to maintain normal differentiation of the cornea and conjunctival membranes (Sommer and West, 1996) • Vitamin A is required for the Rhodopsin Cycle. • Vitamin A is said to have Anti-Oxidant Property too. • Vitamin A is required for the integrity of epithelial cells throughout the body (Gudas et al., 1994). • Retinoic acid plays an important role in embryonic development. • The growth, differentiation, and activation of B lymphocytes requires retinol (Blomhoff et al., 1992).
    22. 22. • Retinoid are necessary for the maintenance of immune function.  Helps in Cell differentiation and proliferation  Maintains adequate levels of NK cells  Shown to increase phagocytic activity in murine macrophages and increase production of IL -1 • Nuclear Retinoid Receptors:  Retinoid Acid Receptors (RAR) - All-trans-retinoic acid + 9-cis-retinoic acid  Retinoid X Receptors (RXR) - 9-cis-retinoic acid • Retinoid X receptors also form dimers with Vitamin D, Thyroid, and other a nuclear acting hormone receptors.
    23. 23. Rich Dietary Sources • Organ Meats (Liver), Cod Liver Oil • Cheese, Milk products • Carrot juice • Sweet Potato with peel • Tomato • Pumpkin • Spinach • Turnip Green • Mixed Green leafy vegetables
    24. 24. RECOMMENDED DIETARY ALLOWANCE • Units: • 1 Retinol Equivalent (R.E) = 1 mcg of Retinol 6 mcg of β-Carotene 12 mcg of other Carotenoids • 1 International Unit (I.U) = 0.3 mcg Retinol 0.6 mcg β-Carotene • RDA:  Children : 400 mcg/day  Adult Male: 900 mcg/day  Adult Female: 700 mcg/day  Pregnant Female : 1000 mcg/day  Lactating female : 1200 mcg/day
    25. 25. DEFICIENCY DISORDERS • Night Blindness (Nyctalopia)
    26. 26. XEROPHTHALMIA Conjunctival Xerosis Corneal Xerosis
    27. 27. Bitot Spot- Plaques In Conjunctiva
    28. 28. Keratomalacia followed by Blindness
    29. 29. Localised corneal Ulcer Adherent Leukoma
    30. 30. Follicular Hyperkeratosis
    31. 31. Histological Finding In Cornea
    32. 32. Xerophthalmia Classification • XN- Night blindness • X1A- Conjunctival Xerosis • X1B- Bitot’s spot • X2- Corneal Xerosis • X3A- Corneal ulceration/Keratomalacia (<1/3rd of the corneal surface) • X3B- Corneal ulceration/Keratomalacia (1/3rd or more of the corneal surface) • XF - Xerophthalmic Fundus • XS - Corneal scars presumed secondary to Xerophthalmia
    33. 33. Some Novel Roles Of Vitamin A
    34. 34. Role In Measles Revised routine Immunization Schedule from NRHM
    35. 35. Role In ARMD • ARMD (Age-related Macular Degeneration) - Notorious for significant vision loss in old age. • Cumulative effect of oxidative stress is postulated to play a role. • Supplements with anti-oxidant carotenoids- β-Carotene, Lutein, Zeaxanthin. • In a more detailed analysis of results, supplementation with Lutein and Zeaxanthin reduced the risk of advanced AMD by 26% in participants with the lowest dietary intakes of these two carotenoids who took a supplement containing them compared to those who did not take a supplement with these carotenoids. (In AREDS II) • Therefore the healthcare provider should consider offering one of the compounds used in AREDS.
    36. 36. ROLE IN SEVERE ACNE • Isotretinoin (or 13-cis-retinoic acid) is an aromatic retinoid similar to vitamin A which is effective in treating recalcitrant nodular acne and other disorders of keratinization. Unlike vitamin A, isotretinoin is not stored in the liver and is not associated with many of the toxic effects of high-dose vitamin A therapy. • MOA- Activation of RAR & RXR. • Category X drug for pregnancy- strictly avoided. • 2nd Generation Retinoid, hence lack of receptor specificity- Side effects. • Hepatotoxicity • Dry Skin(peeling of skin) • Worsening of Hyperlipidemia • Hyperostosis • Vision and Hearing loss
    37. 37. Role In Acute Promyelocytic Leukemia(M3) • All Trans Retinoic Acid (ATRA) is being used in two combinations:  ATRA + Anthracycline derivative ( Daunorubicin, Idarubicin)/Even Cytarabine(Ara-C)  ATRA + Arsenic Trioxide (Trisenox) – In patients who can’t tolerate Anthracyclines. Side effects: Both ATRA and Arsenic may cause Differentiation Syndrome( previously called Retinoic Acid Syndrome) Symptoms include:  Dyspnea due to Hydrothorax.  Hypotension  Renal Damage  Often Ana Sarca
    38. 38. Hypervitaminosis • If there is increase in concentration of Vitamin A Visual and hearing Defects. Severe Headache due to Pseudotumor Cerebri. Increased ALT and AST as it is hepatotoxic in large doses (Liver is the chief storage organ of Vitamin A) Anorexia Irritability In Pregnancy it – Congenital Malformations
    39. 39. Vitamin E
    40. 40. Introduction • Naturally occuring anti-oxidant. • Evans & Bishop(1936)-isolated active vitamin. • Named – Tocopherol. (Tokos : childbirth, pherein: to bring ,ol : alcohol) • Anti-sterility vitamin.
    41. 41. Structure And Chemistry • Elucidated by Paul Karrer. • Name given to a group of tocopherols & tocotrienols. • Derivatives of 6-hydroxy chromane (tocol) ring with isoprenoid side chain. • About eight tocopherols have • been identified. • Named as – α,β,γ,δ (On the basis of the number and position of the methyl group on the chromane ring)
    42. 42. α-tocopherol (5,7,8 trimethyltocol) is most active biologically.
    43. 43. • Normal plasma level - 0.5-1mg/dl. • Absorbed along with fat in Small intestine. • Bile salts necessary. • In liver, incorporated in Lipoproteins & transported. • Stored in ADIPOSE TISSUE, liver & muscle. • During catabolism, chromane ring & side chain may be oxidised. • Excreted in bile- conjugation with glucuronic acid
    44. 44. FUNCTIONS • Antioxidant(most powerful natural) • Free radical scavenger • Protects cell membranes • Protects LDL from oxidation • Protection of double bonds in polyunsaturated fatty acids • Prevention of rancidity • Works in conjunction with selenium
    45. 45. • Protects RBCs from hemolysis. • Structural & functional integrity of all cells. • Slowing down of ageing process. • Boosts immune response. • Reduces risk of atherosclerosis. • Depress leucocyte oxidative bactericidal activity.
    46. 46. • Stabilize reactions or situations that typically produce free radicals • Required for Proper Hair Growth (Beauty Vitamin along with BIOTIN) • Preserves & maintains germinal epithelium of gonads. • Required for cellular respiration. • Optimal absorption amino acids. • Proper storage of creatine in skeletal muscle.
    47. 47. Deficiency Manifestations • Rare in humans. • Major symptoms• Hemolytic anemia – increased red blood cell fragility. • Retrolental fibroplasia-premature babies(LBW). • Muscular weakness & creatinuria.
    48. 48. Recommended Dietary Allowance • Males – 10mg/day. • Females – 8mg/day. • Pregnancy - 10mg/day. • Lactation- 12mg/day. • 15 mg vitamin E = 33 IU. • Pharmacological dose = 200-400IU/day.
    49. 49. Dietary Sources • Richest source –  Vegetable oils – Wheat Germ Oil, Sunflower Oil, Safflower Oil, Cotton Seed Oil. • Coconut oils – relatively low. • Fish liver oils – devoid.
    50. 50. Hypervitaminosis • Severe symptoms not seen in humans. • Tendency of hemorrhage. • Neurological symptoms. • “Vitamin in search of a disease”.
    51. 51. THANK YOU

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