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Vitamin A chemistry, functions and deficiency

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Vitamin A chemistry, functions and deficiency

  1. 1. Professor(Dr.) Namrata Chhabra Biochemistry for medics- Lecture notes www.namrata.co 07/30/15Biochemistry for medics- Lecture Notes 1
  2. 2.  Vitamin A is a fat soluble vitamin  Required for vision, repair, reproduction, growth and tissue differentiation  Two groups of compounds have vitamin A activity  Retinoids and  Carotenoids 07/30/15Biochemistry for medics- Lecture Notes 2
  3. 3.  Vitamin A, in the strictest sense, refers to retinol.  However, the oxidized metabolites, retinaldehyde and retinoic acid, are also biologically active compounds.  The term Retinoids includes all molecules (including synthetic molecules) that are chemically related to retinol. 07/30/15Biochemistry for medics- Lecture Notes 3
  4. 4. • There are more than 600 carotenoids in nature, and approximately 50 of these can be metabolized to vitamin A. • β-Carotene is the most prevalent carotenoid in the food supply that has provitamin A activity. • In humans, significant fractions of carotenoids are absorbed intact and are stored in liver and fat. • The α-, β-, and γ-carotenes and cryptoxanthin are quantitatively the most important provitamin A carotenoids. 07/30/15Biochemistry for medics- Lecture Notes 4
  5. 5. 07/30/15Biochemistry for medics- Lecture Notes 5 β – Ionone ring Unsaturated Isoprenoid side chain (all trans) Attaching group
  6. 6. 07/30/15Biochemistry for medics- Lecture Notes 6 •Site of β cleavage of carotene is shown by * •Although it would appear that one molecule of β carotene should yield two of retinol, this is not so in practice •6 μg of β carotene is equivalent to 1μ g of preformed retinol. •The total amount of vitamin A in foods is therefore expressed as micrograms of retinol equivalents.
  7. 7. • Liver, fish, and eggs are excellent food sources for preformed vitamin A; • Vegetable sources of provitamin A carotenoids include dark green and deeply colored fruits and vegetables. • Moderate cooking of vegetables enhances carotenoid release for uptake in the gut. • Carotenoid absorption is also aided by some fat in a meal. 07/30/15Biochemistry for medics- Lecture Notes 7
  8. 8.  Dietary Vitamin A, from animal sources is available in the form of Retinyl esters, which is hydrolyzed to retinol and fatty acid by pancreatic hydrolases  The absorption of retinol requires the presence of bile salts  In the intestinal cells, retinol is esterified back and secreted with chylomicrons 07/30/15Biochemistry for medics- Lecture Notes 8 Retinyl esters Fatty acid + Retinol
  9. 9. • β-Carotene is cleaved in the intestinal mucosa by carotene dioxygenase, yielding retinaldehyde, which is reduced to retinol, esterified and secreted in chylomicrons together with esters formed from dietary retinol. • The intestinal activity of carotene dioxygenase is low, so that a relatively large proportion of ingested β -carotene may appear in the circulation unchanged. 07/30/15Biochemistry for medics- Lecture Notes 9
  10. 10. • The liver contains approximately 90% of the vitamin A reserves and secretes vitamin A in the form of retinol, which is bound to retinol- binding protein. • The retinol-binding protein complex interacts with a second protein, Transthyretin. • This trimolecular complex functions to prevent vitamin A from being filtered by the kidney glomerulus, to protect the body against the toxicity of retinol and to allow retinol to be taken up by specific cell-surface receptors that recognize retinol-binding protein. 07/30/15Biochemistry for medics- Lecture Notes 10
  11. 11. 07/30/15Biochemistry for medics- Lecture Notes 11
  12. 12. • Vitamin A is essential for vision (especially dark adaptation), • Immune response, • Bone growth, • Reproduction, • Maintenance of the surface linings of the eyes, epithelial cell growth and repair, and the epithelial integrity of the respiratory, urinary, and intestinal tracts. • Vitamin A is also important for embryonic development and the regulation of adult genes. 07/30/15Biochemistry for medics- Lecture Notes 12
  13. 13. • In the retina, retinaldehyde functions as the prosthetic group of the light-sensitive opsin proteins, forming Rhodopsin (in rods) and iodopsin (in cones). • Any one cone cell contains only one type of opsin, and is sensitive to only one color. • The absorption of light by Rhodopsin causes isomerization of the retinaldehyde from 11-cis to all-trans, and a conformational change in opsin. • This results in the release of retinaldehyde from the protein, and the initiation of a nerve impulse. 07/30/15Biochemistry for medics- Lecture Notes 13
  14. 14.  The formation of the initial excited form of Rhodopsin, bathorhodopsin, occurs within picoseconds of illumination.  There are then a series of conformational changes leading to the formation of metarhodopsin II, which initiates a guanine nucleotide amplification cascade and then a nerve impulse. 07/30/15Biochemistry for medics- Lecture Notes 14
  15. 15.  The final step is hydrolysis to release all- trans-retinaldehyde and opsin.  The key to initiation of the visual cycle is the availability of 11-cis-retinaldehyde, and hence vitamin A.  In deficiency, both the time taken to adapt to darkness and the ability to see in poor light are impaired. 07/30/15Biochemistry for medics- Lecture Notes 15
  16. 16. 07/30/15Biochemistry for medics- Lecture Notes 16
  17. 17.  Retinoic acid is a ligand for certain nuclear receptors that act as transcription factors.  The retinoid receptors play an important role in controlling cell proliferation and differentiation.  Like vitamin D, retinoic acid interacts with nuclear receptors that bind to control elements which are specific regions on the DNA to regulate the expression of specific genes. 07/30/15Biochemistry for medics- Lecture Notes 17
  18. 18. Two families of receptors (RAR and RXR receptors) are active in retinoid-mediated gene transcription. RAR binds all-trans retinoic acid and 9-cis retinoic acid, whereas RXR binds only 9-cis retinoic acid. 07/30/15Biochemistry for medics- Lecture Notes 18
  19. 19.  All-trans-RA and 9-cis-RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins.  Within the nucleus, all-trans-RA binds to retinoic acid receptors (RAR) and 9-cis-RA binds to retinoid receptors (RXR).  RAR and RXR form RAR/RXR heterodimer, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). 07/30/15Biochemistry for medics- Lecture Notes 19
  20. 20.  Binding of all-trans-RA and 9-cis-RA to RAR and RXR respectively allows the complex to regulate the rate of gene transcription.  Nuclear Receptors in the Gonads increase gene expression and maintain reproductive tissues while nuclear receptors in epithelial cells regulate cell differentiation. 07/30/15Biochemistry for medics- Lecture Notes 20
  21. 21. 1) Vitamin A and retinoic acid (RA) play a central role in the development and differentiation of white blood cells, such as lymphocytes, which play critical role in the immune response. 2) The skin and mucosal cells (function as a barrier and form the body's first line of defense against infections. Retinol and its metabolites are required to maintain the integrity and functioning of these cells. Keratinization of mucous membranes in vitamin A deficiency add up to the risk to infections. 3)Retinol binding protein (RBP) is a negative ‘Acute phase protein’, that results in decreased circulatory concentration of the vitamin with further deterioration of the immune system. 07/30/15Biochemistry for medics- Lecture Notes 21
  22. 22.  Vitamin A is required for-  General body growth  Bone and  Brain development 07/30/15Biochemistry for medics- Lecture Notes 22
  23. 23. Vitamin A deficiency can result from inadequate intake, fat malabsorption, or liver disorders. Deficiency impairs immunity and hematopoiesis and causes skin rashes and typical ocular effects (e.g., xerophthalmia, night blindness). Diagnosis is based on typical ocular findings and low vitamin A levels. Treatment consists of vitamin A given orally or, if symptoms are severe or malabsorption is the cause, parenterally. 07/30/15Biochemistry for medics- Lecture Notes 23
  24. 24.  Primary vitamin A deficiency o Prolonged dietary deprivation o Vegetarians, o Refugees, and o Chronic alcoholics, o Toddlers and o Preschool children 07/30/15Biochemistry for medics- Lecture Notes 24
  25. 25.  Secondary vitamin A deficiency o Sprue, o Cystic fibrosis, o Pancreatic insufficiency, o Duodenal bypass, o Chronic diarrhea, o Bile duct obstruction, o Giardiasis, and cirrhosis. 07/30/15Biochemistry for medics- Lecture Notes 25
  26. 26.  Bitot spots - Areas of abnormal squamous cell proliferation and keratinization of the conjunctiva can be seen in young children with VAD.  Blindness due to retinal injury - Vitamin A has a major role in photo transduction. VAD leads to a lack of visual pigments; this reduces the absorption of various wavelengths of light, resulting in blindness.  07/30/15Biochemistry for medics- Lecture Notes 26
  27. 27.  Poor adaptation to darkness (nyctalopia), which can lead to night blindness, is an early symptom.  Xerophthalmia results from keratinization of the conjunctiva.  Keratomalacia- In advanced deficiency; the cornea becomes hazy and can develop erosions, which can lead to its destruction (Keratomalacia). 07/30/15Biochemistry for medics- Lecture Notes 27
  28. 28.  Increased susceptibility to infections- Keratinization of the mucous membranes of respiratory tracts and urinary tract takes place, increasing the susceptibility to infections.  During infection the synthesis of retinol binding protein is reduced in response to infection since it is a negative ‘Acute phase protein’, that results in decreased circulatory concentration of the vitamin with further deterioration of the immune system. 07/30/15Biochemistry for medics- Lecture Notes 28
  29. 29.  Fatigue  Anemia  Diarrhea  Respiratory infections  Decreased growth rate  Decreased bone development  Infertility 07/30/15Biochemistry for medics- Lecture Notes 29
  30. 30.  Serum retinol level-Normal range is 28 to 86 μg/dL (1 to 3 µmol/L). The level decreases in vitamin A deficiency.  Serum RBP level  Serum zinc level is useful because zinc deficiency interferes with RBP production.  An iron panel is useful because iron deficiency can affect the metabolism of vitamin A. 07/30/15Biochemistry for medics- Lecture Notes 30
  31. 31.  Albumin levels are indirect measures of vitamin A levels.  Complete blood count (CBC) with differential if anemia, infection, or sepsis is a possibility.  An electrolyte evaluation and liver function studies should be performed to evaluate for nutritional and volume status. 07/30/15Biochemistry for medics- Lecture Notes 31
  32. 32.  In children, radiographic films of the long bones may be useful when an evaluation is being made for bone growth and for excessive deposition of periosteal bone 07/30/15Biochemistry for medics- Lecture Notes 32
  33. 33.  Any stage of xerophthalmia should be treated with 60 mg of vitamin A in oily solution, usually contained in a soft-gel capsule.  Mothers with night blindness or Bitot's spots should be given vitamin A orally.  A common approach to prevention is to supplement young children living in high-risk areas with 60 mg every 4–6 months, with a half-dose given to infants 6–11 months of age. 07/30/15Biochemistry for medics- Lecture Notes 33
  34. 34.  Extremely low-birth-weight infants (<1000 g), are likely to be vitamin A–deficient and should be supplemented with 1500 μg (or RAE) of vitamin A, three times a week for 4 weeks.  Children hospitalized with measles should receive two 60-mg doses of vitamin A on two consecutive days.  The patients with malabsorption syndrome require vitamin A supplements. 07/30/15Biochemistry for medics- Lecture Notes 34
  35. 35.  The diet should include dark green leafy vegetables, deep- or bright-colored fruits (e.g., papayas, oranges), carrots, and yellow vegetables (e.g., squash, pumpkin).  Vitamin A–fortified milk and cereals, liver, egg yolks, and fish liver oils are helpful.  Carotenoids are absorbed better when consumed with some dietary fat. 07/30/15Biochemistry for medics- Lecture Notes 35
  36. 36.  In developing countries, prophylactic supplements of vitamin A palmitate in oil 60,000 RAE (200,000 IU) po every 6 mo are advised for all children between 1 and 5 years of age  Infants < 6 mo can be given a one-time dose of 15,000 RAE (50,000 IU), and  those aged 6 to 12 mo can be given a one-time dose of 30,000 RAE (100,000 IU). 07/30/15Biochemistry for medics- Lecture Notes 36
  37. 37.  Vitamin A toxicity can be acute (usually due to accidental ingestion by children) or chronic.  Both types usually cause headache and increased intracranial pressure.  Acute toxicity also causes nausea and vomiting. 07/30/15Biochemistry for medics- Lecture Notes 37
  38. 38.  Chronic toxicity also causes changes in skin, hair, and nails; abnormal liver test results; and, in a fetus, birth defects.  Diagnosis is usually clinical. Unless birth defects are present, adjusting the dose almost always leads to complete recovery. 07/30/15Biochemistry for medics- Lecture Notes 38
  39. 39.  Vitamin A deficiency can result from inadequate intake, fat malabsorption, or liver disorders.  Deficiency impairs immunity and hematopoiesis and causes skin rashes and typical ocular effects (e.g., xerophthalmia, night blindness). 07/30/15Biochemistry for medics- Lecture Notes 39
  40. 40.  Diagnosis is based on typical ocular findings and low vitamin A levels.  Treatment consists of vitamin A given orally or, if symptoms are severe or malabsorption is the cause, parenterally.  Excessive intake can lead to toxicity since the vitamin is stored in the body.   07/30/15Biochemistry for medics- Lecture Notes 40

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