Vitamin A

Medical biochemistry

1. VITAMIN A Prof. Dr. V.P. Acharya

2. What do we learn??? How it was found and named?- History How it looks and behaves- the chemistry What happens to it in our body?- The metabolism What’s its role?- Biochemical functions How much is required?- RDA How much is too much?- Hypervitaminosis A What’s new?- Recent advances

3. General format Vitamin (Synonym if any) Chemistry Metabolic functions Dietary source RDA Deficiency manifestations Hypervitaminosis Other

4. History Greeks - Beef liver raw dipped in honey as a remedy to nightblindness 1913- Mc Collum , Simmonds and Kennedy isolated vitamin A Richard Kuhn- Identified carotene 1931- Paul Karrer identified the structure of Vitamin A1

5. Chemistry Active form only in animals Retinoids – Retinol, Retinal & Retinoic acid; Preformed, found in animal origin Carotenoids - α -, β -, γ - carotenes & Cryptoxanthines, plant origin, Provitamin Vitamin A activity of β - carotene is – 1/12 of retinol activity Vit A1- All trans retinal MC variety

6. Beta- carotene- ideally should yield 2 retinal; conversion inefficient Retinal can be converted to retinol but easily reversible. Retinal → Retinoic acid (Irreversible)

7. The Metabolism

8. Absorption Beta carotene ↓ Retinal NADH/ NADPH ↓ Retinol ↓ Absorbed through intestinal mucosal cell along with other fats and bile salts ↓ Within cell, retinol is re- esterified , incorporated into chylomicrons and taken to liver ↓ Liver to peripheral tissue by RBP (Retinol binding protein) Di-oxygenase Retinal reductase

9. Mechanism of action of Vitamin A RBP-Retinol complex goes to extra-hepatic tissues- Retina, skin, gonads and other tissues ↓ Transport protein on cell surface carries retinol ↓ Retinol oxidized → Retinoic acid ↓ Binds to specific receptor proteins (Retinoic acid receptors RAR ) present in the nucleus ↓ Bind to HRE (Hormone receptor elements) on DNA ↓ Retinoid –specific RNA synthesis

10. Mechanism of action of Vitamin A

11. Biochemical role of Vitamin A

12. Wald’s Visual cycle George Wald NP- 1967

13. The Eye & Phototransduction Light enters from here. Photoreceptors face away. Anterior Posterior

14. The Eye & Phototransduction Rods out number cones by approximately 100 million to 5 million, in each eye. The most central part of the retina contains only cones. Cone density decreases with eccentricity, and in the far periphery, only rods are found. Lumping rods and cones together, photoreceptor density (overall) decreases with eccentricity. So, vision is less sharp in the periphery.

15. P hoto receptor

16. 1- Photo pigment (rhodopsin) 2- G protein transducin 3-CGMP phospho-diesterase enzyme Each disk contains….

17. How Nerve conduction works???

18. When light hits a photoreceptive pigment within the photoreceptor cell ↓ Rhodopsin changes to Metarhodopsin II on photon exposure ↓ Metarhodopsin II activates transducin ↓ Activation of cGMP phosphodiesterase ↓ cGMP → 5’GMP ↓ ↓cGMP ↓ Closes the Na + gated channels ↓ hyperpolarization of the rod ↓ Ca ++ channels closed ↓ stopping the release of neurotransmitters (Glutamate)

19. How to stop this?? Phosphorylation of serine residue of activated rhodopsin ↓ Inhibitory protein Beta- arrestin binds ↓ Inactivates rhodopsin Rhodopsin kinase

20. Dark adaptation Bright light bleaches rhodopsin In Vit A deficiency dark adaptation time increases ↑

21. Cones for c o l o u r vision Conopsin 3 types of cones- Cyanopsin , iodopsin , porphyropsin Similar mechanism as rods

22. Growth and differentiation Regulation of gene expression-- All-trans- retinoic acid & 9-cis-retinoic acid- act like steroid hormones All-trans retinoic acid binds to RAR & 9-cis-retinoic acid binds to RXR Cell differentiation Epithelial maintenance Immune cell proliferation Matrix protein sulfation - bone growth

23. Vitamin A deficiency leads to hamper Vitamin D action !! RAR & RXR receptors Vitamin D binds to RXR receptors Vit A deficiency- receptor dimers of Vit. D is not formed. Retinol- reproductive function β - Carotene- antioxidants

24. Vitamin A Dr. V.P.Acharya Dietary source

25. Daily requirement Infants & children- 400-600 μ g / day Male- 750-1000 μ g / day Female- 750 μ g / day Pregnancy- 1000 μ g / day Lactation- 1200 μ g / day

26. Bitot’s spot Keratomalacia Deficiency manifestation How deficiency occurs?? ↓ intake Obstructive jaundice Cirrhosis of liver Severe malnutrition- RBP synthesis ↓ Chronic nephrosis- RBP excreted

27. Nyctalopia / Night-blindness Xerophthalmia Bitot’s spots Keratomalacia Blindness Hyperkeratosis / Phrynoderma Keratinizing metaplasia of resp epithelium, GIT, genitourinary tract Urinary calculi ↑Infections Growth retardation- skeletal growth

28. Vitamin A is toxic in excess Unbound Vitamin A causes toxicity CNS- pseudotumour cerebri Hepatomegaly Hyperlipidaemia Hypercalcaemia, thickening of long bones, calcinosis Drying of skin, desquamation, alopecia

29. Therapeutic use Tretinoin (All trans retinoic acid)- synthetic preparation Retinol- dietary supplement Retinoic acid- Dermatology Isotretinoin (isomer of retinoic acid)–used for severe and disfiguring cystic acne but is teratogenic

30. Vitamin A supplementation ?? 1970- National Prophylaxis Programme against Nutritional Blindness due to vitamin A deficiency ( NPPNB due to VAD )  1lakh IU- 9mth along with measles vaccine 2lakh IU 6 mthly upto 5 years Therapeutic dose- 2 lakh unit at 4 week’s interval twice

31. Vitamin A fortification

32. What’s new?? Can cure cold and flu when supplemented with Vitamin D

33. Thanks for a patient listening

34. For more ppt on Medical Biochemistry please visit my website www.vpacharya.com