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

2.  -Carotene is split in the middle by β-carotene oxygenase into two molecules of retinol.  -carotene - the major provitamin A carotenoid Retinol (Vitamin A) Vitamin A and Carotenoids

3. β-Carotene  -Carotene  -Carotene Beta carotene and two examples of other provitamin A carotenoids

4. Carotenes = Hydrocarbon Carotenoids β-Carotene Lycopene -Carotene

5. Oxycarotenoids = Xanthophylls β-Cryptoxanthin Zeaxanthin Lutein OH

6. Vitamin A Sources in Diet Vitamin A Sources in Diet Preformed vitamin A (primarily as retinyl esters) comes from animal products. Plant sources of vitamin A actually supply provitamin A carotenoids. In US, carotenoids provide only 25% Vitamin A in diet.

7. Foods Rich in Carotenoids -carotene β-carotene lycopene lutein β-carotene lutein β-carotene -carotene β-carotene

8. Foods Rich in Carotenoids β-carotene in cantaloupe, lycopene in watermelon β-cryptoxanthin lycopene β-carotene β-cryptoxanthin

9. Retinyl palmitate  11 -cis- retinal Retinal, retinaldehyde all-trans-retinal Retinoic acid Retinoids: Biologically Important Vitamin A compounds

10. Note: Meat (i. e., muscle) is low in Vitamin A Foods Rich in Vitamin A

11. β-carotene -carotene retinyl esters β-carotene

12. Retinol Activity Equivalent (RAE): 1μg RAE = 1 μg retinol = 2 mg  -carotene in oil = 12 μg dietary β-carotene = 24 μg other pro-A carotenoids Previously vitamin A activity of dietary pro-A carotenoids was overestimated by a factor of 2. Retinol Equivalent: 1μg RE = 6 μg dietary  -carotene or 12 μg other pro-A carotenoids (National Research Council, 1989). 1μg retinol= 3.33 IU retinol = 20 IU  -carotene IU (International Unit) =0.3 μg retinol =0.6 μg β-carotene Vitamin A activity of carotenoids

13. Adequate Intake 0- 6mo 400 μg RAE 7-12 mo 500 μg RAE Recommended 1- 3 y 300 μg RAE Dietary 4- 8y 400 μg RAE Allowance (RDA) 9-13y 600 μg RAE >14y males 900 μg RAE >14y females 700 μg RAE Pregnancy RDA 770 μg RAE Lactation RDA 1300 μg RAE Tolerable Upper Intake Level (UL) 3000 μg RAE 2001 Dietary Reference Intakes for Vitamin A

14. Dietary Vitamin A Digestion Food Beta Carotene Retinyl Esters Retinol Pancreatic and Brush Border Lipases Carotene-15,15’- oxygenase

15. Dietary Vitamin A Absorption

16. Provitamin A Conversion Provitamin A carotenoids are thought to be converted by the intestine to vitamin A in inverse proportion to the amount present in the lumen (?) and with great individual variability. Absorbed intact provitamin A carotenoids circulate in blood and are deposited in various tissues, which also may convert them to vitamin A (liver, kidney, testis, ovary). Low absorption and conversion of provitamin A carotenoids make it impossible to produce vitamin A toxicity from plant sources.

17. Chylo remnants retinyl esters Vitamin A stored in stellate cells as retinyl esters RBP = Retinol Binding Protein Transthyretin = T 4 -binding protein Hepatic Metabolism and Storage of Vitamin A

18. (TTR = Transthyretin)

19. Vitamin A Functions Normal vision Gene expression control Reproduction (spermatogenesis) Fetal development Normal growth Epithelial cell differentiation Immune function

20. Carotenoid Actions and Associations Protection of skin and eyes from light Antioxidant capacity (quenching free radicals, protecting cells from oxidative damage) Decreasing risk of cancer (inhibition of neoplastic transformations) Enhancement of cell communication (expression of gap junction protein)

21. 11-cis retinal All-trans retinal Retinol Retinyl esters Rhodopsin Opsin Bleached rhodopsin LIGHT photon Signal to optic nerve Vitamin A in Visual Cycle

22. Retinoic acid a vertebrate morphogen a therapeutic agent a known human teratogen

23. Retinal Oxidase (irreversible) Retinal Retinoic acid NAD or FAD NADH or FADH 2 Synthesis of Retinoic Acid

24. Gene Expression Control by Retinoic Acid via DNA-binding nuclear receptors

25. Immune Functions of Vitamin A Maintaining level of circulating killer cells (anti-viral, anti-tumor) Increasing phagocytosis of macrophages Increasing production of lymphocytes Maintaining epithelial integrity

26. Retinoic acid and analogues are used topically and systemically for treatment of psoriasis and acne. Severe acne before & after sytemic treatment with 13-cis retinoic acid (isotretinoin, Accutane™) Before After

27. Retinoic acid and related compounds are teratogenic when used in pharmaceutical doses. This is directly related to their role as morphogens in embryonic development. The use of retinoic acid or synthetic analogues by pregnant women carries a high risk of birth defects in their infants. The most critical period is the first trimester of pregnancy. For this reason, the use of retinoic acid, isotretinoin (13-cis-retinoic acid, Accutane) is contraindicated for pregnant women or women who may become pregnant.

28. Birth defects in child of woman taking systemic retinoic acid for psoriasis

29. Vitamin A Toxicity Acute intoxication (150 mg dose): nausea, vomiting, headache, vertigo, blurred vision, bulging fontanel in infants due to increased cerebrospinal fluid pressure Chronic intoxication (30 mg/day): fatigue, irritability or lethargy, desquamation, alopecia, brittle nails, liver abnormalities (hepatomegaly, fibrosis, cirrhosis), bone loss and bone pain Skeletal bone loss – osteoporosis (3 mg/day = UL) in older subjects

30. Hypercarotenosis = Carotenemia

31. Vitamin A Deficiency - Xerophthalmia The impaired dark adaptation found in vitamin A deficiency is followed by conjunctival xerosis and keratinization. The latter gives rise to plaques comprised of layers of keratinized epithelial cells known as Bitot’s spots As deficiency progresses, keratomalacia develops, i.e., cornea becomes soft and milky in appearance and finally disentegrates, leading to blindness

32. Early conjunctival xerosis (xerophthalmia) Reduction in Goblet Cell Mucin leads to dry eyes

33. Later Stages of Vitamin A deficiency – Bitot’s Spots

34. Bitot’s Spot

35. Severe Vitamin A Deficiency - Keratomalacia Keratomalacia, involving cornea, results in blindness. Vit A deficiency is the leading cause of preventable blindness in the world.

36. Other Symptoms of Vitamin A Deficiency Failure of growth in children Faulty bone modeling Nerve lesions Increased cerebrospinal fluid pressure Follicular hyperkeratosis Increased morbidity and mortality from measles and diarrhea  vitamin A is used for treatment of measles

37. Vitamin A deficiency Follicular hyperkeratosis