Fat Soluble Vitamins

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

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

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

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

5. Oxycarotenoids = Xanthophylls β-Cryptoxanthin OH Lutein Zeaxanthin

6. 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 lutein β-carotene lycopene -carotene β-carotene β-carotene lutein β-carotene

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

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

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

11. Foods Rich in Vitamin A β-carotene -carotene retinyl esters β-carotene retinyl esters

12. Vitamin A activity of carotenoids 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

13. 2001 Dietary Reference Intakes for Vitamin A 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

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 Hepatic Metabolism and Storage of Vitamin A Vitamin A stored in stellate cells as retinyl esters RBP = Retinol Binding Protein Transthyretin = T4-binding protein

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

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

23. Retinal NAD or FAD Retinal Oxidase(irreversible) NADH or FADH2 Retinoic acid 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™) After Before

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