Fat Soluble VitaminsFat Soluble VitaminsVitamin AVitamin DVitamin EVitamin K

-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 Vitamin A and CarotenoidsCarotenoids

β-Carotene

-Carotene

-Carotene

Beta carotene and two examples Beta carotene and two examples of other provitamin A carotenoids of other provitamin A carotenoids

Carotenes =Carotenes =Hydrocarbon CarotenoidsHydrocarbon Carotenoids

β-Carotene

Lycopene

-Carotene

Oxycarotenoids = XanthophyllsOxycarotenoids = Xanthophyllsβ-Cryptoxanthin

Zeaxanthin

Lutein

OH

Vitamin A Sources in DietVitamin 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 .

Foods Rich in CarotenoidsFoods Rich in Carotenoids

-caroteneβ-carotene

lycopene

luteinβ-carotene

luteinβ-carotene

-caroteneβ-carotene

β-carotene

Foods Rich in CarotenoidsFoods Rich in Carotenoids

β-carotenein cantaloupe,lycopenein watermelon

β-cryptoxanthinlycopene

β-carotene

β-cryptoxanthin

Retinyl palmitate

11-cis-retinal

Retinal, retinaldehydeall-trans-retinal

Retinoic acid

Retinoids: Biologically ImportantVitamin A compounds

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

Foods Rich in Vitamin AFoods Rich in Vitamin A

Foods Rich in Vitamin AFoods Rich in Vitamin A

β-carotene-carotene

retinyl esters

retinyl estersβ-carotene

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 -caroteneIU (International Unit) = 0.3 μg retinol =0.6 μg β-carotene

Vitamin A activity of Vitamin A activity of carotenoids carotenoids

Adequate Intake 0- 6mo 400 μg RAE 7-12 mo 500 μg RAERecommended 1- 3 y 300 μg RAE Dietary 4- 8y 400 μg RAEAllowance (RDA) 9-13y 600 μg RAE >14y males 900 μg RAE >14y females 700 μg RAE Pregnancy RDA 770 μg RAELactation RDA 1300 μg RAE

Tolerable Upper Intake Level (UL) 3000 μg RAE

2001 Dietary Reference Intakes 2001 Dietary Reference Intakes for Vitamin Afor Vitamin A

Dietary Vitamin A DigestionDietary Vitamin A Digestion

FoodBeta Carotene Retinyl Esters

Retinol

Pancreatic and Brush Border

Lipases

Carotene-15,15’-

oxygenase

Dietary Vitamin A AbsorptionDietary Vitamin A Absorption

Provitamin A ConversionProvitamin 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.

Chyloremnants

retinylesters

Vitamin A storedin stellate cellsas retinyl esters

RBP =RetinolBindingProtein

Transthyretin =T4-bindingprotein

Hepatic Metabolism and Storage of Vitamin AHepatic Metabolism and Storage of Vitamin A

(TTR = Transthyretin)

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

Carotenoid Actions and Carotenoid Actions and AssociationsAssociations

• 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)

11-cisretinal

All-transretinal

Retinol

Retinylesters

Rhodopsin

Opsin

Bleachedrhodopsin

LIGHTphoton

Signal tooptic nerve

Vitamin A in Visual Cycle Vitamin A in Visual Cycle

Retinoic acidRetinoic acid

• a vertebrate morphogen• a therapeutic agent• a known human teratogen

Retinal Oxidase(irreversible)

Retinal

Retinoic acid

NAD or FAD

NADH or FADH2

Synthesis of Retinoic AcidSynthesis of Retinoic Acid

Gene Expression Control by Retinoic AcidGene Expression Control by Retinoic Acidvia DNA-binding nuclear receptorsvia DNA-binding nuclear receptors

Immune Functions of Immune Functions of Vitamin AVitamin A

• Maintaining level of circulating killer cells (anti-viral, anti-tumor)

• Increasing phagocytosis of macrophages

• Increasing production of lymphocytes

• Maintaining epithelial integrity

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

Before After

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.

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

Vitamin A ToxicityVitamin 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

Hypercarotenosis = Carotenemia

Vitamin A Deficiency -Vitamin A Deficiency -XerophthalmiaXerophthalmia

• 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

Early conjunctival xerosis Early conjunctival xerosis (xerophthalmia)(xerophthalmia)

Reduction in Goblet Cell Mucin

leads to dry eyes

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

Bitot’s Spot

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

Other Symptoms of Vitamin A DeficiencyOther 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

Vitamin AVitamin Adeficiencydeficiency

Follicularhyperkeratosis