Vitamin A and Carotenoids

VITAMIN A

Discovered to be an essential growth factor in animal foods in 1915.

Vitamin A = preformed vitamin A or RETINOIDS

• Refers to a group of compounds that possess the biological activity of ALL-TRANS RETINOL
• RETINOIDS: retinol, retinal, retinoic acid, retinyl ester, and synthetic analoguess
• Structural similar
• B-ionone ring
• Polyunsaturated side chain (4 isoprenoid units with a series of conjugated double bonds in a trans or cis confirmation) with
• Alcohol group (retinol)
• Aldehyde group (retinal)
• carboxyl group (retinoic acid)
• ester group (retinyl ester)
• CAROTENOIDS
• Red, orange, yellow lipid-soluble pigments found mainly in plants
• 600 carotenoids in nature and <20 in human blood and tissue
• 3 carotinoids can be converted to RETINAL are known as PROVITAMIN A CAROTINOIDS
• B-carotene - exhibits greatest amount of provitamin A activity
• a-carotene
• b-cyptoxanthin
• Other important carotinoids that are not provitamin A precursors:
• LYCOPENE (an open chain analog of b-carotene)
• Oxycarotenoids
• Canthaxanthin
• Lutein
• Zeaxanthin

• Structurally: Expanded carbon chain containing conjugated double bonds with an unsubstituted B-ionone ring

SOURCES

DIGESTION/ABSORPTION

Vitamin A is bound to other food components and requires digestion:

• Retinol bound to fatty acid, 70-80% absorbed
• Carotenes bound to protein, <5% if uncooked to 60% in oils
• Reduced absorption if:
• Fiber esp pectin intact
• Excessive vitamin E

Synthesis of Vitamin A begin in enterocyte:

• B-carotene
• noncentral cleavage
• central cleavage
• Retinoids
• Reduced by retinal aldehyde reductase (NADH dependant) to Retinol
• Retinol is re-esterified for incorporation into chylomicrons
• Primary pathway: Cellular Retinol Binding Protein (CRBPII)
• Acyl-Co A Transferase (ARAT)

TRANSPORT/STORAGE

To leave the enterocyte for transport to tissues, newly formed retinyl esters are incorporated into CHYLOMICRONS which enters lymph and then into circulation by the thoracic duct bypassing the liver.

Tissue delivery includes:

• Bone marrow
• Blood cells
• Spleen
• Muscle
• Lungs
• Kidneys
• Adipose - stores about 15-20%

Remainder (65-75%) goes to Liver, taken up by endocytosis and degraded in lysosomes in the Hepatic Cell. Some retinol is esterified and stored in the STELLATE CELLS of the liver. 

Retinol transport in blood requires 2 specific proteins:

• Retinol binding protein (RBP)
• Transthyretin

Carotenoids reaching the liver undergo metabolism and may be incorporated into VLDLs. Carotenoids are taken up by tissues as part of a lipoprotein.

FUNCTIONS/MOA

Vitamin A

Functions:

• vision
• 11-cis retinal form that binds opsin of visual pigments to mediate phototransduction (the process in which light converted to electrical signals)
• For all other function, all trans-retinoic acid and 9-cis retinoic acid
• cellular differentiation
• growth
• reproduction
• bone development
• immune function

(1) VISION:

• Retina contains 2 types of cells:
• Cones: center of retina, vision in day
• Rods: active in darker light
• Rhodopson - a vitamin A containing pigment protein

(2) SIGNALING ~ retinol

Insulin response
Lipid homeostasis

(3) Cellular differentiation, proliferation, and growth ~ retinoic acid

Roles:

• Involved in cellular differentiation by which an immature cell is transformed into a specific type of mature cell.
• Epithelial cells in skin and all internal body tracts (respiratory, GI, GU tracts) all require vitamin A.
• Retinoic acid directs the differentiation of KERATINOCYTES into mature epidermal cells through interactions with nuclear chromatin and gene expression. 
• With Vit A deficiency, keratin producing cells replace mucous secreting cells (eyes, skin, GIT, trachea) and disrupt function.
• Regulates proliferation and differentiation of myeloid precursor cells in bone marrow. These stem cells differentiate into dendritic cells and mature after antigen exposure to T cells.
• Role in cell cycle ~ cancer
• Because of its ability to induce differentiation and apoptosis and to inhibit proliferation, retinoids have been used as chemotherapeutics.
• Modify cell surfaces 

(4) Other functions

• Reproductive processes
• Bone development and maintenance
• Regulation of osteoblasts and osteoclasts
• Deficiency ~ excessive deposition of bone by blasts
• Excess vit A ~ stimualtes osteoclasts
• Hematopoiesis
• Immune system functions
• Morphogenesis and Embryogenesis

Carotenoids

 Found in lipoproteins and in cell membranes, soluble in lipids and capable of quenching singlet oxygen (O2) and free radicals. 

Functions:
(1) Antioxidant

• Quenching 

(2) Eye health

• Zeaxanthin and Lutein are present in macula, inhibit oxidation and protect against eye damage. 

(3) Heart Disease

• Prevents oxidation of LDL

(4) Cancer protection

• Inhibit cell proliferation and stimulate cell differentiation

INTERACTIONS

Excess vit A intake interferes with vit K absorption
High B-carotene intake decreases vit E concentrations
Protein and zinc influence vit A status and transport:

• Protein interferes with carotenoid dioxygenase which cleaves B-carotene
• Zinc required for protein synthesis (RBP and transthyretin) and converting retinol to retinal

Iron metabolism:

• Iron is a cofactor for enzyme responsible for B-carotene conversion to retinal
• Vit A ~ decreased iron into RBCs and diminished iron mobilization
• ~ Fe def anemia

EXCRETION

Excreted in urine and feces

RDA

Expressed as retinol activity equivalents (RAE) to account for differences in the activity of the carotenoids.

• Vit A = men 900 mcg RAE (3,000 IU), women 700 (2,310)

DEFICIENCY

Manifestations:

• Anorexia
• Retarded growth
• Increased infections
• Hair follicle obstructions
• Ketinization of skin 
• Dry skin/scaly
• Eyes
• Retina, conjunctiva, cornea
• Inability to adapt to dim light
• Xerosis ~ dry cornea
• Bitot's spots - small white ketanization of cornea

RX:

• 2,000-200,000 IU (600-60,000 mcg RAE) daily

At risk:

• Fat malabsorption with Steattorhea
• Acute protein deficiency, nephritis, parasites, infections

TOXICITY

TUL is 3,000 mcg RAE (10,000 IU) per day

Hypervitaminosis A:

• Acute: increased ICP, headache, diarrhea, skin peeling
• Chronic: anorexia, alopecia, skin peeling, ataxia, bone and muscle pain
• Teratogenic

Carotenoids have few toxic side effects.

ASSESSMENT OF STATUS

Electroretinograms
Plasma retinol ~ excess