Vitamin A and Vitamin E

Dr. Abhishek Roy

Email: mail@abhishek.ro

Junior Resident, Dept. of Biochemistry,

Grant Govt. Medical College & Sir J.J. Group of Hospitals, Mumbai.

Categories:• Brief History

• Chemistry

• Functions

• Deficiency Disorders

• Treatment of Def. Disorders.

• Clinical Importance in Modern Medicine

• Hypervitaminosis

Definition

• Vitamins are organic bio-molecules which are required by a living organism in micro quantities and is to be derived from food sources as they cant be synthesized in the body (with the exception of Vitamin D and Niacin).

Classification

Fat Soluble Water Soluble

Fat Soluble Vitamins

•Vitamin A

•Vitamin D

•Vitamin E

•Vitamin K

WATER SOLUBLE

•Vitamin B Complex

•Vitamin C

WHY DOES DEFICIENCY OCCUR?

Reduced Intake

Impaired Absorption

Impaired Metabolism

Additional Requirements

Increased Losses

Vitamin A

Brief History

• François Magendie (1816)

• Nicolai Lunin (1880s)

• Carl Socin

• Frederick Gowland Hopkins (1906)

• Wilhelm Stepp (1911)

• In 1913, Elmer McCollum and Marguerite Davis at Wisconsin and Thomas Osborne and Lafayette Mendel at Yale showed butter and egg yolk were not equivalent to lard and olive oil in supporting the growth and survival of rats.

• The growth-supporting 'accessory factor' became known as 'fat-soluble A' in 1918 and then ‘Vitamin A' in 1920.

• Paul Karrer described the chemical structure of vitamin A in 1932.

• Harry Holmes and Ruth Corbet isolated and crystallized vitamin A in 1937.

• Methods for the synthesis of vitamin A came with the work of David Adriaan van Dorp and Jozef Ferdinand Arens in 1946 and Otto Isler and colleagues in 1947.

(Source: http://www.ncbi.nlm.nih.gov/pubmed/23183288)

Chemistry Of Vitamin A

• Fat Soluble Vitamin

• Active form is present only in Animal Tissue

• 20 carbon structure with a methyl substituted cyclohexenyl ring (β-ionone ring) and a tetraene side chain with a –OH(retinol), -CHO(retinal), -COOH (retinoic acid), -COOR(retinyl ester) at carbon-15.

• Pro-vitamin is documented in food sources - (α-carotene, β-carotene, β-Cryptoxanthin)- only in plants.

• β-carotene has two β ionone rings connected by a polyprenoid chain.

Active Forms• Consists of 3 biologically active forms collectively called Retinoids.

1. Retinol (Alcohol)

2. Retinal (Aldehyde)

3. Retinoic Acid (Acid)

Absorption And Transport• Dietary retinyl esters are hydrolysed by pancreatic/intestinal

hydrolases in intestine releasing retinol & free fatty acids.

• Carotenes are hydrolysed by β-carotene 15-15’ dioxygenase of intestinal cells to release 2 moles of retinal which is reduced to retinol.

• In intestinal mucosal cells, retinol is re-esterified to LCFA incorporated into chylomicrons & transferred to lymph.

• Retinol esters of chylomicrons are taken up by liver & stored.

• When required Vitamin A is released from liver as free retinol.

• Retinol is transported in circulation by Plasma Retinol Binding Protein in association with albumin(transthyretin).

• Retinol-RBP complex binds to specific receptors on cell membrane of peripheral tissues & enters cells.

• Carry retinol by Cellular Retinol Binding Protein(CRBP)and Cellular Retinoic Acid Binding Protein(CRABP-I, CRABP-II) to nucleus & binds to chromatin(DNA).

WALD’S VISUAL CYCLE

• G. Wald was awarded Nobel Prize in 1967

• Studied role of vitamin A in vision.

• 1) Generation of nerve impulse

• 2) Regeneration of 11-cis-retinal

Generation Of Nerve Impulse

•RHODOPSIN

Pivotal Role in the visual cycle.Membrane protein in photoreceptor of retina.Protein opsin and 11 cis-retinal.

• Visual pigments are G-protein coupled receptors.

• 11cis retinal locks opsin(receptor protein) in its inactive form.

• The isomerization & photoexcitation leads to activation of G-protein & regeneration of cyclic GMP.

cGMP(Na + Channel Open) 5’ GMP (Na + Channel Closed)

Inactive Phosphodiesterase Active Phosphodiesterase

GDP Transducin-GTP

Metarhodopsin

GTP Transducin-GDP

Pi

• Cyclic GMP acts as the gate for cation specific channels.

• TRANSDUCIN is the G-protein in retina.

• The nerve impulse thus generated in retina is transmitted to visual centers in brain.

• The signal is terminated by phosphorylation of serine residue of activated rhodopsin.

• Enzyme- Rhodopsin Kinase.

• Inhibitory protein β-arrestin binds & inactivates rhodopsin.

Dark Adaptation

• Torsten Wiesel -1981 Nobel prize.

• Bright light depletes stores of rhodopsin in rods.

• After few minutes rhodopsin is resynthesised & vision improved.

• This period called -Dark Adaptation Time.

• Increased in vitamin A deficiency.

Photosensitive Cells In Retina

•RodsDim Light

Contains Rhodopsin (opsin+11cis-retinal)

Def. of 11cis-retinal - Increased Dark Adaptation Time

(Night Blindness)

In humans:

1 eye =120 million rods

=120 million molecules of rhodopsin

• CONES• Bright Light & Color Vision

• Contains conopsin(photosensitive protein)

• 3 types of cones – characterised by different conopsin that is maximally sensitive to:

• Blue – Cyanopsin

• Green – Iodopsin

• Red – Porphyropsin

1 eye has 6 million cones.

FUNCTIONS• The 11-cis-retinaldehyde (retinal) form of vitamin A is required by the eye for the

transduction of light into neural signals necessary for vision (Saari, 1994).

• The Retinoic Acid form is required to maintain normal differentiation of the cornea and conjunctival membranes (Sommer and West, 1996)

• Vitamin A is required for the Rhodopsin Cycle.

• Vitamin A is said to have Anti-Oxidant Property too.

• Vitamin A is required for the integrity of epithelial cells throughout the body (Gudas et al., 1994).

• Retinoic acid plays an important role in embryonic development.

• The growth, differentiation, and activation of B lymphocytes requires retinol (Blomhoff et al., 1992).

• Retinoid are necessary for the maintenance of immune function.

Helps in Cell differentiation and proliferation

Maintains adequate levels of NK cells

Shown to increase phagocytic activity in murine macrophages and increase production of IL -1

• Nuclear Retinoid Receptors: Retinoid Acid Receptors (RAR) - All-trans-retinoic acid + 9-cis-retinoic

acid

Retinoid X Receptors (RXR) - 9-cis-retinoic acid

• Retinoid X receptors also form dimers with Vitamin D, Thyroid, and other a nuclear acting hormone receptors.

Rich Dietary Sources

• Organ Meats (Liver), Cod Liver Oil

• Cheese, Milk products

• Carrot juice

• Sweet Potato with peel

• Tomato

• Pumpkin

• Spinach

• Turnip Green

• Mixed Green leafy vegetables

RECOMMENDED DIETARY ALLOWANCE

• Units: • 1 Retinol Equivalent (R.E) = 1 mcg of Retinol

6 mcg of β-Carotene

12 mcg of other Carotenoids

• 1 International Unit (I.U) = 0.3 mcg Retinol

0.6 mcg β-Carotene

• RDA: Children : 400 mcg/day

Adult Male: 900 mcg/day

Adult Female: 700 mcg/day

Pregnant Female : 1000 mcg/day

Lactating female : 1200 mcg/day

DEFICIENCY DISORDERS

• Night Blindness (Nyctalopia)

XEROPHTHALMIA

Conjunctival Xerosis Corneal Xerosis

Bitot Spot- Plaques In Conjunctiva

Keratomalacia followed by Blindness

Localised corneal Ulcer

Adherent Leukoma

Follicular Hyperkeratosis

Histological Finding In Cornea

Xerophthalmia Classification

• XN- Night blindness

• X1A- Conjunctival Xerosis

• X1B- Bitot’s spot

• X2- Corneal Xerosis

• X3A- Corneal ulceration/Keratomalacia (<1/3rd of the corneal surface)

• X3B- Corneal ulceration/Keratomalacia (1/3rd or more of the corneal surface)

• XF - Xerophthalmic Fundus

• XS - Corneal scars presumed secondary to Xerophthalmia

Some Novel Roles Of Vitamin A

Role In Measles

Revised routine Immunization Schedule from NRHM

Role In ARMD• ARMD (Age-related Macular Degeneration) - Notorious for significant

vision loss in old age.

• Cumulative effect of oxidative stress is postulated to play a role.

• Supplements with anti-oxidant carotenoids- β-Carotene, Lutein, Zeaxanthin.

• In a more detailed analysis of results, supplementation with Lutein and Zeaxanthin reduced the risk of advanced AMD by 26% in participants with the lowest dietary intakes of these two carotenoids who took a supplement containing them compared to those who did not take a supplement with these carotenoids. (In AREDS II)

• Therefore the healthcare provider should consider offering one of the compounds used in AREDS.

ROLE IN SEVERE ACNE

• Isotretinoin (or 13-cis-retinoic acid) is an aromatic retinoid similar to vitamin A which is effective in treating recalcitrant nodular acne and other disorders of keratinization. Unlike vitamin A, isotretinoin is not stored in the liver and is not associated with many of the toxic effects of high-dose vitamin A therapy.

• MOA- Activation of RAR & RXR.

• Category X drug for pregnancy- strictly avoided.

• 2nd Generation Retinoid, hence lack of receptor specificity- Side effects.

• Hepatotoxicity

• Dry Skin(peeling of skin)

• Worsening of Hyperlipidemia

• Hyperostosis

• Vision and Hearing loss

Role In Acute Promyelocytic Leukemia(M3)

• All Trans Retinoic Acid (ATRA) is being used in two combinations: ATRA + Anthracycline derivative ( Daunorubicin, Idarubicin)/Even Cytarabine(Ara-C) ATRA + Arsenic Trioxide (Trisenox) – In patients who can’t tolerate Anthracyclines.

Side effects:

Both ATRA and Arsenic may cause Differentiation Syndrome( previously called Retinoic Acid Syndrome)Symptoms include: Dyspnea due to Hydrothorax. Hypotension Renal Damage Often Ana Sarca

Hypervitaminosis

• If there is increase in concentration of Vitamin AVisual and hearing Defects.Severe Headache due to Pseudotumor Cerebri.Increased ALT and AST as it is hepatotoxic in large

doses (Liver is the chief storage organ of Vitamin A)AnorexiaIrritabilityIn Pregnancy it – Congenital Malformations

Vitamin E

Introduction

•Naturally occuring anti-oxidant.

•Evans & Bishop(1936)-isolated active vitamin.

•Named – Tocopherol.

(Tokos : childbirth, pherein: to bring ,ol : alcohol)

•Anti-sterility vitamin.

Structure And Chemistry

• Elucidated by Paul Karrer.• Name given to a group of tocopherols & tocotrienols.• Derivatives of 6-hydroxy chromane (tocol) ring with

isoprenoid side chain.• About eight tocopherols have • been identified.

• Named as – α,β,γ,δ (On the basis of the number and position of the methyl group on the chromane ring)

α-tocopherol (5,7,8 trimethyltocol) is most active biologically.

• Normal plasma level - 0.5-1mg/dl.

• Absorbed along with fat in Small intestine.

• Bile salts necessary.

• In liver, incorporated in Lipoproteins & transported.

• Stored in ADIPOSE TISSUE, liver & muscle.

• During catabolism, chromane ring & side chain may be oxidised.

• Excreted in bile- conjugation with glucuronic acid

FUNCTIONS

• Antioxidant(most powerful natural)

• Free radical scavenger

• Protects cell membranes

• Protects LDL from oxidation

• Protection of double bonds in polyunsaturated fatty acids

• Prevention of rancidity

• Works in conjunction with selenium

• Protects RBCs from hemolysis.

• Structural & functional integrity of all cells.

• Slowing down of ageing process.

• Boosts immune response.

• Reduces risk of atherosclerosis.

• Depress leucocyte oxidative bactericidal activity.

• Stabilize reactions or situations that typically produce free radicals

• Required for Proper Hair Growth (Beauty Vitamin along with BIOTIN)

• Preserves & maintains germinal epithelium of gonads.

• Required for cellular respiration.

•Optimal absorption amino acids.

• Proper storage of creatine in skeletal muscle.

Deficiency Manifestations

• Rare in humans.

•Major symptoms-

•Hemolytic anemia – increased red blood cell fragility.

• Retrolental fibroplasia-premature babies(LBW).

•Muscular weakness & creatinuria.

Recommended Dietary Allowance

•Males – 10mg/day.

• Females – 8mg/day.

• Pregnancy - 10mg/day.

• Lactation- 12mg/day.

• 15 mg vitamin E = 33 IU.

• Pharmacological dose = 200-400IU/day.

Dietary Sources

• Richest source –

Vegetable oils – Wheat Germ Oil, Sunflower Oil, Safflower Oil, Cotton Seed Oil.

• Coconut oils – relatively low.

• Fish liver oils – devoid.

Hypervitaminosis

•Severe symptoms not seen in humans.

•Tendency of hemorrhage.

•Neurological symptoms.

•“Vitamin in search of a disease”.

THANK YOU