VITAMIN A

Vitamin A is a fat soluble vitamin It’s active form is found only in

animal tissues RETINOIDS-include vit.A and

natural and synthetic chemicals that are structurally related to it

Those with Vit.A activity are retinol,retinal and retinoic acid

CAROTENOIDS(30%)-are provitamins of plant origin that can be metabolised to active Vit.A

Metabolism of vit.A- Absorption-bile,pancreatic enzymes. Both retinol& β-carotene(later converted to

retinol)is absorbed in intestine and carried in chylomicrons to liver

Receptor in liver-apoprotein-E 90% stored in liver as retinol ester in

perisinusoidal stellate cells(Ito) In healthy persons – 6 month reserves

mobilisation of retinol ester –retinol binds to specific RBP synthesized in liver

Uptake by peripheral tissuesdepends upon specific RBP receptors;retinol binds to cellular RBP and RBP released into blood

Retinol stored as retinol ester or converted to retinoic acid

FUNCTIONS Maintenance of normal vision Cell growth and differentiation Metabolic effects of retinoids Host resistance to infections

Maintenance of normal vision

Vision involves vitamin A containing rhodopsin and 3 iodopsin

SYNTHESIS OF RHODOPSINo Oxidation of retinol to all-trans-retinalo Isomerisation to-11-cis-retinalo Covalent association with 7-

transmembrane rod protein opsin to form rhodopsin

MECHANISM OF VISIONo Photoexcitation causes splitting of

rhodopsin and isomerization of 11-cis-retinal to all-trans-retinal

o Conformational change in opsinseries of eventsnerve impulse from retina to brain

o In Dark adaptation,all-trans-retinal converted to 11-cis-retinal which is reduced to retinol and lost in retina continuous supply

CELL GROWTH AND DIFFERENTIATION

Orderly differentiation of mucus-secreting epithelium

Deficiency-squamous metaplasia-keratinizing epithelium

Activation of retinoic acid recerptos by their ligands causes release of corepressors and formation of heterodimers with retinoic x receptor

RAR/RXR heterodimers bind to retinoic acid response elements located in regulatory gene regions that encode receptors for GFs,tumor suppresor genes and secreted proteins

Thus retinoids(all-trans-retinoic acid- highest affinity for RARs)control cell growth,differentiation,cell cycle control and other biologic responses

METABOLIC EFFECTS OF RETINOIDS

RXR(activated by 9-cis retinoic acid) form heterodimers with nuclear receptors involved in drug metabolism,PPARS,and vitamin D receptors

Peroxisome proliferator-activated receptors regulate fatty acid oxidation in fat tissue and muscle,adipogenesis,and lipoprotein metabolism

Association b/w RXR and PPARγ-explanation for matabolic effects of retinoids on adipogenesis

HOST RESISTANCE TO INFECTIONS

Diarrhea-maintenance and restoration of integrity of epithelium of gut

Measles-stimulation of immune system Infections inhibit RBP synthesis in liver

through acute phase response,causing a decrease in circulating retinol leadind to reduced bioavailability of Vit.A

Other functions Retinoids and carotenoids are

photoprotective and antioxidant agents Retinoids used for treatment of severe

acne,psoriasis,acute promyelocytic leukemia All-trans-retinoic acid induces differentiation

and apopotosis if apl cells by binding to PML-RARβ fusion protein that characterises this form of cancer

13-cis retinoic acid –treatment of childhood neuroblastoma

VITAMIN A DEFICIENCY Vitamin deficiency may be primary or

secondary Primary- due to dietary deficiency of

the vitamin Secondary-due to disturbances in

intestinal absorption,transport in blood,tissue storage,or metabolic conversion

In children stores of vit.A are depleted by infection

In adults malabsorption syndromes such as celiac disease,Crohn disease,colitis,may develop vit.A deficiency

Bariatric surgery and continuous use of mineral oil as laxative lead to deficiency

Impaired vision in reduced light-night blindness

Persistant deficiency leads to epithelial metaplasia and keratinisation

Effects on EYE: Xerophthalmia(dry eye)-it is due to

replacement of normal lacrimal and mucus secreting epithelium by keratinized epithelium

Bitots spot-devolopment of keratin debris in small opaque plaques

Keratomalacia-bitots spot progresses to erosion of corneal surface,softening and destruction of cornea and blindness

Loss of mucociliary epithelium of the airways predisposes to secondary pulmonary infection

Devolopment of keratin debris in urinary tract predisposes to renal and bladder stones

Hyperkeratinisation of epidermis with plugging of ducts of adnexal glands produce follicular or papular dermatosis

Vit.A deficiency also produce immune deficiency,making the individual susceptible to infections measles,pneumonia,and infectious diarrhea

HYPERVITAMINOSIS

Symptoms of acute Vit.A toxicity(similar to brain tumor) include:HeadacheDizzinessVomitingStupor andBlurred vision

Chronic toxicity produces:Weight lossAnorexiaNauseaVomitingBone and joint pain

• Retinoic acid stimulates osteoclast production and activity leading to bone resorption and risk of fractures

• Synthetic retinoids have teratogenic effects

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