Vitamin A (fat Soluble Vitamin)

FAT SOLUBLE VITAMINS BY BRIG ABDUL KHALIQ NAVEED DEAN, PROF & HEAD DEPT OF BIOCHEMISTRY & MOLECULAR BIOLOGY

LIPID SOLUBLE VITAMINS

C H3 H2 C C H

C CH2

LIPID SOLUBLE VITAMINS • ABSORBED ALONG WITH FATS/LIPIDS • TPT ALONG WITH LIPOPROTEINS OR SPECIFIC BINDING PROTEINS • VIT A-RETINOIDS FOR NIGHT VISION AND EPITHELIAS • VIT D FOR Ca & P - METABOLISM • VIT E-ANTIOXIDANTS PROTECT LIPID PEROXIDATION • VIT K-BLOOD CLOTTING, POST TRANSLATIONAL MODIFICATION OF CLOTHING FACTORS; II, VII, IX, & X

FAT SOLUBLE VITAMINS • THE LIPID SOL (FATE SOLUBLE) VIT ARE APOLAR HYDROPHOBIC MOLECULES WHICH ARE ALL ISOPRENOID DERIVATIVES EXCEPT VIT-D WHICH IS STEROL DERIVATIVE. • ABSORBED BY GIT LIKE FATS SO FATS SHOULD BE ABSORBED NORMALLY • “STEATORRHOEA AND BILIARY DISORDERS” WILL DISTURB FAT ABSORPTION SO LEAD TO MALABSORBTION OF THESE VITAMINS • TRANSPORTED IN BLOOD BY LIPOPROTEINS OR SPECIFIC BINDING PROTEINS.

FAT SOLUBLE VITAMINS • STORED IN LIVER (VIT A, D,K). VIT-E IS STORED IN ADIPOSE TISSUE • NOT EXCRETED IN URINE BUT VIA BILE AND THUS EXCRETED VIA FECES. BUT ONLY WATER SOLUBLE VARIANT • BECAUSE BODY CAN STORE EXCESS VIT SO TOXICITY CAN RESULT DUE TO OVER DOSAGE ESPECIALLY FOR VIT-A AND VIT-D (1,25 DIOH-D3) • IN TRUE SENSE VIT-D (CHOLECALCIFEROL) IS A HORMONE INTIMATELY INVOLVED IN REGULATION OF Ca++ AND PHOSPHATE METABOLISM [CALCITRIOL]

FUNCTIONS OF VITAMIN A (RETINOIDS) • • • •

SUPPORT GROWTH AND HEALTH VISION (ROD-VISION) - RETINAL REPRODUCTION - RETINOL MUCOUS SECRETIONS AND EPITHELIAS (RETINOID ACID)

VITAMIN A (RETINOL) •

• • •

(RETINOIDS) SOURCE: RETINOL FROM FOODS OF ANIMAL ORIGIN. LIVER, OILS OF FISH ARE RICHEST SOURCE IN FOOD. MILK, BUTTER, EGG YOLK, LIVER, HEAT STABLE RETINAL, RETINOIC ACID AND RETINOL EXHIBIT BIOLOGICAL ACTIVITY OF VIT A ONLY RETINOL HAS FULL “VIT A” ACTIVITY VIT A HAS A PROVITAMIN ( CAROTENE IN VEGETABLE CARROT (1/6 EFFECTIVE AS VITA) DARK GREEN VEGETABLE & FRUITS, YELLOW

RETINOIC ACID  PARTICIPATE IN GLYCOPROTEIN SYNTHESIS  PHOSPHORYLATED RETINOIC ACID ACT AS CARRIER OF SPECIFIC OLIGOSACCHARIDES RESIDUES. TO FORM GLYCOPROTEINS;  DEFICIENCY OF THIS MOITY CAUSE REDUCTION OF 80% MANNOSE BOUND TO LIVE GLYCOPROTEINS  RETINOIC ACID; PARTICIPATE IN GLYCOPROTEIN SYNTHESIS THIS ACTION OF RETINOIC ACID IS FOR PROMOTING GROWTH AND DIFFERENTIATION OF TISSUE

RETINOIC ACID; PARTICIPATE IN GLYCOPROTEIN SYNTHESIS THIS ACTION OF RETINOIC ACID IS FOR PROMOTING GROWTH AND DIFFERENTIATION OF TISSUE

ABSORPTION, TPT & METABOLISM OF VIT.A • DIGESTION OF VIT A ACCOMPANIES THAT OF LIPIDS FOLLOWED BY TRANSFORMATIONS IN THE INTESTINAL MUCOSA • RETINOL ESTERS IN DIET ABSORBED IN INTESTINE • ß-CAROTENE RETINAL RETINOL + RETINOIL ACID IN CELL RETINOL ESTERS CHYLOMICRONS LIVER

FUNCTIONS • RETINOL ACTS LIKE A STEROID HORMONE • RETINOL CRBP+ NUCLEAR PROTEIN CONTROL OF EXPRESSION OF GENES. SUPPORT OF THE REPRODUCTIVE SYSTEM MAY BE ASCRIBED TO THIS FUNCTION

ß - ( CAROTENE DIOXYGENASE ß-( CAROTENE

RETINALDEHYDE O2 BILE SALTS LECITHIN

(TWO MOLECULES

REDUCTASE RETINALDIHYDE

RETINOL (VIT A) NADPH

OXIDIZED (RETINOIC ACID)

NADP+

VITAMIN A IS STORED IN LIVER AND RELEASED INTO BLOOD ATTACHED TO BINDING PROTEINS • RETINOL BINDING PROTEIN (RBP) [APORETINOL BINDING PROTEINS] • CELLULAR RETINOL BINDING PROTEIN (CRBP) (IN CYTOPLASM OF CELL) • RETINOL, RETINAL AND RETINOIL ACID EACH HAVE THEIR OWN UNIQUE BIOLOGIC FUNCTION • RETINOL RETINAL • RETINOIC ACID ONCE FORMED CAN NOT BE RECONVERTED BACK TO RETINAL OR RETINOL

VIT A ROLE IN DIM VISION (NIGHT VISION) [RETINAL] VIT A RHODOPSIN DARK

11-CIS RETINAL

NADH

LIGHT

OPSIN ALL-TRANS RETINAL ISOMERASE

NADH ALCOHOL DEHYDROGENASE

NAD

NAD

11-CIS RETINOL

ALL TRANS RETINOL ISOMERASE

DEFICIENCY SYMPTOMS LACK OF VITAMIN A CAUSES CHARACTERISTIC DEFICIENCY SYMPTOMS. THESE ARE DUE TO MALFUNCTION OF THE VARIOUS CELLULAR MECHANISMS IN WHICH RETINOIDS PARTICIPATE  DEFECTIVE NIGHT VISION – NIGHT BLINDNESS [RETINAL]  KERATINIZATION OF OF TISSUES OF EPITHELIALS OF EYES, LUNGS, G.URI, TRACT WITH REDUCTION IN MUCOUS SECRETIONS [RETINOIC ACID] [RETINOL]  XEROPHTHALMIA AND KERATOMALACIA  BOTH RETINOIDS AND CAROTENOIDS HAVE ANTICANCER ACTIVITY BY VIRTUE OF THEIR ANTIOXIDATION PROPERTY

DEFICIENCY SYMPTOMS  RETINOID FOR NORMAL CELL DIFFERENENTIATION  RETINOIDS DECREASED EFFECT OF SOME CARCINOGENS  BETA CAROTENE IS AN ANTIOXIDANT IT TRAPES PEROXY – FREE RADICALS IN TISSUES AT LOW PARTIAL PRESSURE OF O2  VIT E HAS THIS PROPERTY AT HIGH O2 CONC THESE TWO LIPID SOL VITAMINS MAY WELL ACCOUNT FOR THEIR POSSIBLE ANTICANCER ACTIVITY, IN CONJUCTION WITH ASCORBIC ACID, WHICH REDUCES TH OXIDIZED FORM OF VIT E, TO BE UTILIZED AS ANTIOXIDANT

VIT A DEFICIENCY • DEFECTIVE NIGHT VISION-WHEN LIVER STORES ARE NEARLY EXHASTED • KERATINIZATION OF EPITHELIUM OF EYES, LUNGS, GIT, GENIT URINARY TRACT • REDUCTION IN MUCOUS SECRETIONS • XEROOPHTHALMIA • KERATOMALACIA • POOR DIET, ALCOHOLICS

VIT A TOXICITY • OCCURS WHEN CAPACITY OF CRBP HAS BEEN EXCEEDED • EXCESSIVE USE OF VIT-A SUPPLEMENT • ARCTIC EXPLORER CONSUMING POLAR BEAR LIVER ACUTE;  HEADACHE, NAUREA, VOMITTING,  BONE PAIN, PELLING SKIN CHRONIC  ANOREXIA, DRY ITCHING SKIN,  ALOPECIA, HEPATOSPLECNOMEGALY  ANAEMIA,  BLEEDING

FULL SYNDROME OF DEFICIENCY • • • • • •

NIGHT BLINDNESS XERODERMA XEROPHTHALMIA (BITOT,S SPOTS) KERATOMALACIA SEVERE GROWTH ( ↓ ) NERVOUS SYSTEM GLANDULAR DEGENERATION

Effects of atRA (Renova) on photoaged skin 18 months topical treatment once daily

before

after

C.N. Ellis, et al., J. Amer. Acad. Dermatology 23, 629-637 (1990).

Effects of retinoic acid on human skin protective barrier epidermis

dermis

-RA

+RA

Retinoids and cystic acne

before

after RA

Systemic dosing of RA and cystic acne

before

after RA

Severe Darier’s disease

before

after

Retinoids and psoriasis vulgaris

before

after RA