1 What do vitamins do Metabolically they have

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What do vitamins do? • • Metabolically they have diverse functions as: Coenzymes (B vitamins, vitamin K) Hormones (retinoic acid, vitamin D) Modulators or regulators of growth and development (retinoic acid, folic acid) • (apparently non-specific) antioxidants (Vitamins C and E) 2

• • • • Primarily organic molecules May have inorganic component or cofactor Some work with/are part of an enzyme Promote or catalyze biochemical reactions Most cannot be made by human body Water-soluble = all B vitamins, vitamin C Vitamins A, D, E, K are lipid-soluble Vitamins are structurally diverse, so methods are tailored for particular vitamin Assay methods include physicochemical methods and microbiological assays Most approved by AOAC (Association of Official Analytical Chemists) In most cases, vitamins extracted first Water-soluble – may be treated with acid/base, heat to hydrolyze linkages Fat-soluble – often in ester form, extraction w/nonpolar solvent followed by saponification Antioxidants may be added to prevent oxidation 3

Vitamin classification Name(Letter) RDI Retinol (A) 5000 IU Calciferol (D) 400 IU Tocopherol (E) 30 IU Phylloquinone (K) 70 g 4

Fat-soluble Vitamins • Absorbed with dietary fat in small intestine • 40 -90% absorption efficiency • Absorption typically regulated by need – need absorption • Transported away from small intestine in chylomicra via blood and lymph (depending on size) • They are not easily excreted through urine. • Substantial amounts are stored in liver and fat tissue. • Therefore, toxicity is possible. 5

Vitamin B-complex Vitamin Chemical name B 1 B 2 B 3 B 4 B 5 B 6 B 7 B 8 B 9 B 10 B 11 B 12 Thiamine Riboflavin Nicotinamide (niacin) Adenine (no longer considered a vitamin) Pantothenic acid Pyridoxine Biotin Inositol Folacin (folic acid) p-aminobenzoic acid (PABA) / H 1 L-carnitine / b-hydroxy-g-trimethylammonium butyrate (or choline) Cyanocobalamin 6

Vitamin A Compounds with 20 -carbon structure. Contain a methyl substituted cyclohexenyl ring ( -ionone ring), and an isoprenoid side chain with either a hydroxyl group, and aldehyde group, a carboxylic acid group, or an ester group (retinyl ester) at the terminal C 15. All-trans-retinal Retinol 11 -cis-retinal Retinoic Acid Can’t be reduced to retinol or retinal in the body. 7

Vitamin A 1. Active vitamin A- Preformed vitamin A can be obtained either directly from foods that are substantial in vitamin A (beef liver, fish liver oils, egg yolks and butter) • • 2. The active form of vitamin is retinol, an alcohol which can be converted to other forms (e. g. vitamin A esters) for storage in liver and tissues. much the body's vitamin A is stored in the liver as retinyl palmitate Provitamin A- provitamins, substances that are transformed into vitamins in the body • • • Beta-carotene is the most abundant and widespread provitamin A. Beta-carotene comes from a group of compounds called the "carotenoids (C 40 polyisoprenoids). One need to eat approximately six times as much beta-carotene to get the same amount of vitamin A as in retinol. Dark-green leafy vegetables (spinach) and yellow-orange fruits (apricots and mango) and vegetables (carrots, yellow squash and sweet potatoes) are high in beta-carotene and other carotenoids ( -carotene, -cryptoxathin, etc. ) Carotenoids are not toxic even at high doses for long times. 8

Vitamin A: Biological functions • Role in vision. Vitamin A (retinal) is an essential precursor formation of the visual pigment, rhodopsin, in the retina of the eye. Retinal plays an important role in vision, especially night vision. Lowers cataract incidence. • Role in growth. Helps regulate cell development, cell differentiation and cell division. • Role in Bone and teeth formation. Promotes the proper growth of bones and teeth. Bone cells (osteoblasts and osteoclasts) depend on vitamin A for their normal functioning. – Is important in the formation and maintenance of healthy hair, skin and mucous membranes. • Role in reproduction. Vitamin A holds an important place in sexual reproduction. Adequate levels of vitamin A are needed for normal sperm production. The female reproductive cycle requires sufficient amounts of vitamin A. • Boosts the body's immune system helping to increase body resistance to infectious diseases. 9

Role of Vitamin A in Vision (Wald’s visual cycle) 1. When the rhodopsin is exposed to light it is bleached releasing the 11 -cis-retinal from opsin. 2. Isomerization of the cis-isomer of retinal to all-trans-retinal, causes conformational changes in rhodopsin, hyperpolarization of the retinal rod cell, and extremely rapid transmission of electrical activity to the brain via the optic nerve 3. Trans-retinal is isomerized to cis-retinal in the dark, which associates with opsin to regenerate rhodopsin. All trans retinol = main circulating form of Vit A 10 Visual Pigment

Vitamin A: Biological functions (Cell growth and differentiation) • Regulation of gene expression by retinoic acid, the acid form of vitamin A • Retinoic acid is formed within the target cell from retinol transported in the bloodstream. • Retinoic acid, combined with protein receptor, acts as transcription regulator by binding to specific sequences of DNA in the nucleus • Affected cells include epithelium of numerous tissues, including skin and gut, and bone, ovary and testis. • Retinoic acid is an especially important regulator of embryonic cell differentiation. 11

Vitamin A: Deficiency symptoms 1. Night blindness" - lessened ability to see in dim light. 2. Increased susceptibility to infection and cancer and anemia equivalent to iron deficient. 3. Prolonged lack of vitamin A (keratinization of the cornea, a condition known as xerophthalmia). 4. Abnormal bone development in fetal and neonatal life. 5. Various congenital defects. Retinol and its precursors are used as dietary supplements to prevent the above symptoms. Retinoic acid is used in dermatology to cure acne and psoriasis: 1. Mild acne (Darier’s disease) and aging Topical application of tretinoin (all-trans retinoic acid), along with benzoyl peroxide and antibiotics. 2. severe recalcitrant cystic acne Oral consumption of isotretinoin (13 -cis retinoic acid). This drug is teratogenic. Should not be prescribed during pregnancy. It may lead to hyperlipidemia and increased LDL/HDL ratio (increased chance of heart disease) in long term. 12

Vitamin A: Toxicity • Hypervitaminosis A in humans – Symptoms include dry, pruritic skin with excessive itching and increase in intracranial pressure. – is becoming an increasing problem in Western countries because of selfmedication and overprescription. – has occurred through eating polar bear or seal liver by polar explorers. • Eat polar bear liver sparingly, 30 grams contain 450, 000 IU of retinol! Continued ingestion causes peeling of the skin from head to foot. • It is possible that some early Arctic explorers died from eating their sled dogs in an attempt to survive. 13

Vitamin D • Vitamin D is a family of fat-soluble sterol compounds: • • • Vitamin D 1 (lamisterol) Vitamin D 2 (ergocalciferol) Vitamin D 3 (cholecalciferol) Vitamin D 4 (dihydroergocalciferol) Vitamin D 5 (7 -dehydrositosterol) 14

Vitamin D: Types and Sources • For humans, the two most important forms of vitamin D are: – vitamin D 2 – vitamin D 3. • Vitamin D 2 (ergocalciferol) is derived from plants and irradiated yeast and fungi. • Vitamin D 3 is synthesized in the body when skin is exposed to sunlight – Cholesterol + sunshine = Vitamin D 3 – “sunshine vitamin” – UV-B rays (5 -10 minutes arms and legs, mid-day sun). • Vitamin D 3 can be obtained from foods like milk, fortified cereals, tuna, salmon and fish oils. 15

Sunlight Vitamin D 2 (Ergocalciferol) Ergosterol (in plants) Diet Sunlight 7 -Dehydrocholesterol Vitamin D 3 Cholecalciferol) 16

Activation of Vitamin D • Vitamin D 2 and vitamin D 3 are biologically inactive but can have equal biological activity: • Both can be converted first to calcifediol in the liver and then to calcitriol, also known as 1, 25 dihydroxycholecalciferol, in the kidneys. • Calcitriol, which is the most active form of vitamin D 3, is then transported via a carrier protein to the various sites in the body where it is needed. Calcitriol is also called 1, 25 -dihydroxy vitamin D 3, or (1, 25 -(OH)2 D 3. 17

1, 25 -dihydroxyvitamin D 3 Conversion of 25 -(OH)D 3 to its biologically active form, calcitriol, occurs through the activity of a specific D 3 -1 -hydroxylase present in the proximal convoluted tubules of the kidneys, and in bone and placenta. Cytochrome P 450, O 2 and NADPH are needed. 25 -hydroxyvitamin D 3 In the liver cholecalciferol is hydroxylated at the 25 position by a specific D 3 -25 -hydroxylase generating 25 -hydroxy-D 3 [25(OH)D 3] which is the major circulating form of vitamin D. 18

Functions of vitamin D • Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting reabsorption of calcium in the kidneys. • It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton. • It inhibits parathyroid hormone secretion from the parathyroid gland. • Vitamin D affects the immune system by promoting immunosupression, phagocytosis, and anti-tumor activity. 19

Vitamin D: Hormone for Calcium and Phosphate regulation • • Nerves and muscles must function properly; calcium is vital for nerve cell transmissions and muscle fiber contractions. Calcitriol functions in concert with parathyroid hormone (PTH) and calcitonin to regulate serum calcium and phosphorous levels by: 1. 2. 3. Increasing dietary calcium absorption from the small intestine. Decreasing the urinary calcium excretion (increasing renal reabsorption). Stimulating resorption of calcium from bone • • • Instrumental in the growth, hardening and repair of bones. Too much vitamin D, however, can increase calcium losses from bone Vitamin D is essential for normal insulin secretion by the pancreas and therefore control of blood sugar levels. 20

When vitamin D goes abnormal • Too little (northern latitudes) leads to Vit D deficiency: – Rickets (bone deformities in children) – Osteoporosis – Osteomalacia (weak bones) – Demineralization of bones • Too much (5 times the RDA, chronically): It is most toxic of the vitamins. – Nausea, thirst, loss of appetite, stupor – Hypercalcemia: calcium gets deposited in soft tissues, arteries and kidneys. 21

Diseases caused by deficiency • Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as – – – – – High blood pressure tuberculosis cancer periodontal disease multiple sclerosis chronic pain depression schizophrenia several autoimmune diseases • The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards. • Liquid "drops" of vitamin D for infants. 22

Vitamin E (tocopherols / tocotrienols) A family of eight different molecules. Four of the eight vitamin E molecules are called tocopherols (alpha, beta, gamma and delta) [also known as “Natural Tocopherols”] while the remaining four are called tocotrienols (alpha, beta, gamma and delta). D-alpha-tocopherol is the most biologically active in humans. It is otherwise called as anti-sterility vitamin. a-Tocopherol is the most potent of the all tocopherols. 23

Functions • Vitamin E in the form of d-alpha-tocopherol is an important fat-soluble antioxidant, scavenging oxygen free radicals, lipid peroxy radicals and singlet oxygen molecules before these radicals can do further harm to cells. [Free radicals are very reactive atoms or molecules that typically possess a single unpaired electron. ] • New studies have revealed that the tocotrienol forms of vitamin E are even more potent antioxidants than the tocopherol isomers. • Vitamin E helps maintain the structural integrity of cell membranes throughout the body. • d-alpha-tocopherol has been shown to inhibit the "clumping" of blood platelets (thus helping to avoid blood clots) and enhancing vasodilation (the opening of blood vessels). • d-alpha-tocopherol protects the fat component in low-density lipoproteins (LDLs) from oxidation and has shown moderate cholesterol-lowering capabilities. Studies have shown that gamma- and delta-tocotrienols may be better suited than the tocopherols at inhibiting the manufacture of cholesterol in the liver and hence in contributing to a greater cholesterol lowering effect. 24

Vitamin E (deficiency) • Deficiency: rare in adults usually due to impaired fat absorption or transport; seen usually in children (anemia, edema in infants) – Muscular dystrophy (weaken the musculoskeletal system and hamper locomotion) – Hemolytic anemia – Dietary hepatic necrosis (Acute liver failure, Jaundice) Excess: very safe below 800 IU/day Source: – Vitamin E is present in animal fats, meat, green vegetables, nuts/seeds. – Alpha-tocopherol is found in a number of vegetable oils, including safflower and sunflower. – It is also found in wheat germ. – Soybean and corn oils contain mainly gamma-tocopherol. • • • The major site of vitamin E storage is in adipose tissue. Estimated requirements: 5 mg/day = 0. 6 mg/day of unsaturated fat. Uses: – Hemolytic anemia in premature infants, unresponsive to B 12, Fe and folic acids. – Macrocytic megaloblastic anemia seen in children with severe proteincalorie malnutrition. 25

The symptoms of Vitamin E deficiency • Muscle weakness • Lethargy (Fatigue, exhaustion, tiredness) • Apathy (state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion) • lack of vitality • indigestion • muscle cramps • inability to concentrate • irritability • disinterest in physical activity • red blood cell breakage • anemia • neurological problems 26

Vitamin K • The "K" in vitamin K comes from the German word "koagulation, " which refers to blood clotting (coagulation). • Vitamin K is essential for the functioning of several proteins involved in normal blood clotting. • There are several forms K 1 -K 7 • It is the only fat soluble vitamin with a specific coezyme function 27

Vitamin K 1 (Phylloquinone) • Naturally occurring vitamin K is absorbed from the intestines only in the presence of bile salts and other lipids through interaction with chylomicrons. Therefore, fat malabsorptive diseases can result in vitamin K deficiency. • Present in green leafy vegetables, spinach and various greens (beet and mustard). • Broccoli and certain vegetable oils (soybean, cottonseed, and olive) are also a good source of vitamin K 1. __ 28

Vitamin K 2 (Menaquinone) • Vitamin K 2 is a group of compounds called "menaquinones. " • Synthesized by intestinal bacteria "n" can be 6, 7 or 9 isoprenoid groups. – The number of isoprene residues in the side chain of the vitamin K 2 molecule designate the individual menaquinone compounds, e. g. , menaquinone-4 (MK-4) has four isoprene units in the side chain of vitamin K 2; menaquinone-7 (MK-7) has seven isoprene units in the side chain. • Vitamin K 2, which is the most biologically active form of vitamin K, is found in egg yolks, butter, liver and cheese. 29

Vitamin K 3 (Menadione) • The synthetic (man-made) vitamin K 3 is water soluble and absorbed irrespective of the presence of intestinal lipids and bile. Uses : essential cofactor in blood clotting. Excess: Dangerous if taking anti-coagulants. Hemolytic anemia, jaundice in infants. 30

Functions 1. Blood coagulation • • – – Post-translational carboxylation of some glutamate residues in blood factors. Vitamin K is needed for the body to make four of the blood's coagulation factors, including prothrombin (also known as factor II), proconvertin (factor VII), Christmas factor (factor IX) and Stuart-Power factor (factor X). It occurs in the liver Vitamin K has to change to Hydroquinone to function as coenzyme for carboxylase. 2. Calcium binding proteins – Carboxylation of specific glutamate residues in calcium binding proteins. 3. Role in oxidative phosphorylation 31

Deficiency 1. 2. 3. 4. 5. Prolonged use of antibiotics Malabsorption and biliary tract obstruction Use of dicumarol (vit K antagonist) Short circuiting of the bowel In immediate post-natal infants – Sterile bowels (no intestinal microflora) – Low Vit K in mothers milk – Hemorrhagic disease of the newborn. 32