Vitamins

Vitamins Fat-soluble Vitamin A: vision, epithelial tissue, growth in children Vitamin D: bone mineralization, blood Ca 2+ regulation Vitamin E: antioxidant Vitamin K: clotting factor Water-soluble Energymetabolism Amino acid metabolismRBC/NeuraldevelopmentCollagensynthesis Thiamine (B 1 ) Riboflavin (B 2 ) Niacin (B 3 ) Biotin Pantothenic acid (B 5 ) Pyridoxine pyridoxal, pyridoxamine (B 6 ) Folic acid Cobalamin (B 12 ) Ascorbic acid (Vitamin C)

Water-soluble Vitamins A) B-Complex 1.Thiamine (B 1 ) Sources: whole-grain cereals, meats, legumes, nuts Active form is thiamine pyrophosphate (TPP) Functions : 1.Oxidative decarboxylation of pyruvic acids,conversion of pyruvic acid to acetyl coA. 2.In transketolation reaction,transfer of ketol group. 3.TPP is also essential for the process of nerve conduction and structure of nerve membrane. Deficiency: Deficiency: most common in alcoholics and malnourished individuals Decreased ATP production

 Wet beri-beri :Affects cardiovascular system  1. Extensive edema.  2. Congestive heart failure.  Dry beri-beri : Affects nervous system.  1. Polyneuritis.  2. Hyperesthesia  Muscle wasting and loss of weight.  Wernicke’s disease  1. Occular distrubance  2.Ataxia

 Korsakoff’s syndrome  Defective memory.  Impaired learning ability.  Recommended dietary allowance:RDA  1-1.5mg/day.

2. Riboflavin (B 2 ) (UV sensitive) Sources: milk, eggs, meat, poultry, fish, green leafy vegetables Active forms are FMN and FAD FAD: cofactor in succinate dehydrogenase reaction (TCA) FMN: component of ETC – accepts 2 electrons from NADH in NADH dehydrogenase reaction Deficiency: Deficiency: not associated with major human disease but commonly seen in conjunction with other vitamin deficiencies Deficiency symptoms include: dermatitis cheilosis glossitis

 Occular disturbance.  1. photophobia  2. vascularization of cornea.  Angular stomatitis: inflammation of angles of mouth.  3. Seborrheic dermatitis:inflammtion of sebaceous glands of skin.  Requirements: mg/day.

3. Niacin (nicotinic acid) (B 3 ) Sources: meat, whole-grain cereals, synthesis from tryptophan-containing foods (milk, eggs) Active forms are NAD + and NADP + Excess tryptophan is metabolized to niacin and supplies approx. 10% of RDA Clinical correlations: deficiency causes pellagra(4D) RDA effective in treatment of type IIb hyperlipoproteinemia ( reduces lipolysis of fatty acids, activates lipoprotein lipase, less VLDL and LDL)

 Niacin 13-19mg/day depending upon the age and sex  Tryptophan 13 x 60 mg/day to 19 x 60 mg/day.  Hypervitaminonsis  1. Skin flushing.  2. Gastrointestinal disturbance.  3. Pruritis

4. Pantothenic acid (B 5 ) present in a wide variety of foods esp. eggs, liver, yeast Active form is Cofactor A (i.e. succinyl CoA, acetyl CoA, fatty acyl CoA) part of fatty acid synthase complex Clinical correlations: deficiency is uncommon no RDA established

5. Pyridoxine, pyridoxal, pyridoxamine (B 6 derivatives) Sources: whole-grain cereals, eggs, meat, fish, soybeans, nuts Active form is pyridoxal phosphate Important function in transamination, deamination, decarboxylation, and condensation reactions

 Clinical correlations:  Isoniazid (isonicotinic acid hydrazide) used to treat TB may induce B6 deficiency -> need B6 supplement while taking isoniazid  Deficiencies seen in alcoholics, infants given deficient formula, and women on oral contraceptives  Toxicity: neurological symptoms if >2g/day

6. Cobalamin (B 12 ) contains Co, corrin ring system Sources: meats, shellfish, poultry, eggs, dairy products (not present in plants) Active forms are 5’-deoxyadenosylcobalamin (fatty acid oxidation) and methyl cobalamin (met synthesis) Needed for synthesis of methionine from homocysteine, forming tetrahydrofolate isomerization of methyl malonyl CoA to succinyl CoA. Vit B12 hepls in the formation of myelin sheath through the metabolism of odd numbers fatty acids.

Vitamin B 12 Metabolism 1.The absorption of vitamin B12,it combines with a glycoprotein secreted by the gastric parietal cells called intrinsic factors 2.This IF-B12 complex binds with specific ileal receptors. 3.A pH above 6 and Ca ions required to promote vitamin absorption. 4.Vitamin B12 passes via portal circulation to the liver to the general circulation. 5.Vitamin B12 is carried in the plasma by number of carrier globulins,namely transcobalmin II,transcobalmin I and R proteins.They transport B12 to the tissue.It bind to specific cell receptor cell surface to enter the cell.

 Clinical correlations:  Deficiency causes accumulation of abnormal fatty acids -> neurological effects  Pernicious anemia – not usually a vitamin deficiency but inability to absorb B12 (no intrinsic factor) because of autoimmune destruction of parietal cells  Treatment: Lifetime intramuscular injections of cyanocobalamin  Anemia reversible, but not CNS effects

 deficiency in either vitamin B12 or folic acid causes increase in plasma homocysteine levels, which damages blood vessels and poses a risk for thrombosis  megaloblastic anemia must be treated with both folate and vitamin B12  other causes of B12 deficiency:  pure vegan diet  terminal ileal disease (i.e. Chron’s disease)

6. Biotin Sources: bacterial synthesis in intestine,egg yolk,yeast, animal tissues and tomatoes. Important function as cofactor in carboxylation reactions (I.e. pyruvate carboxylase, acetyl CoA carboxylase) Clinical correlations: Deficiency (uncommon) caused by: 1. eating raw egg whites (contain avidin) 2. broad-spectrum antibiotics (kill intestinal bacteria)

7. Folic acid Sources: green leafy vegetables, liver, lima beans, whole- grain cereals Active forms are tetrahydrofolate derivatives Important in 1-C transfer reactions especially in DNA synthesis Metabolism: 1.Folic acid ingested as polyglutamates -> converted to monoglutamates in jejunum by intestinal conjugase enzyme 2.Monoglutamate is reabsorned in jejunum. 3.Folic acid circulated and is measured in blood as methyltetrahydrofolate. 4.Only a 3-4 month supply is stored in the liver.

Clinical correlations: Folic acid deficiency is most common vitamin deficiency in U.S., most common in pregnant women and alcoholics Folic acid before pregnancy reduces risk of neural tube defects.

Deficiency caused by: 1. Diet lacking in fruit and vegetable 2. Drugs: methotrexate, trimethoprim (chemotherapeutic drugs which inhibit dihydrofolate reductase thus preventing purine and pyrimidine biosynthesis -> kills blast cells and causes macrocytic anemia) 4. Oral contraceptives (block reabsorption of monoglutamate in jejunum) 5. Alcohol (block reabsorption of monoglutamate in jejunum) 6. Rapidly-growing cancers (malignant cells use folic acid) 7. Small bowel malabsorption (I.e. celiac disease) 8. Sulfa drugs (sulfanilamide) inhibits folic acid synthesis

B. Non-B-Complex B. Non-B-Complex Ascorbic acid Source: citrus fruits, potatoes, tomatoes, green vegetables Action – coenzyme in hydroxylation reactions esp. proline and lysine in collagen synthesis antioxidant activity – helps prevent formation of free radicals Clinical correlations:Clinical correlations: deficiency and cigarette smoking causes scurvy megadoses claimed to be effective against common cold (very controversial) no toxic effects but oxidized form (dehydroascorbic acid) is toxic Excess intake may cause renal calculi (kidney stones)

Classification and Functions of Vitamins Vitamins Fat-soluble Vitamin A: vision, epithelial tissue, growth in children Vitamin D: bone mineralization, blood Ca 2+ regulation Vitamin E: antioxidant Vitamin K: clotting factor Water-soluble Energymetabolism Amino acid metabolismRBC/NeuraldevelopmentCollagensynthesis Thiamine (B 1 ) Riboflavin (B 2 ) Niacin (B 3 ) Biotin Pantothenic acid (B 5 ) Pyridoxine pyridoxal, pyridoxamine (B 6 ) Folic acid Cobalamin (B 12 ) Ascorbic acid (Vitamin C)

Vitamin A Vitamin A consists of three biologically active molecules, retinol, retinal (retinaldehyde) and retinoic acid Essential for vision, reproduction, growth and maintenance of epithelial tissues Associated with reduced heart disease, lung cancer, skin cancer, lower cataract risk Sources: liver, kidney, cream, butter, egg yolk RDA: 1000 retinol equivalents (RE) for males 800 retinol equivalents (RE) for females 1 RE = 1  g retinol, 6  g  -carotene, or 12  g of other carotenoids

Each of these compounds are derived from the plant precursor molecule,  -carotene (a member of a family of molecules known as carotenoids). Beta-carotene, which consists of two molecules of retinal linked at their aldehyde ends, is also referred to as the provitamin form of vitamin A. Retinol -> dietary supplements Retinoic acid -> dermatological applications

Metabolism of Vitamin A 1.Ingested  -carotene is cleaved in the lumen of the intestine by  - carotene dioxygenase to yield retinal. 2.Retinal is reduced to retinol by retinaldehyde reductase, an NADPH requiring enzyme within the intestines.

vision is the function of 11-cis retinal coupled to opsin to form rhodopsin Rhodopsin is coupled to a G-protein called transducin. When exposed to light 11-cis is converted to all-trans-retinal. This conformational change activates transducin. Increased GTP binding. cGMP maintains Na + channels in open state activation of cGMP phosphodiesterase drop in cGMP closes channels and leads to hyperpolarization of the rod cell Vision and the Role of Vitamin A

Additional Roles of Retinol 1.Growth – retinoic acid required for appetite, bone growth 2.Spermatogenesis (males) and prevention of fetal resorption (females) – requires retinal or retinol (retinoic acid doesn’t work!) 3.Maintenance of epithelial cells + mucus secretion

Vitamin A - Clinical Correlations 2. Acne, psoriasis Retinoic acid used to treat mild acne (Darier’s disease) Tretinoin (all-trans retinoic acid) used to treat skin aging (topical) Isotretinoin (13-cis retinoic acid) used to treat severe acne (oral admin) ** teratogenic contraindicated for women with childbearing potential prolonged treatment with isotretinoin causes hyperlipidemia and increased LDL/HDL ratio

Vitamin A - Clinical Correlations 1.Dietary Deficiency treated with retinol or retinyl esters night blindness early sign of Vitamin A deficiency increased susceptibility to infection and cancer severe deficiency leads to progressive keratinization of the cornea (xerophthalmia)

Vitamin A - Clinical Correlations 3. Toxicity Hypervitaminosis A = > 7.5 mg per day Early signs of Hypervitaminosis A : dry, pruritic skin, hepatomegaly, rise in intracranial pressure (can mimic brain tumor) teratogenic

 Sources : generated from the provitamin ergosterol(in plants)and 7- dehydrocholesterol(in human and animals) by ultra violet irradiation of sun.  Liver,egg and yeast are rich diet  Fish liver oils.cod liver oil,shark liver oil.

Metabolism of Vitamin D D 2 and D 3 are activated in vivo by 2 sequential hydroxylation reactions hydroxylase in liver 2.25-cholecalciferol-1-hydroxylase in kidney product is 1,25-dihydroxycholecalciferol (1,25-diOH D 3 )

Function of Vitamin D – to increase plasma Ca 2+ stimulates calcium (and phosphate) uptake by intestine by inducing synthesis of a calcium-binding protein increases calcium reabsorption by the kidney mobilizes bone calcium by resorption

Vitamin D - Clinical Correlations Deficiency of vitamin D 1.Rickets – in children collagen matrix formed but mineralization is incomplete soft pliable bones – “bow-legged” mutation in vitamin D receptor can cause vitamin D- independent rickets 2. Osteomalacia – in adults demineralization of bones = fractures (less sunlight) problem more severe 3. Renal rickets (renal osteodystrophy) = chronic renal failure results in low synthesis of 1,25 vitamin D 3 (calcitrol) calcitrol supplementation is effective treatment

Toxicity Very toxic vitamin D can be stored -> accumulates in liver and fat high doses = loss of appetite, nausea, thirst, hypercalcemia (leads to calcium deposits in arteries and kidneys Vitamin D - Clinical Correlations

 Three forms : K1,K2 and K3  Sources:  1. leafy vegetable(K1), intestinal flora present in small intestine (K2),K3 is synthetic,it is water soluble and more potent than vitamin K1 and K2.

Vitamin K Role = posttranslational carboxylation of blood clotting factors Sources: cabbage, cauliflower, spinach, egg yolk, liver, synthesis from intestinal bacteria RDA: no RDA but recommendation is  g/day Exists in several forms: phylloquinone = vitamin K 1 (plants) menaquinone = vitamin K 2 (intestinal bacteria) menadione = synthetic derivative of vitamin K 1

Interaction of prothrombin with platelets  -carboxylates chelate calcium and allow prothrombin to associate with membrane phospholipids in platelets 2. conversion to thrombin is stimulated

Vitamin K - Clinical Correlations Deficiency of vitamin K deficiencies are unusual antibiotic treatment can lead to hypothrombinemia in undernourished/ very ill patients second generation cephalosporins have warfarin-like activity supplement treatment with vitamin K newborns are deficient and breast milk below RDA prophylactic i.m. injection can be used

Toxicity prolonged treatment causes hemolytic anemia, jaundice in infants (rbc membrane effects) Vitamin K - Clinical Correlations

Vitamin E 8 different types –  -tocopherol is most common absorbed in intestines Major storage site is adipose tissue function – antioxidant activity inhibits nonenzymatic oxidation by free radicals sources – vegetable oils, liver, eggs RDA = 10 mg/day for males 8 mg/day for females RDA increases as intake of polyunsaturated fats increases

Vitamin E - Clinical Correlations Deficiency restricted to premature infants in adults, deficiency associated with defective lipid transport/absorption -> results – rbc membrane fragility, abnormal cell membranes Toxicity none known

Vitamin E - Clinical Correlations Benefits may protect against chronic disease (heart disease, cancer, cataracts, aging) due to its antioxidant activity

Fat soluble Vitamins