Vitamins Introduction

Vitamins Introduction - Vitamins are organic molecules which are vital and essential micronutrients that an organism needs in small quantities for the proper functioning of its metabolism. An essential nutrient is a nutrient required for normal physiological function that cannot be synthesized in the body – either at all or in sufficient quantities - and therefore must be obtained through the diet. - The term “naming” is conditional both on the organism and on the circumstances. It is called a vitamin if: 1- It is required in the diet, e.g. ascorbic acid is required in the human diet and is called Vitamin C. However, in animals (e.g. dogs) it is not required and thus it is termed as ascorbic acid. Same for vitamin B and vitamin D which are required in the human diet only in certain circumstances -. 2- It may be synthesized in the organism under normal physiological conditions, thus, not calling it a vitamin. However, in certain conditions (e.g. body stops synthesizing) it may become vital and will be considered a vitamin. - The inability of an organism to produce a certain vitamin doesn’t necessarily mean that vitamins are not synthesized inside that organism. It means that there is no special pathway for producing that vitamin inside the organism’s cells, but it might be synthesized by an external source (e.g. bacteria living inside the human intestine) - Vitamers, are compounds that are converted to the active form of a vitamin in the body. - There are 13 vitamins in total, categorized into fat and water-soluble vitamins: 1|Page a- 9 Water-soluble Vitamins (which we took over the last semester)  Vitamins C and B 1/2/3/5/6/7/9/12 - They are readily excreted in the urine. - They act as coenzymes and are not stored in the body. - Toxicity arising due to excess amounts of water-soluble vitamins is rare. b- 4 Fat-soluble Vitamins (discussed through this sheet)  Vitamins A, D, E, K - They are not readily excreted in the urine. - They have long chain of carbons unlike water soluble vitamins. - They are released, absorbed, and transported with fats. - They are stored in the liver and adipose tissue. - Overdoses of fat-soluble vitamins may lead to toxicity. - As opposed to water-soluble vitamins, a fat-soluble vitamin has no single common defining structure, instead, they’re a group of chemically related compounds performing a similar function. - Vitamins have diverse biochemical functions: a- Hormone-like functions (regulators): Regulators of mineral metabolism (e.g. vitamin D), or regulators of cell & tissue growth & differentiation (e.g. vitamin A). b- Vitamins E & C: Anti-oxidants, they fight free radicals which are not stable and tend to hit any unstable molecule to stabilize it. c- Vitamin B subclasses: Precursors for enzyme cofactors. -------------------------------------------------------------------------------------------------------------------- Vitamin A - Vitamin A is a group of unsaturated organic compounds, called retinoids, that includes retinol, retinal and retinoic acid. - Vitamin A has multiple functions: it is important for growth, reproduction, maintenance of the epithelial tissue and good vision. 2|Page Vitamin A (Retinoids) Sources: From animal sources  Liver, kidney, cream, butter, and egg yolk. From plant sources  In the form of β-carotene; a red-orange pigment found in plants and fruits, especially carrots and colorful vegetables. Vitamin A Structure: - As mentioned, retinoids can be found in 4 forms: 1- Retinol which is a primary alcohol. 2- Retinal which is an aldehyde. 3- Retinoic acid which is a carboxylic acid. 4- β-carotene which is broken down in the intestines to yield 2 retinal molecules, which is why β-carotene is also called provitamin A. (as shown in the figure, discussed more later). - Retinol is the form of vitamin A acquired in the diet from animal tissue ingestion, it is a primary alcohol and can be oxidized to retinal. Retinal can be reduced back to retinol, thus they can be interconvertible. - However, retinal can be oxidized to retinoic acid but it can’t be reduced back to retinal due to the absence of a reductase in our body. This indicates that retinol and retinal have similar functions in the body that are different from the functions of retinoic acid. Retinal and Retinol For vision and spermatogenesis. Retinoic acid  Mediates most of the actions of the retinoids, mainly differentiation and proliferation of cells. Absorption and Transport of Vitamin A: 1- Vitamin A can be acquired from the diet as: A- Retinyl Esters with long FA chains, from animal sources:  They are first hydrolyzed in the intestinal mucosa, yielding retinol and FA.  Retinol then is absorbed by intestinal cells, while long FA chains can’t be absorbed.  Retinol inside the cells is re-esterified and Fatty acyl CoA donates FA forming Retinyl ester again. 3|Page B- β-carotene (provitamin A), from plant sources:     It is absorbed by the intestinal cells without modification. In the intestinal cells, it is broken down to give 2 molecules of retinal. The retinal molecules are reduced forming retinol. The retinol molecules are then esterified to give Retinyl esters. Both forms end up in forming Retinyl esters. 2- Retinyl esters are then transported from the intestinal cells to the liver, through the lymphatic system and blood, by chylomicrons, where in the liver it can be stored as Retinyl esters. 3- When in need of vitamin A, the Retinyl esters are hydrolyzed to give retinol which is then transported to extra hepatic tissue. 4- Retinol is highly hydrophobic, it can’t be transported in the blood freely. Thus, they are transported through a Retinol Binding Protein (RBP) named transthyretin (TTR); transported as Retinol-RBR complex. (Refering to the figure in the next page would make this much easier) Mechanism of Action of Vitamin A: In Tissues: (refer to a more detailed figure in Lippincot page 384) After being transported as retinol-RBR and reaching target tissues, the complex is broken down releasing retinol to be absorbed and then oxidized to retinoic acid. 1- Retinoic acid then binds with high affinity to specific nuclear receptors of target tissues, such as epithelial cells. 2- Activated retinoic acid receptor complex interacts with nuclear chromatin by binds to transcription factors that regulates RNA synthesis, controlling gene expression, stimulating or inhibiting them, e.g. regulating gene for keratin in most epithelial tissues of the body. In the Retina: 1- Retinol is oxidized to retinal, which binds to opsin, forming Rhodopsin which is the visual pigment of the rod cells in the retina. 2- When rhodopsin is exposed to light, retinal and opsin are released from rhodopsin and this activates a G-protein which then triggers a nerve impulse. 4|Page Note: Rhodopsin is a biological pigment found in the rods of the retina and is a G-protein-coupled receptor involved in visual phototransduction. It is extremely sensitive to light, enabling vision in low-light conditions. Summary of Metabolism, absorption and action of Vitamin A Functions of Vitamin A: 1- Visual cycle: 11-cis Retinal specifically binds with the protein opsin forming rhodopsin. 2- Reproduction: Retinol and retinal (not retinoic acid) are essential for spermatogenesis in the male and in preventing fetal resorption in the female. 3- Growth (retinoic acid): Vitamin A deficiency results in a decreased growth rate and bone development in children. 4- Maintenance of epithelial cells (retinoic acid): Vitamin A is essential for normal differentiation of epithelial tissues & mucus secretion. Note: Animals given vitamin A only as retinoic acid from birth, were blind and sterile. 5|Page Clinical Indications: - Vitamin A deficiencies aren’t usually fatal. However, it can cause severe symptoms. Deficiency in vitamin A, prevents the eye cells from maturing and differentiating normally. Also, it prevents the formation of rhodopsin; which is responsible for phototransduction. a- Mild deficiency: Causes night blindness (nyctalopia) as the visual threshold increases from the decrease in rhodopsin level. b- Prolonged deficiency: Causes scarring of the eye which leads to irreversible loss of some visual cells. c- Severe deficiency: Leads to Xerophthalmia, which is the ulceration and dryness of conjunctiva and cornea, followed by scarring and blindness. It affects over 500,000 children worldwide every year. - Since Retinoic acid is a regulator for protein synthesis or gene expression, it is prescribed for issues caused by over expression which lead to over production, such as dermatologic problems including acne and psoriasis. Note: Retinol and its precursor are used as dietary supplements, whereas various forms of retinoic acid are useful in dermatology. Toxicity of Retinoids: - Excessive amounts of fat-soluble vitamins may lead to many diseases. - Excessive intake of any fat-soluble vitamin is termed hypervitaminosis X, where X is replaced by the letter of the vitamin, ex: hypervitaminosis A is excessive vitamin A. - Hypervitaminosis A leads to: a- Dry skin, due to a decrease in keratin synthesis. b- Enlargement of the liver, which can become cirrhotic. c- A rise in the intracranial pressure in the CNS where it might mimic a brain tumor. - Pregnant women shouldn’t ingest excessive amount of vitamin A as it is teratogenic; meaning it might cause congenital malformations in the developing fetus. -------------------------------------------------------------------------------------------------------------------- 6|Page Vitamin D - The D vitamins are a group of sterols that have a hormone-like function. - The active form of Vitamin D is: 1, 25-dihydroxycholecalciferol (1,25-diOH-D3). - It binds to intracellular receptor proteins, interacting with DNA in the nucleus of target cells in a manner similar to that of vitamin A, which stimulates gene expression or represses gene transcription. - The most prominent action of 1,25-diOH-D3 is to regulate the plasma levels of calcium and phosphorus. Vitamin D Sources: 1- Diet (Exogenous): Ergocalciferol (vitamin D2), found in plants. Chole-calci-ferol (vitamin D3) in animal tissues. Note: Ergocalciferol and cholecalciferol differ chemically only in the presence of an additional double bond and methyl group in the plant sterol (Vit. D2). 2- Endogenous: 7-Dehydrocholesterol, an intermediate in cholesterol synthesis, is converted to cholecalciferol in the dermis and epidermis of humans when exposed to sunlight. Note: Vitamin D is a dietary requirement only in individuals with limited exposure to sunlight. Metabolism of vitamin D: - Vitamins D2 and D3 are not active. They are converted to the active form 1,25-diOH-D3 by two sequential hydroxylation reactions: 7|Page 1- The first hydroxylation occurs in the liver where cholecalciferol is hydroxylated at the 25-position, catalyzed by cholecalciferol 25-hydroxylase. Note: The product of the reaction, 25-hydroxy cholecalciferol (25-OH-D3, calcidol) is the predominant form of vitamin D in the plasma and the major storage form of the vitamin. 2- The second hydroxylation reaction occurs in the kidney where 25-OH-D3 is further hydroxylated at the 1-position by 25-hydroxycholecalciferol 1- hydroxylase, resulting in the formation of 1,25-diOH-D3 (calcitriol). - The 1-hydroxylation reaction is tightly regulated: a- Increased directly by low levels of phosphate ions present in the serum. b- Increased indirectly by Calcium, where it stimulates the production of the parathyroid hormone (PTH), which upregulates the 1-hydroxylase. c- Feedback inhibition, where the product (1,25-diOH-D3), inhibits the 1-hydroxylase. Functions of vitamin D: - The overall function of 1,25-diOH-D3 is to maintain adequate plasma levels of calcium: a- Increasing uptake of calcium by the intestine. b- Minimizing loss of calcium by the kidney. c- Stimulating resorption of bone when necessary. Note: Vitamin D has the same functions as the PTH. This is why Vit. D is given to people who can’t produce PTH. Clinical Indications: 1- Nutritional Rickets: Insufficient exposure to daylight and/or deficiencies in vitamin D consumption occur predominantly in infants and the elderly. It leads to the loss of calcium ions in the serum (Recall the functions of Vit. D), which leads to the demineralization of bone. a- Rickets in children:  Continuous formation of the collagen matrix of bone with Incomplete mineralization.  Soft, pliable bones. b- Osteomalacia in adults:  Demineralization of pre-existing bones increasing their susceptibility to fracture. 8|Page 2- Renal Rickets (renal osteodystrophy): Chronic renal failure results in decreased ability to form the active form of vitamin D. Note: Hypoparathyroidism is the lack of PTH. Toxicity of Vitamin D: - High doses of vitamin D leads symptoms like loss of appetite, nausea, thirst, and stupor (which is a state of unconsciousness). - It can also cause hypercalcemia, which leads to calcium deposition in the body, which leads to atherosclerosis in the arteries and stones in kidneys. --------------------------------------------------------------------------------------------------------------- Vitamin K - Vitamin K is a group of quinones since their structures contain a cyclic di-ene molecule. - Vitamin K is an exception to the lipid soluble vitamins; all are not coenzymes except K. Vitamin K function: - Vitamin K is required in the hepatic synthesis of prothrombin and blood clotting factors II, VII, IX, and X. - Blood clotting factors are synthesized as inactive precursor molecules. Vitamin K is needed as a coenzyme in the carboxylation of certain glutamic acid residues (present in the precursors of the clotting factors) forming mature blood clotting factors containing γ-carboxyglutamate (Gla).  More negative charges due to carboxylation, allows the mature clotting factors to be able to bind to calcium ions.  Allowing them to bind to platelets, leading to platelet aggregation. - The formation of Gla is sensitive to inhibition by Warfarin. 9|Page Vitamin K exists in several forms: a- In plants: as phylloquinone (vitamin K1). b- Intestinal bacterial flora as menaquinone (vitamin K2). c- Present in low concentration in milk Clinical Indications: 1- Deficiency of vitamin K A true vitamin K deficiency is unusual, because adequate amounts are generally produced by intestinal bacteria or obtained from the diet. If the bacterial population in the gut is decreased, for example, due to antibiotics, the amount of endogenously formed vitamin is depressed, and this can lead to hypoprothrombinemia (deficiency in blood prothrombin factor II). This condition may require supplementation with vitamin K. 2- Deficiency of vitamin K in the newborn Newborns have sterile intestines and so initially lack the bacteria that synthesize vitamin K. Because human milk provides only about 20% of the daily requirement for vitamin K, it is recommended that all newborns receive a single intramuscular dose of vitamin K as a prophylaxis against hemorrhagic disease. 3- Toxicity of vitamin K Prolonged administration of large doses of vitamin K can produce hemolytic anemia and jaundice in the infant, due to toxic effects on the membrane of red blood cells; therefore, it is no longer used to treat vitamin K deficiency. -------------------------------------------------------------------------------------------------------------------- 10 | P a g e Vitamin E - The E vitamins consist of eight naturally occurring tocopherols, of which α-tocopherol is the most active. - The primary function of vitamin E is as an antioxidant against free radicles. Vitamin E deficiency - Vitamin E deficiency is rare as it is needed in very small amounts. It is almost entirely restricted to premature infants (not every premature infant, but only those who are born around the 6th month of pregnancy). When observed in adults, it is usually associated with defective lipid absorption or transport. - The signs of human vitamin E deficiency include sensitivity of erythrocytes to peroxide, and the appearance of abnormal cellular membranes. 11 | P a g e