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VITAMIN A AND CAROTENOIDS: Complex biochemistry and metabolism of a highly-regulated nutrient Oct 8, 2014 BIOCHEMISTRY OF VITAMIN A Chief functions of vitamin A -The aldehyde, also know as retinal, is needed for the function of the light-sensitive cells in the retina (called: photoreceptors) -The acid form, also known as retinoic acid, is needed to regulate the activity of MANY genes, perhaps thousands. one famous retinoic-acid dependent gene is MUCIN, a protein needed for form a healthy cornea in the eye Curiously, vitamin A deficiency effects both main components of the eye: the retina, and the cornea! VITAMIN A IS A FAT-SOLUBLE VITAMIN: -stored in fat droplets in cells -body can accumulate > 1 year supply -absorption from diet much better if there is also fat in the diet -in the United States, both deficiency and toxicity occur -worldwide, there is a great deal of vitamin A deficiency: one of the world’s major nutrition problems HISTORY OF THE DISCOVERY OF VITAMIN A McCollum and others found during the period 1910-1920 if animals were fed highly purified diets, the addition of egg-yolk, or of butterfat, was necessary to maintain health. Osborne and Mendel (1916) later found that codliver oil also supplied this nutrient (cod liver oil does not have any carotene). This led to the conclusion that a trace nutrient (vitamin) was present in some dietary fats. The active principle was named in 1913 by McCollum: FAT-SOLUBLE VITAMIN A •1919 Steenbock found that the bright-yellow carotene fraction of plants had vitamin A activity. Steenbock therefore argued that carotene was the source of dietary vitamin A. 1929 Moore demonstrated the conversion of carotene to vitamin A, by showing with chemical methods that vitamin A accumulated in the liver of a chick fed only carotene mixed with vegetable oil. This data, from 1919, was important in showing that SOME component in the carrot was a source of vitamin A. Each of these, in some way, contributes to activity of “vitamin A”. WHERE DO WE GET VITAMIN A IN THE DIET: • Dairy products (as retinyl esters). Vitamin A deficiency does not occur where people drink milk, or consume cheese or butter • Green and yellow vegetables (spinach, sweet potatoes, carrots). We convert the beta-carotene to vitamin A, in the digestive tract • Vitamin pills, and vitamin A added to foods, such as breakfast cereal These carotenoids all have vitamin A activity. ZEAXANTHIN LUTEIN Do these carotenoids have vitamin A activity? In small intestine Much of our vitamin A comes from the cleavage of β-carotene. The conversion of β-carotene to vitamin A only creates safe amounts – excess dietary vitamin A is harmful, but excess dietary β-carotene only turns your skin a bit orange! This form of vitamin A is: -added to the diet as a vit A supplement -used to transport vitamin from intestine to liver -the formed stored in liver and other tissues What change must occur, for humans to use retinyl palmitate as a form of vitamin A? OVERVIEW OF VITAMIN A METABOLISM: PART 1 DIETARY CONSTITUENTS B-carotene Retinol Partly cleaved to Retinol (5%-20%) Retinol: ~80% absorbed into cells that line ihe intestine Retinyl palmitate Enzyme hydrolysis Converted to Retinyl palmitate, excreted to lymphatics Transported to liver >75% of total body vitamin A stored in liver, mostly as retinyl palmitate LIVER storage ~ 100 mg OVERVIEW OF VITAMIN A METABOLISM: PART 2 Stored as Retinyl Palmitate LIVER storage ~ 100 mg Excreted to plasma as Retinol, carried in Retinol Binding Protein (RBP) Absorbed by the retina, and converted to Retinal Retinal forms part of rhodopsin, a light-sensitive protein that allows you to see! Much plasma Retinol recycled back to liver Absorbed by skin, mucosa, other tissues, converted to Retinoic Acid Retinoic acid directs gene expression needed for healthy skin and mucous membranes This diagram from the text provides some sense of the COMPLEXITY of vitamin A biochemistry. There are many BINDING proteins in the cell. Mysteries of vitamin A regulation (there are MANY): Plasma vitamin A is carried on a binding-protein, called PLASMA RETINOL BINDING PROTEIN. Levels in healthy adults are held at 50-60 micrograms/100ml. What sets that plasma level? We don’t know that mechanism. The same level in plasma is seen for intakes between 0.5 mg/day and 5 mg/day. In the liver, storage can vary from 50-250 mg total. Your tissues use up about 500 micrograms/day or less. For Americans the hepatic stores are usually enough for 1 year or longer. The Eye: Vitamin A is critical! These light-sensitive cells require presence of RETINAL. RETINAL: Cis-Form Signals to brain RETINAL: Trans-FORM The Cis-Retinal is part of the protein RHODOPSIN (the visual pigment). When light causes the conversion to Trans-Retinal, the affects the protein, which then initiates signal transduction to the optic nerve. All-trans-RETINOL (vitamin A alcohol) circulates in the blood, and is delivered to tissues carried on a binding protein. In the tissues, it’s converted to RETINAL, which is used for function of the photoreceptors. The conversion requires: NAD+, and the enzyme retinol dehydrogenase. ZINC IN THE BIOCHEMISTRY OF VITAMIN A MANY of the enzymatic transformations, such as packaging vitamin A into binding proteins, require zinc. Zinc deficiency often leads to defects in the functions of vitamin A-dependent mechanisms. The specific details are being clarified. This illustrates the interdependence of different micronutrients for total function. The whole cycle is very complex! Fig. 10-7, p. 383 Active in the retina Active in control of gene activity LACK OF RETINAL FOR THE PHOTORECEPTORS CAUSES AN EARLY SYMPTOM OF VITAMIN A DEFICIENCY; IMPAIRED DARK ADAPTATION The rod photoreceptors, critical for night vision, are very sensitive to deprivation of RETINAL. BOTH FORMS OF VITAMIN A ARE NEEDED FOR VISION COMPONENT OF THE PHOTORECEPTOR PROTEIN (RHODOPSIN) IN THE RETINA NEEDED TO ACTIVATE EXPRESSION OF MANY GENES, INCLUDING GENES IN THE CORNIA WITHOUT RETINOIC ACID, EPITHELIA TENDS TO REMAIN IN THE SQUAMOUS FORM. ON THE CORNEA, THIS LEADS TO DRY SCALY TISSUE AND IRREVERSIBIBLE SCARRING OF THE CORNEA. THIS IS A MAJOR DISEASE THAT CAN RESULT FROM VITAMIN A DEFICIENCY. One of the proteins that requires retinoic acid for production of its mRNA is mucin… If mucin is not made, the cornea becomes more and more like SKIN. DIFFERENT TYPES OF EPITHELIA TYPICAL OF SKIN CELLS: DRY AND SCALY TYPICAL OF CORNEA: MUCUS-SECRETING Retinoic acid is required for this cell type to develop. During 15-20 weeks on vitamin A deficient, expression of mRNA for mucin5 and ASGP declines in the cornea of rats. These proteins play an essential role in maintaining the normal mucous epithelium of the cornea. The paper on bypass surgert deals with some aspectof vitamin A deficiency, following a procedure to reduce the size of the stomach and intestine. Homework assgnment: Do an Internet search, for the number of bypass operations done in the US each year. Are patients with bypass now the most important group of nutritionally-deficient Americans? Website, Britain: Cystic Fibrosis Medicine http://www.cfmedicine.com/htmldocs/CFText/vitamins.htm Malabsorption of fat soluble vitamins is likely in most patients with CF, particularly those who are pancreatic insufficient. Biochemical evidence of fat soluble vitamin deficiency has been found by two months of age in untreated screened infants with CF (Sokol et al, 1989; Feranchak et al, 1999). Patients should have plasma levels checked annually (Borowitz et al, 2002; Cystic Fibrosis Trust, 2002; Sinaasappel et al, 2002) and receive supplementation with the fat soluble vitamins A, D and E. The recommended daily supplements of the fat soluble vitamins for pancreatic insufficient patients are: • Infants: Vitamin A 4,000 IU (1,200 mcg), vitamin D 400 IU (10 mcg) and vitamin E 37-75 IU (25-50 mg) • Children over 1 year of age: Vitamin A 4,000 -10,000 IU (1,200 -3,000 mcg), vitamin D 400 -800 IU (10-20mcg) and vitamin E 150-300 IU (100-200 mg) • Adolescents and adults: Vitamin A 4,000 -10,000 IU (1200-3,000 mcg), vitamin D 800-2,000 IU (20-50mcg) and vitamin E 150-300 IU (100-200 mg) WHAT’S GOING ON? The pancreas often does not work well! RETINOIC ACID INTERACTS WITH A DORMANT BINDING PROTEIN TO ACTIVATE SOME GENES (Such as Mucin) On this graph, Gene #2 is activated by retinoic acid. (However, Gene#1 remains dormant.) GENE #1 REGULATORY DOMAIN #1 REGULATORY DOMAIN #2 GENE #2 (FOR MUCIN) RA + Retinoic acid ACTIVATED BINDING PROTEIN (called: Transcription factor) Dormant binding protein (abundant in cell) RA GENE #2 GENE #1 REGULATORY DOMAIN #1 REGULATORY DOMAIN #2 mRNA IS MADE AFTER BINDING OF ACTIVATED BINDING PROTEIN Mucin expression dependent on these pathways. mRNA for protein To Mucin synthesis How does vitamin A deficiency affect vision? -What is the early symptom (mild deficiency)? -What is the late symptom (severe deficiency)? Vitamin A Deficiency and Toxicity VITAMIN A UNITS: The tough reality One IU of vitamin A is 0.3 micrograms Some papers report IU, other papers report units. Be able to convert, as needed! BECAUSE OF OUR POLICY OF ADDING VITAMIN A (USUALLY, RETINYL PALMITATE) TO MOST DAIRY PRODUCTS, VITAMIN A DEFICIENCY DOES NOT EXIST IN THE US IN PEOPLE WITH NORMAL GI-TRACT FUNCTION IN FACT..WE ARE CONCEIVABLY MORE IN A SITUATION OF BEING OVERLOADED WITH VITAMIN A! THIS MAY ACTUALLY BE RESPONSIBLE FOR EXCESS SKELETAL FRACTURES. THERE HAS BEEN A SHIFT AWAY FROM SUPPLEMENTING WITH RETINOL COMPOUNDS, AND TOWARD SUPPLEMENTING WITH β-CAROTENE, WHICH IS NON-TOXIC. Risk ratios, ANY fracture, and serum vitamin A Michaellson et al, New Eng J. Med, 2003 DIETARY VITAMIN A INTAKE (2 mg/day = 6,500 units/day) SEEMED TO BE ASSOCIATED WITH FRACTURE RISK. This dose would be considered harmless, by earlier guidelines. There was no risk with higher intakes of β-carotene. Serum vitamin A and hip fracture risk: Opotowsky, Amer J. Med, 2004 Lowest Highest http://www.youtube.com/watch?v=xUgfuWmNnu0 Therapy with 9-cis-retinoic acid (Isotretinoin). Week 1 Week 16 High-dose 13-cis-retinoic acid is EFFECTIVE because it sends cells into a differentiated phenotype. The cells in the skin are dividing very rapidly, and this produces “acne pustules”. The retinoic acid effect is to make the cells more stable and they stop their excessive rate of division. The Wikipedia article is very useful. http://en.wikipedia.org/wiki/Isotretinoin Only one form of vitamin A, shown here, can be consumed at high doses, with no harmful side effects.