Exam Three Vitamins PDF

Vitamin L-Carnitine → Hydrophilic Amine Location External → “Red Meats and Dairy” ● Typically consume between (50 - 200 mg/day) Internal → 98% found in “Skeletal and Cardiac Muscles” ● Greatest concentrations found in “Testes and Sperm” 75% comes from the diet, 25% synthesized from L-Lysine Stru...

Vitamin L-Carnitine → Hydrophilic Amine Location External → “Red Meats and Dairy” ● Typically consume between (50 - 200 mg/day) Internal → 98% found in “Skeletal and Cardiac Muscles” ● Greatest concentrations found in “Testes and Sperm” 75% comes from the diet, 25% synthesized from L-Lysine Structure D-Carnitine (Toxic) L-Carnitine (Biologically Active) Absorption and Transport Absorption take place in the “Small Intestine” BRUSH BORDER ● OCTN2 (Organic Cation Transport Number 2) → Sodium Dependent BASOLATERAL BORDER (Into the Plasma) ● B⁰+ (Amino Acid Transporter) Absorption Rates… ● Non-Vegetarian → 55% to 75% ● Vegetarian → 65% to 85% “Unabsorbed” L-Carnitine → Converted into…in the large intestine ● Gamma Butyrobetaine ● Trimethylamine ○ Flavin Monooxygenase → Oxidizes Trimethylamine to → Trimethylamine Oxide ■ The form that is excreted Biosynthesis requires (5) co-factors… ● SAMe, Vitamin C, Iron, Vitamin B6, and Vitamin B3 (Niacin) Enters “Skeletal and Cardiac Muscles” → OCTN2 Enters “Testes” → OCTN2 and OCTN3 Important Enzymes Gamma Butyrobetaine Hydroxylase → Found in Kidney, Liver and Brain ● Kidney synthesizes 3x’s more than Liver and 6x’s more than Brain Trimethyllysine Hydroxylase Mitochondria Carnitine Shuttle → Long-Chain Fatty Acid (LCFA) Transport ● CPT-1 (Carnitine Palmitoyltransferase) → Rate Limiting Step ○ Transfer LCFA into the Mitochondria → Malonyl CoA inhibits Carnitine Palmitotransferase 1 → 3 Isoenzyme Forms… ● CPT-IA → All Tissues (except Skeletal, Cardiac, and Testes) ● CPT-IB → Found in the “Skeletal, Cardiac, and Testes Tissues” ● CPT-IC → Found in “Neurons” ○ Nonfunctional in transport Carnitine Acetyltransferase → Removes the “Carnitine” from “Acetyl CoA” ● Decreased Carnitine = Increased Acetyl CoA ○ Will limit Beta-Oxidation Deficiencies and Supplements Trimethyllysine Hydroxylase Defect ● Can be linked with males on the “autism” spectrum OCTN2 Defect → Genetic Disorder ● Urinary Carnitine Wasting → Primary Systemic Carnitine Deficiency ○ Carnitine Uptake defect ○ Cardiomyopathy, muscle weakness, hepatomegaly Genetic Disorder os CPT-IA, CPT-II and Carnitine Acylcarnitine Translocase ● Impair oxidation of Long-Chain Fatty Acids ○ Same symptoms as above Secondary Carnitine Deficiency ● Can be caused by renal failure = decreased L-Carnitine Synthesis ● Vitamin C deficiency related to decreased synthesis of L-Carnitine Supplementation… ● Prevention of heart disease, kidney disease, cognitive disorders and male infertility ● Improves energy metabolism in “Cardiac Cells” ○ Angina free with supplementation ○ Decreased Myocardial Infarction rates ● Improve Insulin sensitivity → promote glucose uptake ● Reduction of Plasma Liver Enzymes (ALT and AST) Toxicities >3 g/day → Nausea, abdominal cramps, and diarrhea ● Linked to “Fishy Body Odor” Acetyl L-Carnitine (ALCAR) ● Increases frequency of seizures (those with the disorder) Upper Tolerable Limits NA Excretion and Excretion → Elimination through the Kidneys Other Notes ● Reabsorbed in Proximal Renal Tubules by OCTN2 Other Notes… ● Acetyl L-Carnitine → Crosses the BBB more readily L-Carnitine ○ Converted to L-Carnitine upon passing ○ Improves cognitive performance ● L-Carnitine → DOES NOT possess direct “Free Radical Scavenging” ● 2 g/day for 12 weeks = reduced body weight (3 pounds) Vitamin Vitamin A → Retinoid compounds (All Trans-Retinol) Location External → Foods of “Animal Origins” ● Liver (Cod Liver) and Dairy Products ● Polar Bear Liver → Extremely High → Fatal ● In the form of ‘Retinyl Esters” → Transport form ○ Most common being → Retinyl Palmitate Internal → In the Liver and Stellate Cells Structure Made up of (4) Isoprenoid Units w/ Conjugated double bonds Know… ● All Trans- Retin(ol) ● Retin(al) ● Retinoic Acid Isomers → All Trans Retinoic Acid & 9 Cis Retinoic Acid Absorption Vitamin A → FAT SOLUBLE and Transport ● Retinyl Esters “coalesce” to form “fat globules in the stomach” ● Bile Salts and Phospholipids REQUIRED for absorption ○ They break down the globules Need 10 g/day of fat to get absorption started (Gallbladder and Pancreas) ● Stimulates the release of CCK in the stomach Vitamin A → Hydrolyzed by “Pepsin” and “HCl” in the Stomach BRUSH BORDER → on the MICELLE ● Facilitated Diffusion using (2) carries… ○ Fatty Acid Binding Protein 2 (FABP2) ○ Fatty Acid Transport Protein/Fatty Acid Translocase (FAT) In the ENTEROCYTE ● CRBPII (Cellular Retinol Binding Protein II) → Chaperon Protein ○ Delivers “Retinol” to “LRAT” (Lecithin Retinol AcylTransferase) ● LRAT → Adds a Fatty Acid on (typically Palmitate) ○ Creates → CRBPII-Retinyl-Palmitate ● Transported by “Chylomicrons” (30%) → To the Lymph System ○ Drain in the Thoracic Duct and Left Subclavian Vein ● Remaining (70%) → Taken up by the Liver by Chylomicron remnants Four Metabolic Pathways of Retinyl Esters… 1. Stored in Hepatic Stellate Cells → 90% a. Hypervitaminosis A → Occurs when Stellate Cells are full 2. Attach to Retinol Binding Proteins (RBP) and released from the Liver a. All Trans Retinol → Induced of RBP synthesis i. Dependent upon ZINC Status 3. Oxidized to Retinoic Acid → Which enter the Nucleus 4. Conjugation with Glucuronic Acid (Kiss of Death)→ Excretion in the Bile Vitamin A locations… ● 70% in the Liver, 20% in Adipose Tissue, and 10% spread elsewhere Cellular Retinoid Binding Proteins: CRBP’s and CRABP’s ● Two functions… ○ Prevent Oxidation of Retinoids ○ Act as Chaperone Proteins for transport ● CRBP’s (Retinol Binding) ○ CRBP-I → Found in ALL tissues ○ CRBP-II → Found in the Small Intestine ● CRAB’s (Retinoic Acid Binding) ○ CRABP-I → Found in ALL tissues ○ CRABP-II → Found in the Skin and Female Repro Organs ● Proteins found in the “Retina of the Eye” ○ CRALBP → Cellular Retinal Binding Protein ○ IRBP → Interphotoreceptor Retinol Binding Protein Important Enzymes, Metabolism and Reactions Retinal Oxidase → Uses NAD+ ● Retinal to Retinoic Acid (Hormone) ○ Irreversible Retinal Reductase → Used NADH ● Retinal to Retinol Glucuronidase ● Adds Glucuronic Acid to “Retinol” and “Retinoic Acid” to make them easily excreted Metabolism (Retinoic Acid) - RA ● Formed in the LIVER → No storage though ○ Exported into the blood → picked up by “Albumin” ● Retinol Dehydrogenase → Rate Limiting Step for RA production) ● Induces Cytochrome P₄₅₀26 (CYP26) ○ Retinoic Acid to 4-Oxo-Retinoic Acid Trimolecular Complex (TMC) and Stra6 (Cellular RBP Receptor) ● The TMC binds to the surface receptor “Stra6” ○ Stra6 → Mediated the transport of Retinol ■ Not found in LIVER CELLS ■ Mostly in the EYE ■ Activates Janus Kinase STAT5 (JAK-STAT5) ● TMC = T4, Retinol, and TTR (Transthyretin) Mechanism (Vision Cycle) ● Retinal is the “Chromophore” in the Photopigment ● 11 Cis Retinal → Covalently bound to “Rhodopsin” in Rods and (3) “Idoposins” in Cones (Red, Green, and Blue) Retinoic Acid Expression → RAR and RXR (Steroid Receptors) ● RAR (Retinoic Acid Receptors) → All Trans Retinoic Acid (17%) ● RXR (Retinoid X Receptors) → 9 Cis Retinoic Acid (1%) Retinolation of Proteins → Done by Retinoyl CoA Cellular Differentiation and Growth ● Retinoic Acid → Important for cell differentiation ○ EX: Epithelial Cells ■ RA stimulates the growth of these Epithelial Cells Cell to Cell Communication → Connexin 43 ● Used to form “Gap Junctions” ● Lack of Gap Junctions = Uncontrolled Growth → Cancer Induced the production of Cytokine (CD1d) → Increased IgA and Treg Reproductive Functions → Vitamin A is essential for reproduction ● In both females and males (spermatogenesis) ○ Remember testes have the 2nd highest Stra6 density ■ Retina is the 1st Embryogenesis ● Vitamin A → Effects “gene expression” in embryonic development Dermatological Functions → Influences the physiology of the skin ● “Accutane” → Can treat acne ○ However, induces depressive disorders and suicide Bone Metabolism ● Excess Vitamin A = Increased Osteoclast and Inhibits Osteoblast ○ Decreases the bone mineral density and increase fracture risk = “Osteoporosis” Hematopoiesis → Iron distribution among the tissues ● Can result in Iron Deficiency Anemia Clinical Observations and Deficiencies and Cancer Most common Vitamin Deficiency in the WORLD → Mainly pregnant women and children ● Dry scaly skin with “Goose Bumps” Decreased Vitamin A levels has an association with higher risk of “ Epithelial Cancers (Lung and Ovarian) ● Proliferation of immature undifferentiated cells and decreased apoptosis of cancer cells ● RAR and RXR = Inactivation of Tumor Suppressor Genes Liver Cancer → Alcohol Induced ● Ethanol is a “Inhibitor” of Retinol Dehydrogenase → Induces CYP26 ○ Enhances the mobilization of Vitamin A to the Liver Stra6 Gene Defect → Causes “Microphthalmia” ● Matthew-Wood Syndrome → NO EYES Vitamin A Deficiency → Night Blindness ● Night Blindness precedes “Xerophthalmia” ○ Xeropthalmia → Bitot’s Spots and Corneal Ulcers Retinitis Pigmentosa → Complete Blindness ● Mutations of RPE65 or CRALBP RXR → Vitamin D Deficiency Toxicities Hypervitaminosis A → Large dose over 100,000 IU (international units) ● Nausea, Vomiting, Double Vision, Headaches, Dizziness High Doses can be FATAL → Polar Bear Liver (2,000,000 IU) 10,000 IU/day → Increased Osteoporosis and hip fractures 30,000 IU/day → Anorexia, Dry and Itchy Skin, Ataxia, Headaches Teratogenicity = Birth Defects → Vitamin A intake greater than 15,000 IU Upper Tolerable Limit 10,000 IU Excretion and Other Notes Excretion → Oxidized and Conjugated in the Liver ● Kidney is the main organ… ○ 40% in the Feces ○ 60% in the Urine Other Notes… ● Vitamin A → Acts as a “Chemotherapeutic” for Leukemia, Lung and Skin Cancers ● “Anti-Infective” → Vitamin A maintains the Epithelial Barriers ○ It acts at the “First Line of Defense” Vitamin Carotenoids (50 are converted to Retinol) Location External → Color fruits and some veggies ● Red, Orange, and yellow ○ Beta Carotene → Carrots ○ Lycopene → Tomatoes ○ Beta-Cryptoxanthin → Oranges and Tangerines ○ Zeaxanthin → Corn ○ Lutein → Kale and Spinach, and EGG YOLK Internal → In Fat (Adipose) Structure Provitamin A Carotenoids (One RING on each end) Alpha Carotene Beta Carotene (Orange) Beta-Cryptoxanthin Non Vitamin A Precursors Lutein (Yellow) Absorption and Transport Zeaxanthin and Canthaxanthin (No Rings) Lycopene (Red) (Trans- Main source) Carotenoid Biosynthesis Pathway (40 Carbons from 8 Isoprene Units) 5% - 65% of Carotenoids → Absorbed by “Passive Diffusion” ● Absorption of “Uncooked Veggies” → 5% Absorption by TWO transport proteins… ● Fatty Acid Translocase (CD-36) ● SR-B1 (Scavenger Receptor Class B Type 1) 12 ug of Beta Carotene → 1 ug of Retinol 24 ug of Alpha Carotene/Beta Cryptoxanthin → 1 ug of Retinol Negative Feedback Mechanism ● Caused by Retinoic Acid inducing the expression of the ISX Transcription Factor ○ ISX → Intestine Specific Homeobox ■ Inhibits SR-B1 and BCO1 ● BCO1 (Beta Carotene 15, 15’ Monooxygenase) Transport → THREE Routes to the Liver ● Cleavage and reduced to form Retinol ● Packaged and released from the Liver → VLDL’s ● Stored in Liver’s “Stellate Cells” Enter Tissue Cells → SR-B1 Endocytosis Brain Tissue → Primarily Lutein and Zeaxanthin Functions, Mechanisms and Important Enzymes Higher levels of Serum Carotenoids = Lower incidences of CVD, Cancer, and Cataracts Functions…FOUR main functions ● Antioxidant Function → Protect against chronic diseases ○ Lutein and Zeaxanthin work “synergistically” make them the most effective carotenoid ■ Tomato juice decreases LDL Cholesterol Levels and resistance to Oxidation ● Photoreception for SKIN and RETINA ○ Beta Carotene → SPF of approx. 4 ■ Orange People ○ Age Related Macular Degeneration (AMD) ■ Yellow Spot on the Macula Lutea ● Yellow due to Lutein and Zeaxanthin ● Affect Cell Proliferation, Growth, and Differentiation ○ Inhibit cell proliferation → stimulate cell differentiation ■ Inhibit cancer cell growth ● Anti-Inflammatory → Carotenoids bind to PPARy ○ Inhibit NFkB gene activation → reduced COX2 enzymes BCO1 → Cleaves/chops Beta Carotene into 2 Retinal units ● 1:8:1 Ratio ● Cleaves at the Central Bond BCO2 (Beta Carotene 9’, 10’ dioxygenase) ● Eccentric Cleavage of Beta Carotene (double bonds other than the central bond) ● Produces → Apocarotenoids ○ Can interfere with normal cell function (inhibit cell growth) Deficiencies None Listed Toxicities Hypercarotenemia → 30mg/day for 30 days ● Yellow/Orange color of the skin = Carotenoderma Beta Carotene Supplementation >20mg/day ● Detrimental to “smokers and chronic alcoholics ● Increases Lung and Liver Cancer by (16 - 28%) Upper Tolerable Limit No UTL has been established Excretion and Other Notes Excretion… ● 80% excreted in the Feces and Bile ● 10% are Polar Metabolites in the Urine Vitamin Vitamin D (Cholecalciferol) → D3 (The Sunshine Vitamin) Location Externally → Food of “animal origin” (poor source) ● Milk, Margarine, and OJ → Fortified with Vit D ● “SUN” is the most efficient source 40% of Vit D is from Supplements Structure Vitamin D3 → Cholecalciferol (Three intact rings) - STABLE Derived from a “Steroid” Absorption, Transport and Storage From the Diet ● Absorbed by a “Micelle” through “Passive Diffusion” ○ Absorbed in the “Distal Small Intestine” ● Roughly 50% is absorbed ● In the “Enterocyte” → Incorporated into “Chylomicrons” In the Blood → Delivered to the LIVER by “Endocytosis” ● DBP (Vitamin D Binding Protein) → 60% ● Chylomicrons → 40% ○ Also delivered to “extrahepatic tissues” by “Lipoprotein Lipase” Hydroxylation in the Liver (Cholecalciferol → Calcidiol/25-OH Vit D) ● Calcidiol/25-OH Vit D ○ Remains in the Liver ○ Half Life → 2 - 3 Weeks ● 25 Hydroxylase Isoenzymes ○ CYP2R1 (Microsomal Cytochrome P-450) ○ CYP27A1 (Mitochondrial Cytochrome P-450) Hydroxylation in the Kidney (Calcidiol/25 OH Vitamin D → Calcitriol) ● Calcitriol (Active Form of Vit D) → Released from the Kidney ○ Bound to DBP in the Blood ○ Half Life → 2 - 6 Hours ● 1 Alpha-Hydroxylase/CYP27B1 (Mitochondrial Cytochrome P-450) Adipose Tissue → Sink for Vitamin D ● Obese Individuals → Low 25-OH Vitamin D Blood is the largest single pool of 25-OH Vitamin D Important Enzymes and Mechanisms 7-Dehydrocholesterol → Synthesizes Vitamin D ● In the “sebaceous gland” → found throughout the epidermis and dermis ● Highest concentrations in the “Stratum Basale” and Stratum Spinosum” Double bonds in the B ring → Absorb UVB photons ● This breaks the ring → Produces “previtamin D3/precalciferol” ● Precalciferol is “isomerized” Cholecalciferol ○ Cholecalciferol → Diffuses from skin into the blood ○ Transported in the Blood by “Transcalciferin” ■ Vitamin D Binding Protein Renal Synthesis of “Calcitriol” → Regulation in Calcium and Phosphate ● Parathyroid Hormone (PTH) ○ Stimulates 1 Alpha-Hydroxylase (when Ca levels are low) ○ Three Functions (Up-regulates Genes) ■ TRPV5 ■ Calbindin D28K ■ Ca2+ ATPase ● Fibroblast-Like Growth Factor 23 (FGF-23) ○ Inhibits 1 Alpha-Hydroxylase (when Phosphate levels are high) ○ Inhibits Calcitriol Synthesis High Calcitriol Levels ● Stimulates 24-Hydroxylase (Kiss of Death) ○ CYP24A1 (Mitochondrial Cytochrome P-450) ■ Calcitriol in inactive metabolites NON-Genomic Mechanism ● Calcitriol binds to cell membrane VDR (Vit D Receptor) or MARRS ○ Rapid changes in body processes ● Generate Secondary Messengers ○ cAMP, Diacylglycerol (DAG), Inositol Triphosphate (IP3), NFkB, and Arachidonic Acid ■ These open chemically gated Ca Channels Genomic Mechanism ● Calcitriol bind to VDR → Regulates gene expression ○ Creates the Calcitriol-VDR Complex Important Functions ● Transepithelial Calcium Transport ● Modulation of Bone Metabolism ○ RANKL → Osteoclast ● Modulation of Intracellular Calcium ● Regulation of Cell Proliferation and Differentiation Deficiencies and Mortality Subjects with >75 nmol/L of 25-OH ● 30% Reduction in mortality Deficiencies ● Rickets → Failure of Bone Mineralization (infants) ● Osteomalacia → PTH elevations are to high ○ Bone reabsorption Insufficiencies ● Osteoporosis, Cancer, Cardiovascular Disease ○ Cancer → Breast, Colon, Prostate ■ African Americans → Higher Incidence ● Autoimmune disease, Respiratory Disease, Diabetes ○ Diabetes → Insulin is negatively regulated ○ Autoimmune → Crohns, RA, and MS Vitamin D and the Prevention of Cancer ● Cell differentiation by E-Cadherin ● Inhibit cell “Proliferation” → Inhibit oncogenes (Myc) ● Promote cell “apoptosis” → Activating Bax and Caspase ● Inhibits NK activity Toxicities 50,000 IU/daily for months → Toxic ● Hypervitaminosis D ○ Hypercalcemia ○ Hyperphosphatemia ○ Hypertension ○ Anorexia, Nausea, Weakness, Headaches Upper Tolerable Limits Litim is 4,000 IU but can be up to 10,000 IU Excretion Excretion → Less than 30% is excreted ● Calcitetrol and Calcitroic Acid (from Calcitriol) ○ Excreted in the bile and urine Other Notes Other Notes… ● Dark Skinned People → Require 5-10 times longer sun exposure ○ Due to “Melanin” blocking UVB photons ● Sufficient Vitamin D levels → >75nmol/30ngrams ● Vit D → Enhances the absorption of Phosphorus and Magnesium