Vitamin D


Vitamin D -  Cholecalciferol: From Vitamin to Steroid Hormone

I. Historical Review

                A.Opening Comments

                B. History

                               1. Prior to 1700

                               2. From 1700 to 1920

                               3. From 1920 to 1960

                               4. From 1960 to present time

                C. Biological Facts Realted to Vitamin D

                D. The Steroid Hormone Mode of Action of Vitamin D



The Provitamins D

I. Background Considerations

                A. Definition of a Provitamin

                B. Identification of the Concept of a Provitamin

                C. Chemical Characterization of Provitamins

II. Occurence

III. Chemistry

                A. Structural Requirements forActivity

                B. Chemical Synthesis



The Vitamins D

I. Background Considerations

                A. Minimal Structural Requirements for Activity

                B. Chemical Characterization

                               1. Vitamin D2

                               2. Vitamin D3

II. Natural Occurence of Vitamins D

III. Chemistry of Vitamins D

                A. Structure and Physical Properties of Vitamin D and Related Steroids

                               1. Vitamin D3 or Cholecalciferol (C27H44O)

                               2. Vitamin D2 or Ergocalciferol (C28H44O)

                               3. Lumisterol2 (C28H44O)

                               4. Pyrocalciferol and Isopryrocalciferol

                               5. Tachysterol2 (C28H44O)

                               6. Previtamin D2 (C28H44O)

                               7. Suprasterol I and Suprasterol II


                               9. Dihydrotachysterol 2 (Antitetany Compound 10, AT-10)

                B. Conformation

                C. Photochemical Production

                D. Chemical Synthesis

                E. Synthesis of Radioactive Vitamin D and Metabolites

                F. Industrial Production of Vitamin D

IV. Methods of Chromatographic Separation of Vitamin D Compounds



Biological and Chemical Assay of Vitamin D, Its Metabolites, and Analogs

I. Introduction

                A. Types of Methods and Their Sensitivity

                B. Definition and Standardization of Activity

II. Biological Determinations

                A. Official Assays

                               1. Rat Line Test

                               2. AOAC Chick Test

                B. Other Assays

                               1. Stimulation of Intestinal Calcium Absorption

                               2. Mobilization of Bone Calcium

                               3. Stimulation of Growth

                               4. Immunoassay for Calcium-Binding Protein

III. Chemical Determiations

                A. Ultraviolet Abrosption

                B.Colorimetric Methods

                C. Gas Chromatography

                D. Gas Chromatograhy - Mass Spectrometry

                E. High-Pressure Liquid Chromatography

IV. Summary



Vitamin D Metabolites and Analogs

I. Introduction

                A. Metabolism of Vitamin D

                B. Opportunity for Structure - Function Studies

II. Isolation, Characterization, and Chemical Synthesis of Vitamin D Metabolites

                A. 25 (OH)D3

                B. 25 (OH) D2

                C. 1,25 (OH)2 D3

                D. 1,25 (OH) 2 D2

                E. 24,25 (OH)2 D3

                F. 1,24,25 (OH)3 D3

                G. 25,26 (OH) 2 D3

                H. 1- (OH)- 24,25,26,27-Tetranor-23-COOH D3

                I. 25- (OH)-26,23-Lactone-D3                                   

                J. 25,26,27-Trinor-24-COOH-D3

III. Analogs of Vitamin D and Its Metabolites

                A. General Considerations

                B. A-Ring Analogs

                               1. 5,6 cis-Steroids

                               2. 5,6 trans-Steroids

                C. Side-Chain Analogs

                D. Other Analogs Related to Vitamin D

IV. Structure-Function Studies

                A. Problems of Evaluation

                B. Structural Features Required for Optimization of Vitamin D Activity

                C. Possible Realtionship of Steroid Conformation to Bioogical Activity

                D. Analog Studies

                               1. Selectively Active Analogs

                               2. Analogs Which May Function as "Anti-Vitamins"

                               3. Summary



I. Introduction

                A. Background

                B. Discovery of Vitamin D Metabolism

II. Vitamin D

                A. Photochemical Production

                B. Possible Nonphotochemical Production

                C. Intestinal Absorbtion

                D. Vitamin D 25-Hydroxylase

                               1. Localization and Properties of the Enzyme

                               2. Regulation of Vitamin D 25-Hydroxylase

III. 25-Hydroxyvitamin D

                A. 25-Hydroxyvitamin D 1-Hydroxylase

                               1. Localization and Properties of the Enzyme

                               2. Regulation of 25 (OH) D3 1-Hydroxylase

                B. 25-Hydroxyvitamin D 24-Hydroxylase

                               1. Localization and Properties of the Enzyme

                               2. Regulation of 25 (OH) D3 24-Hydroxylase

                C. Production of 1,24,25 (OH)3 D3

                D. Integrated Regulation of the Renal Metabolism of 25 (OH)D3

                E. Production of 25,26 (OH)2 D3

IV.  1,25 (OH)2 D3 Metabolism: Unresolved Problems

V. Vitamin D Metabolism in Human

VI. Metabolism of Vitamin D Analogs

                A. 1α-Hydroxyvitamin D3

                B. Pseudo 1α- Analogs

VII. Effects of Chlorinated Hydrocarbons on Vitamin D Metabolism



The Tissue and Subcellular Localization of Vitamin D and Its Metabolites: A Basis for Their Hormonal Mode of Action

I. Tissue Distribution Studie

                A. Early Studies (Prior to 1960)

                B. Modern Studies (After 1960)

II. Subcellular Distribution Studies

                A. Intestinal Mucosa

                               1. Studies in Vivo

                               2. Studies in Vitro

                B. Bone

                C.Parathyroid Gland

                D. Other Organs (Kidney, Liver, Brain)

III. Intestinal Nuclear Localization of 1,25 (OH)2 D3 as a Basis for Steroid Hormone Mode of Action

                A. Lag in Action of Vitamin D and 1,25 (OH)2 D3

                B. Effects of Actinomycin D and Other Antibiotics on Intestinal Calcium Absorbtion

                C. Molecular Basis of Steroid Hormone Mode of Action of 1,25 (OH)2 D3

                D. Effects of Vitamin D and 1,25 (OH)2 D3 on RNA Metabolism

                E. Effects of Vitamin D and 1,25 (OH)2 D3 on Protein Synthesis

IV. Summary



Binding Proteins and Receptors for Vitamin D and Its Metabolites

1. Vitamin D

                A. Binding Proteins

                B. Competetive Binding Assay

II. 25 (OH) D

                A. Binding Proteins

                B. Competetive Binding Assay

III. 1,25 (OH)2 D

                A. Binding Proteins

                B. Competetive Binding Assay

IV. 24,25 (OH)2 D Assay

V. Bone Calvaria Assay for Vitamin D Metabolites



Interrelationships between Vitamin D and Other Hormones

I. Inductory Comments

                A. Physiological Roles of Vitamin D, Parathyroid Hormone, and Calcitonin

                B. Dynamics and Requirements of Calcium and Phosphate Metabolism

II. Parathyroid Hormone and Calcitonin

                A. Effects of Parathyroid Hormone on Vitamin D Metabolism

                B. Effects of Vitamin D Metabolites on Parathyroid Gland

                                1. Parathyroid Gland Size

                               2. Parathyrois Hormone Secretion

                               3. Feedback Mechanisms

                C. Calcitonin

                D. Integrated View of Calcium Homeostasis

III. Adrenal Cortical Steroids

                A. Background

                B. Hydrocortisone- Parathyroid Hormone Interaction

                C- Hydrocortisone Inhibition of Intestinal Calcium Absorption

                D. Effects of Glucocorticoids on Vitamin D Metabolism

IV. Other Hormones


                B. Thyroxine

                C. Growth Hormone- Somatomedin

                D. Insulin




I. Background Consderations

                A. Introduction

                B. Intestinal Morphology and Cytology

                C. Intestinal Calcium and Phosphorus Absorbtion - The Problem

                D. Methods of Study

II. Early Work on the Intestinal Absorption of Calcium and Phosphorus

III. Modern era

                A. Adaptation of Intestinal Ca+2 Absorption

                B. Contrasting Views on the Mechanism of Calcium and Phosphorus Transport

                C. Factors That Affect Intestinal Absorption of Calcium and Phosphorus

                D. Effects of Plant Extracts

                E. Use of the Polyene Antibiotic Filipin as a Tool to Study Calcium Transport

                F. Calcium - Binding Protein

                G. Alkaline Phosphatase, ATP ase, and Phytase

                H. Concluding Remarks



Vitamin D Actions in the Kidney (Excluding Vitamin D Metabolism)

I. The Kidney and Mineral Homeostasis

                A. Introductory Comments

                B. Role of the Kidney and Vitamin D in Calcium  and Phosphorus Homeostasis

II. Effects of Vitamin D and Metabolites on Renal Tubular Function

                A. Calcium-Binding Protein

                B. Calcium

                C. Phosphate

                D. Other Ions (Na+, HCO3-, K+)

                E. Amino Acids

III. Other Vitamid D - Kidney Interactions

                A. Mitochondrail Ion Transport

                B. Vitamin D and Citric Acid Metabolism

IV. Toxic Effects of Vitamin D on the Kidney



Vitamin D Actions on Bone

I. Background Considerations

                A. Introduction

                B. Calcium and Phosphorus Homeostasis - Role of the Bone

                C. Bone Tissue - morphology and Physiology

                D. The Problem

II. Effects on Bone Collagen

III. Effects of Bone Mineral Metabolism

                A. Bone Accretion

                B. Bone Resorption

                C. Morphological and Historical Alterations

IV. Effects on Bone Organic Acid Metabolism

V. Differential Actions of Vitamin D Metabolites



Vitamin D and Its Clinical Relationships

I. Introduction

                A. Background

                B. Serum Levels of Vitamin D and Its Metabolites and Their Rates of Production and Turnover

                C. Normal Human and Vitamin D

                               1. Adaptation of Intestinal Calcium and Phosphorus Absorption

                               2. Photochemical Production of Vitamin D and Its Intestinal Absorption

                               3. Nutritional Requirement for Vitamin D

                D. Etiology of Clinical Disorders That May Be Related to Vitamin D

                E. Clinical Applications of Vitamin D Metabolites

II. Human Disease States Realated to Vitamin D

                A. Liver

                               1. Cirrhosis and Obstructive Jaundice

                               2. Metabolism Induced by Drugs (Particularly Anticonvulsants)

                B. Kidney

                               1. Chronic Renal Disease

                               2. Vitamin D - Resistant Rickets or Hypophosphatemic Rickets

                               3. Vitamin D - Dependent Rickets

                C. Parathroid

                               1. Primary Hyperparathyroidism

                               2. Secondary Hyperparathyroidism

                               3. Hypoparathyroidism

                               4. Pseudohypoparathyroidism

                D. Thyroid

                               Medullar Carcinoma

                E. Intestinal Relationships

                               1. Idiopathic Hypercalciuria

                               2. Sarcoidosis

                               3. Glucocorticoid Antagonism

                               4. Sprue (Coeliac Disease)

                F. Bone

                               1. Rickets /Osteomalacia

                               2. Osteoporosis

                               3. Osteitis Fibrosa Cystica

                               4. Osteopenia - Osteopetrosis

                               5. Fibrogenesis Imperfecta Ossium

III. Animal Health Applications

                A. Poultry Nutrition

                B. Postparturient Paresis (Milk Fever)



A. Molecular weights, Units and Mole-Equivalents for Vitamin D, Its Metabolites, and Important Analogs

B. Diets Used to Raise Vitamin D - Deficient Animals

C. IUPAC Nomenclature Rules for Vitamin D

D. Bibliography: Review Articles and Books Related to Vitamin D