Hormones (eBook)

Helen L. Henry, Anthony W. Norman (Autoren)

eBook Download: PDF | EPUB

2014 | 3. Auflage
430 Seiten
Elsevier Science (Verlag)
978-0-08-091906-5 (ISBN)

Infos

The 3rd edition of Hormones offers a comprehensive treatment of the hormones of humans all viewed from the context of current theories of their action in the framework of our current understanding their physiological actions as well as their molecular structures, and those of their receptors. This new edition of Hormones is intended to be used by advanced undergraduates and graduate students in the biological sciences. It will also provide useful background information for first year medical students as they engage in studies which are increasingly problem-based rather than discipline-focused. As the field of endocrinology itself has expanded so much in the past two decades, the up to date presentation of the basics presented in this book will be a solid foundation on which more specialized considerations can be based. New to this Edition: Hormones, 3rd Edition is organized with two introductory chapters followed by 15 chapters on selected topics of the molecular biology of the major endocrine systems operative in humans. Coverage, for the first time of the following hormones; ghrelin, oxyntomodulin, kisspeptin, adrenomedullin, FGF23, erythropoietin, VIP and extended coverage of NO. Coverage of the hypothalamus has been integrated with the anterior pituitary because of the intimate functional and relationship between the two. Consideration of the role of hormones in cancer has been integrated into the chapters on the relevant hormones. Each of these areas occupies a unique niche in our understanding of the biological world and is part of the universality of signaling systems and how they govern biological systems. - Organized with two introductory chapters, followed by 15 chapters on selected topics of the molecular biology of the major human endocrine systems - New full color format includes over 300 full color, completely redrawn images - Companion web site will host all images from the book as PPT slides and .jpeg files - All chapters have been completely updated and revitalized. Coverage of the hypothalamus has been integrated into the anterior pituitary chapter and coverage of the thymus has been eliminated and left to immunology textbooks - Provides essential basics for advanced undergraduates and graduate students in the biological sciences, as well as first year medical students as they engage in studies which are increasingly problem-based rather than discipline-focused

Anthony W. Norman received his A.B. from Oberlin College in 1959, and an M.S. and Ph.D. in Biochemistry in 1961 and 1963, respectively, from the University of Wisconsin, Madison. Following postdoctoral work in Paul D. Boyer's group at UCLA, in 1964 he joined the Department of Biochemistry at University of California, Riverside, as an Assistant Professor. From 1976 to 1981 he served as Chair of the department and currently holds a Presidential Chair and is a Distinguished Professor of Biochemistry and Biomedical Sciences. Dr. Norman has also been active for some 25 years in medical education on the UC-Riverside campus and at UCLA through participation in the UR/UCLA Program in Biomedical Sciences, of which he was Dean and Director from 1986 to 1991. Dr. Norman's biomedical research career has focused on the mechanism of action of the vitamin D family of steroids. His chief contributions to these areas of cellular and molecular endocrinology have played a pivotal role in defining the boundaries of this research domain via discoveries that have opened new areas of investigation. The first of these was the discovery in 1968, and chemical characterization in 1971, of the hormonally active form of vitamin D, 1a,25(OH)2-vitamin D3. Subsequent achievements include the discovery and characterization of the nuclear receptor for 1a,25(OH)2D3, the clinical evaluation of 1a,25(OH)2D3 in renal osteodystrophy, articulation of the concept of the vitamin D endocrine system, the importance of 1a,25(OH)2D3 to insulin secretion and the discovery of a new rapid, nongenomic, signal transduction process for 1a,25(OH)2D3. Dr. Norman has been the recipient of awards that include a Fulbright Fellowship, 1970; Public Health Service Career Development Award, 1970; Mead Johnson Award, American Institute of Nutrition, 1977; Ernst Oppenheimer Award, Endocrine Society, 1977; Visiting Lecturer Australian Society of Endocrinology, 1978; Visiting Faculty Member, Mayo Clinic, 1981; Prix Andre.

Inhalt

Front Cover 1
Hormones 4
Copyright Page 5
Contents 6
Preface 14
About the Cover 16
Front Cover Image 16
Back Cover Image 16
1 Hormones: An Introduction 18
I. Overview of Hormones 18
A. Introduction 18
B. Review of Animal Cell Structure 19
C. Hormones and Their Communication Systems 22
D. Biosynthesis of Peptide and Protein Hormones 23
E. Regulation of Hormone Synthesis, Secretion, and Serum Levels 25
II. Hormone Receptors 26
A. Introduction 26
B. Membrane Receptors 27
C. The Nuclear Receptor Family 29
D. Measurement of Hormone–Receptor Interactions 31
III. Mechanisms of Hormone Action 33
A. Cell Signaling by Membrane Receptors 33
B. Regulation of Gene Transcription by Steroid Hormones 37
C. Membrane-Initiated Actions by Steroid Hormones 38
IV. Clinical Aspects 39
Further Reading 42
2 Steroid Hormones: Chemistry, Biosynthesis, and Metabolism 44
I. Introduction 44
A. General Comments 44
B. Historical Perspective 44
C. Radioactive Steroids 45
D. Molecular Biology Contributions 45
II. Chemistry of Steroids 45
A. Basic Ring Structure 45
B. Classes of Steroids 45
C. Structural Modification 47
D. Asymmetric Carbons 47
E. Conformational Flexibility of Steroids 49
F. Other Steroid Structures 52
III. Biosynthesis of Steroids 53
A. Introduction 53
B. Properties Steroidogenic Enzymes 56
C. Biosynthesis of Pregnenolone and Progestins 66
D. Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens 67
E. Biosynthesis of Androgens 67
F. Biosynthesis of Progesterone and Estrogens 67
G. Biosynthesis of Vitamin D Metabolites 68
H. Biosynthesis of Bile Acids 68
IV. Serum Binding Proteins for Steroid Hormones 68
A. Introduction 68
B. Serum Binding Proteins for Steroid Hormones 69
Further Reading 70
3 The Hypothalamus and Anterior Pituitary 72
I. Introduction 72
A. Overview and CNS Control of the Hypothalamus 72
B. Hypothalamic Control of the Pituitary Gland 72
C. Pituitary Control of Distal Endocrine Glands 74
D. Neuroendocrine Axis Feedback 75
II. Anatomical Relationships 75
A. Hypothalamic-Pituitary Anatomy 75
B. Hypothalamic Neural Connections 76
C. Hypothalamic-Pituitary Circulatory System 77
III. Structure, Synthesis, Secretion, and Target Cells of the Hypothalamic Releasing Hormones 77
A. Thyrotropin-Releasing Hormone 78
B. Gonadotropin-Releasing Hormone 80
C. Corticotropin-Releasing Hormone 81
D. Hypothalamic Control of Growth Hormone Secretion 82
E. Hypothalamic Control of Prolactin Secretion 83
IV. Chemistry of the Anterior Pituitary Hormones 83
A. Glycoprotein Hormones 83
B. Growth Hormone 84
C. Prolactin 84
D. POMC Derivatives: ACTH, a-MSH, ß-Lipotropin, Endorphin 85
V. Regulation and Biological Actions of Growth Hormone and Prolactin 86
A. Growth Hormone 86
B. Prolactin 91
VI. The Hypothalamus and Appetite Regulation 93
VII. Clinical Aspects 94
A. Hypothalamus 94
B. Pituitary 94
Further Reading 96
4 Posterior Pituitary Hormones 98
I. Introduction 98
II. Anatomy of the Posterior Pituitary 98
III. Chemistry, Biosynthesis, and Secretion of the Posterior Pituitary Hormones 98
A. Structures of Oxytocin and Vasopressin 98
B. Synthesis and Secretion of Vasopressin and Oxytocin 100
IV. Biological Actions of Arginine Vasopressin (AVP) 101
A. AVP Receptors 101
B. AVP Regulation of Water Handling 101
C. Cardiovascular Effects of AVP 101
D. Effects of AVP on Glucose Homeostasis 102
E. Effects of AVP on ACTH Secretion 102
F. AVP and the Brain 103
V. Biological Actions of Oxytocin 103
A. The Oxytocin Receptor 103
B. Oxytocin and Parturition 103
C. Oxytocin and Lactation 104
D. Oxytocin and the Brain 104
VI. Clinical Aspects 104
A. Oxytocin 104
B. Diabetes Insipidus 105
Further Reading 105
5 Thyroid Hormones 106
I. Introduction 106
A. The Thyroid Gland and Its Hormones 106
B. Iodine Metabolism 106
II. Anatomy of the Thyroid Gland 107
III. Chemistry of the Thyroid Hormones 108
IV. Synthesis and Secretion of Thyroid Hormones 108
A. The Thyroid Epithelial Cell 108
B. Thyroglobulin 109
C. Iodide Uptake: The Na+/I Symporter 110
D. Thyroid Peroxidase and DUOX: Tyrosine Iodination and Coupling 111
E. Thyroglobulin Storage, Endocytosis, and Breakdown 112
F. Secretion of T4 and T3 and Recycling of I 113
G. Transport and Metabolism of Thyroid Hormones 113
H. Antithyroid Drugs 115
V. Regulation of Thyroid Hormone Secretion 116
A. The Hypothalamic-Pituitary-Thyroid Axis 116
B. Autoregulation 117
C. Effects of TSH on the Thyroid Epithelial Cell 117
VI. Biological Actions of T3 118
A. Thyroid Hormone Receptor 118
B. Membrane Mediated Actions of Thyroid Hormone 120
C. Basal Metabolic Rate and Thermogenesis 120
D. Metabolic Actions 121
E. Neurodevelopment 121
VII. Clinical Aspects 121
A. Clinical Features of Hyper- and Hypothyroidism 121
B. Hyperthyroidism: Etiology and Treatment 123
C. Hypothyroidism: Etiology and Treatment 123
Further Reading 124
6 Pancreatic Hormones: Insulin and Glucagon 126
I. Introduction 126
A. Background Information 126
B. Regulation of Blood Glucose 126
C. Nutritional and Metabolic Interrelationships 128
II. Anatomical, Morphological, and Physiological Relationships 130
A. Anatomy of the Hepatopancreatic Complex 130
III. Chemistry, Biochemistry, and Biological Activities of the Pancreatic Hormones 133
A. Insulin 133
B. Glucagon and Glucagon-like Peptides 141
C. Insulin and Glucagon Collaborations 145
D. Leptin 149
E. Other Pancreatic Hormones 152
IV. Clinical Aspects 153
A. Diabetes Mellitus 153
Further Reading 155
7 Gastrointestinal Hormones 158
I. Introduction 158
A. Background 158
B. Resume of the Gastrointestinal Hormones 158
C. Problems of Food Processing and Digestion 160
II. Anatomical and Physiological Relationships 160
A. Gastroenteropancreatic System 160
B. Stomach 162
C. Small Intestine and Colon 164
D. Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex 165
E. Pancreatic, Biliary, and Intestinal Secretions 166
F. Coordination of Gastroenteropancreatic Hormone Release 168
G. Motor Functions of the Intestinal Tract 169
H. Brain–Gut Axis 170
III. Biochemical Properties and Molecular Actions 170
A. General Relationships 170
B. Cholecystokinin/Gastrin Family 171
C. Secretin Family: Secretin, Vasoactive Intestinal Peptide 173
D. Pancreatic Polypeptide Family: Peptide YY and Neuropeptide Y 174
E. Bombesin and Related Peptides: Gastrin Releasing Peptide and Neuromedin C 174
F. Tachykinin Family: Substance P and Neurokinins A and B 175
G. Neurotensin 176
H. Calcitonin Gene-Related Peptide Family: Amylin 177
I. Enteroglucagon and Oxyntomodulin 177
J. Motilin 178
K. Somatostatin 179
L. Gastric Acid Secretion 179
M. Ghrelin, Leptin, and Energy Use 181
IV. Clinical Aspects 185
A. Peptic Ulcer Disease 185
B. Carcinoid Syndrome 185
C. Zollinger-Ellison Syndrome 186
Further Reading 186
8 Eicosanoids 188
I. Introduction 188
II. Structure and Nomenclature of Eicosanoids 189
III. Synthesis and Inactivation of Eicosanoids 189
A. Overview of Eicosanoid Synthesis 189
B. Phospholipase A2 191
C. Prostaglandin H Synthase/Cyclooxygenase 194
D. Cyclooxygenase Inhibitors 195
E. Lipoxygenase 195
F. Transport and Inactivation of Prostanoids 197
IV. Eicosanoid Receptors and Signaling 198
V. Examples of Biological Actions of Prostaglandins 198
A. Prostacyclin and Thromboxane in the Vasculature 199
B. Prostaglandins in the Kidney 199
C. Prostaglandins and Pain Perception 200
D. Prostaglandins in Reproduction 201
VI. Clinical Aspects 202
A. Prostaglandins and Cancer 202
B. Leukotrienes in Human Disease 203
Further Reading 204
9 Calcium-Regulating Hormones: Vitamin D, Parathyroid Hormone, Calcitonin, and Fibroblast Growth Factor 23 206
I. Introduction 206
A. Background Information 206
B. Calcium and Phosphorus Homeostasis 207
II. Anatomical and Physiological Relationships 209
A. Intestine 209
B. Bone 209
C. Kidney 212
D. Parathyroid Gland 212
E. Calcitonin-Secreting Cells 212
III. Chemistry and Biochemistry 213
A. Vitamin D and 1a,25(OH)2D3 213
B. Parathyroid Hormone 215
C. Parathyroid Hormone-Related Protein 217
D. Calcitonin 218
E. Fibroblast Growth Factor 23 219
IV. Biology and Molecular Actions 219
A. Parathyroid Hormone Receptor and Biological Actions 219
B. Parathyroid Hormone-Related Protein Receptor and Biological Actions 220
C. Calcitonin Receptor and Biological Actions 222
D. Vitamin D Receptor and Biological Actions 223
E. Fibroblast Growth Factor-23 230
F. Integrated Actions of 1a,25(OH)2D3, PTH, Calcitonin, and FGF23 on Bone Remodeling and Calcium Homeostasis 232
V. Clinical Aspects 234
A. Vitamin D Nutrition 234
B. Osteoporosis 235
C. Tuberculosis 236
D. Parathyroid Hormone 236
E. Parathyroid Hormone-Related Protein 237
F. Calcitonin 237
G. FGF23 237
Further Reading 238
10 Adrenal Corticoids 240
I. Introduction 240
A. Background 240
B. Glucocorticoids 240
C. Mineralocorticoids 240
II. Anatomy 241
A. Adrenal Cortex 241
B. Liver 242
III. Biochemistry and Biosynthesis of Adrenal Steroids and Testosterone Steroids 242
IV. Biological and Molecular Actions of Glucocorticoids 244
A. Hypothalamic-Pituitary-Adrenal Axis 244
B. Corticotropin-Releasing Hormone 244
C. Transport of Glucocorticoids in the Blood (CBG) 244
D. ACTH Modes of Action 247
E. Glucocorticoids and Stress 248
F. Immunosuppression and Apoptosis Induced by Glucocorticoids 250
G. Feedback Effects of Glucocorticoids 250
H. Glucocorticoid Receptor 251
I. Dehydroepiandrosterone and Zona Reticularis 251
V. Clinical Aspects 251
A. Cushing’s Disease 251
B. Addison’s Disease 252
C. Congenital Adrenal Hyperplasia and Others 253
D. Mifepristone (RU-486) 253
Further Reading 255
11 Hormones of the Adrenal Medulla 256
I. Introduction 256
II. Anatomical and Physiological Relationships 256
A. The Adrenal Gland 256
B. The Adrenal Medulla and the Sympathetic Nervous System 257
C. Chromaffin Cells of the Adrenal 259
III. Chemistry and Biochemistry of the Catecholamines 259
A. Biosynthesis and Secretion of Catecholamines 259
B. Regulation of Catecholamine Synthesis and Secretion 260
C. Catabolism of Catecholamines 263
D. Pharmacology of Catecholamines 264
IV. Biological Actions of Catecholamines 265
A. Adrenergic Receptors 265
B. Biological Responses to Epinephrine 265
V. Clinical Aspects 268
A. Pheochromocytoma 268
B. Chronic Stress 270
Further Reading 270
12 Androgens 272
I. Introduction 272
II. Anatomy of the Male Reproductive System 272
A. Testes, Ducts, and Accessory Structures 272
B. Seminiferous Tubules 274
C. Leydig/Interstitial Cells 274
III. Chemistry and Metabolism of Androgens 274
A. Androgens and Related Molecules 274
B. Androgen Biosynthesis 277
C. Modification of Testosterone in Target Tissues 277
D. Sex Hormone-binding Globulin 279
E. Catabolism of Androgens 279
IV. Regulation of Androgen Production 279
A. Hypothalamic-Pituitary-Testes Axis: Hormonal Control of the Testis 279
B. Hypothalamic-Pituitary-Testis Axis: Feedback Control 281
C. Prolactin 282
V. Biological Responses to Androgens 282
A. The Androgen Receptor 282
B. Sexual Differentiation 283
C. Puberty 285
D. Spermatogenesis 287
E. Estrogens in Males 288
F. Androgens in Females 288
VI. Clinical Aspects 289
A. 5a-Reductase Deficiency 289
B. Androgen Insensitivity Syndrome 289
C. Androgen Abuse 289
D. Prostate Cancer 289
Further Reading 290
13 Estrogens and Progestins 292
I. Introduction 292
II. Anatomy of the Female Reproductive System 292
A. Components of the Female Reproductive System 292
B. The Ovarian Follicle and Corpus Luteum 294
III. Chemistry and Metabolism of Female Steroid Hormones 298
A. Female Steroid Hormones 298
B. Synthesis of Progesterone and Estrogens 298
C. Catabolism of Progesterone and Estrogens 299
IV. Hypothalamic-Pituitary-Ovary Axis 300
A. Introduction 300
B. Control of the Ovary by the Hypothalamus and Pituitary 301
C. Feedback Effects on the Hypothalamus and Pituitary 303
D. The Human Menstrual Cycle 303
E. Menopause 306
V. Biological Responses to Female Sex Steroids 306
A. Estrogen and Progesterone Receptors 306
B. Uterine Effects of Estrogen and Progesterone 308
C. Effects of Estrogen on Bone 309
D. Estrogen and the Cardiovascular System 310
VI. Clinical Aspects 310
A. Hormonal Contraception 310
B. Postmenopausal Hormone Replacement Therapy 312
C. Polycystic Ovary Syndrome (PCOS) 312
Further Reading 313
14 Hormones of Pregnancy, Parturition and Lactation 314
I. Introduction 314
II. Anatomical Relationships and the Beginning of Pregnancy 315
A. Fertilization 315
B. Implantation 316
C. Placental Development 317
D. Mammary Glands 319
III. Chemistry, Biochemistry, and Activity of the Hormones of Pregnancy 319
A. Human Chorionic Gonadotrophin 320
B. Placental Lactogen and Placental Growth Hormone 321
C. Other Peptide Hormones 322
D. Steroid Hormones 323
E. Maternal Adaptations to Pregnancy 324
IV. Parturition 325
A. Introduction 325
B. Progesterone and Estrogen 326
C. The Fetal Adrenal, Placenta, and Posterior Pituitary 327
V. Lactation 328
A. Mammogenesis 328
B. Lactogenesis 329
C. Suckling 330
VI. Clinical Aspects 331
A. Assisted Reproductive Technology 331
B. Breast Cancer 334
Further Reading 336
15 Hormones Related to the Kidney and Cardiovascular System 338
I. Introduction 338
A. Background 338
II. Anatomical, Morphological, and Physiological Relationships 339
A. The Kidney 339
B. Cardiovascular System 343
III. Homeostasis of Fluid, Electrolytes, and Blood Pressure 343
A. Introduction 343
B. Renin–Angiotensin II 345
C. Angiotensins I and II 345
D. Aldosterone Biosynthesis and Actions in Renal Tubular Reabsorption 348
E. Atrial Natriuretic Protein System 348
F. Endothelins 353
G. Nitric Oxide System 356
H. Kallikreins and Kinins 358
I. Adrenomedullin 358
J. Summary 360
IV. Hormones and Blood Cell Production 360
A. Introduction 360
B. Process of Erythropoiesis 361
C. Erythropoietin (the Protein) 361
D. Hemoglobin 363
V. Clinical Aspects 363
A. Anemia 363
B. Cardiovascular Events in Hypertension 365
Further Reading 365
16 The Pineal Gland 368
I. Introduction 368
II. Anatomical Features of the Pineal Gland 369
A. Anatomical Location and Cellular Composition 369
B. Connection with the Visual System 369
III. Synthesis and Secretion of Melatonin 369
A. Melatonin Biosynthetic Pathway: Catabolism 369
B. Patterns and Regulation of Melatonin Secretion 371
IV. Biological Actions of melatonin 374
A. The Melatonin Receptors 374
B. Sleep and Jet Lag 375
C. Adrenal Cortex 376
D. Reproduction 376
E. Cancer 377
F. Melatonin as an Antioxidant 377
V. Clinical Aspects 377
Further Reading 378
17 Growth Factors 380
I. Introduction 380
II. Epidermal Growth Factor 380
A. Structure and Synthesis 380
B. EGF Receptors and Signaling 381
III. Fibroblast Growth Factor Family 382
A. Members of the FGF Family 382
B. The FGF Receptors and Signaling 386
IV. Platelet Derived Growth Factors 387
A. Structure of PDGFs 387
B. PDGF Receptors and Signaling 388
V. Insulin-Like Growth Factors 390
A. Structure of IGF1 and IGF2 390
B. Insulin and IGF Receptors and Signaling 390
C. IGF Binding Proteins 392
VI. Transforming Growth Factor ß 393
A. Structure and Secretion of TGFß 393
B. TGFß Receptors and Signaling 393
VII. Clinical Aspects 395
Further Reading 396
Appendix A 398
Appendix B 404
Appendix C 408
Appendix D 410
Appendix E 412
Appendix F 414
Index 416

Textauszug

Chapter 2

Steroid Hormones

Chemistry, Biosynthesis, and Metabolism

This chapter deals with the structural chemistry and biosynthetic pathways of the major classes of steroid hormones. All have a complicated structure of fused rings which can be modified by functional group substitution at many points. Furthermore, the presence of asymmetric carbon atoms introduces steric modifications and isomeric possibilities. The reader will find it prudent to first grasp the essential features of the steroid structures and relationships before attempting to delve into a consideration of their specific hormonal activities in later chapters. Then, when so doing, it may be helpful to turn back to the appropriate portion of this chapter to further heighten understanding of the structures of the hormones under review.

Keywords

Anterior pituitary; hypothalamic-pituitary system; hypothalamic releasing hormone; hypothalamus; steroid structure

I Introduction

A General Comments

This chapter deals with the structural chemistry and biosynthetic pathways of the major classes of steroid hormones. All have a complicated structure of fused rings which can be modified by functional group substitution at many points. Furthermore, the presence of asymmetric carbon atoms introduces steric modifications and isomeric possibilities. The reader will find it prudent to first grasp the essential features of the steroid structures and relationships before attempting to delve into a consideration of their specific hormonal activities in later chapters. Then, when so doing, it may be helpful to turn back to the appropriate portion of this chapter to further heighten understanding of the structures of the hormones under review.

B Historical Perspective

The first steroid hormone, estrone, was isolated in 1929 at a time before the characteristic ring structure of the steroid nucleus had been elucidated. Today well over 230 naturally occurring steroids have been isolated and chemically characterized. In addition, an uncountable number of steroids and steroid analogs have been chemically synthesized and evaluated for their drug properties.

The development of our modern understanding of hormones and the science of endocrinology has closely paralleled studies on the isolation, chemical characterization, and synthesis of steroids and the subsequent elucidation of their pathways of biosynthesis and catabolism. The foundation of many of these developments with steroid hormones is to be found in a lengthy series of papers authored by Professor Adolf O. R. Windaus’ chemistry laboratory in Gottingen, Germany (1925–19351) that led to the structural determination of cholesterol. This was an extraordinarily challenging problem given the limitation that the techniques of nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, and ultraviolet (UV) and infrared (IR) spectroscopy were not available at that time. Instead, the structure was determined through elaborate classical organic chemistry manipulations, which involved the conversion of the compound under study to known reference compounds. At the present time, application of the powerful separation techniques of high-performance liquid chromatography (HPLC) or gas chromatography, combined with the use of continuous on-line monitoring by mass spectrometry with computer-assisted data storage and analysis, frequently permit unequivocal structural determinations on impure samples that contain less than 1 ng of the steroid of interest.

C Radioactive Steroids

An equally important contribution to our present understanding of the biochemical properties and structure of steroids was the introduction and general availability of radioactively labeled compounds in the 1960s. Radioactive steroids offer two major advantages: firstly, the presence of the radioactive label provides a significant increase in the sensitivity of detection of the steroid under study in living animals or cells. Prior to the advent of radioactive steroids, investigators relied upon colorimetric or bioassay procedures to quantitate the steroid of interest. Secondly, the availability of radioactive compounds permitted the investigator to detect, from either in vivo whole animals or in vitro experiments with perfused organs, tissue slices, cell suspensions, cell homogenates, or purified enzyme preparations, the presence of new compounds that in the absence of a radioactive label would otherwise not have been discovered. Thus, it was through the application of radioisotope techniques, modern procedures of chromatography, and structure determination that whole categories of new steroid hormones were discovered. For example, research on vitamin D metabolites (Chapter 9) and catechol estrogens (Chapter 13) benefited from preparations of radioactive vitamin D3 and catechol estrogens.

D Molecular Biology Contributions

Another chapter of steroid biochemical discovery related to the isolation and purification of key steroid enzymes. Initially the premise was one step in steroid metabolism was handled by one enzyme. However, the advent of cloning of the cDNAs of each enzymatic step resulted in the discovery that there were fewer steroid proteins than the number of separate enzyme steps. That is to say, one steroid enzyme could carry out two to three quite different catalytic steps. Also it was learned that certain enzymatic steps that occurred in several different tissues were, in fact, carried out by the same enzyme.

II Chemistry of Steroids

A Basic Ring Structure

Steroids are derived from a phenanthrene ring structure to which a pentano ring has been attached; this yields in the completely hydrogenated form, cyclopentano-perhydrophenanthrene, or the sterane ring structure (see Figure 2-1).

Figure 2-1 Parent ring structures of steroids.
The creation of the 5-carbon (pentano) ring on phenanthrene followed by reduction of all the aromatic double bonds creates the foundational, completely hydrogenated, cyclopentanoperhydrophenathrene, also known as sterane (the middle structure). The bottom structure is a different presentation of sterane that illustrates the numbering system or zip code for each of its 17 carbons and the convention for the A, B, C, and D labels for the 4 rings.

Steroid structures are not normally written with all the carbon and hydrogen atoms as illustrated in the middle panel of Figure 2-1; instead, the shorthand notation as presented in the bottom panel for sterane of Figure 2-1 is usually employed. In this representation the hydrogen atoms are not indicated, and unless specified otherwise it is assumed that the cyclohexane A, B, and C rings and the cyclopentane D ring are fully reduced; that is, each carbon has its full complement of carbon and/or hydrogen bonds. Also, indicated for the bottom sterane structure (Figure 2-1) is the standard numbering system for each of the 17 carbon atoms in the four rings. The three six-carbon cyclohexane rings are designated A, B, and C rings and the five-carbon cyclopentane ring is denoted as the D ring.

B Classes of Steroids

In mammalian systems, there are six families of steroid hormones that can be classified on both a structural and a biological (hormonal) basis (see Figure 2-2). They are the estrogens and progestins (female sex steroids), androgens (male sex steroids), mineralocorticoids (aldosterone), glucocorticoids (cortisol), and vitamin D [1α,25(OH)2D3]. Also, the bile acids are structurally related to cholesterol and thus constitute a seventh member of the steroid family. All of these steroids are biologically derived from cholesterol. Table 2-1 summarizes some fundamental relationships of these principal mammalian classes of steroids.

Figure 2-2 Family tree of the seven principal classes of steroids (bottom row) that are structurally derived from the parent cholestane (top row).
Cholestane has 10 additional carbons added to sterane (see Figure 2-1); these include two methyl groups, C-18 and C-19, added respectively to C-13 and C-10 and an eight-carbon side chain (C-20 to C-27) attached to C-17 of the D-ring.

Table 2-1

Classes of Steroids

Estrogens

Estradiol

18

Estrane

Androgens

Testosterone

19

Androstane

Progestins

Progesterone

21

Pregnane

Glucocorticoids

Cortisol

21

Pregnane

Mineralocorticoids

Aldosterone

21

Pregnane

Vitamin D steroids

1,25-Dihydroxyvitamin D3

27

Cholestane

Bile acids

Cholic acid

24

Cholane

aThe parent ring steroid structures and active steroid hormone are given in Figure 2-2.

The parent ring structure for cholesterol is the fully saturated ring structure cholestane (see top row of Figure 2-3). Cholestane, which has 27 carbons, differs from sterane (Figure 2-2) by the addition of an eight-carbon side chain on carbon-17 of ring D and the presence of two angular methyl groups at the junctures of the A:B (carbon-10) and C:D rings (carbon-13). The cholestane ring structure also gives rise to the parent ring...

Produkt-Details

• Erscheint lt. Verlag: 30.7.2014
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Technik
• ISBN-10: 0-08-091906-5 / 0080919065
• ISBN-13: 978-0-08-091906-5 / 9780080919065