Vitamin A and Carotenoids Chemistry, Function

and Effects

Edited by

Victor R Preedy School of Medicine, College London, UK Email: victor.preedy@kcl. uk

Publishing

Contents

Vitamin A and Carotenoids in Context

Chapter 1 Retinol, Retinoic Acid, Carotenes and Carotenoids: Vitamin A Structure and 3 Gerald Wollard

1.1 3 1.2 Structure and Function of Carotenoids 4

1.2.1 Central Carotenoid Chain 4 1.2.2 The End Ring Systems 5

1.3 thesis 6 1.3.1 Biosynthetic Pathway 6 1.3.2 Key Observations for Carotenoid Biosynthesis 7

Trivial Names of Carotenoids 8 Origins of Trivial Names 8

1.4.2 Major Nutritional Carotenoids 9 1.4.3 Provitamin A Carotenoids 9 1.4.4 Ambiguities in Trivial Names 9

1.5 9 1.5.1 Systematic Names 9 1.5.2 Semi-systematic Names

1.6 Stereochemistry of Carotenoids 14 1.6.1 Stereoisomers 14 1.6.2 Isomers 14

1.7 Structure of Retinol 15 1.7.1 Prototypical Vitamin A Compounds 15 1.7.2 Chemical Nature of Retinol 15 1.7.3 Retinol Systematic Name 1.7.4 Retinol Semi-systematic Name 16

Food and Nutritional Components in Focus No. 1 Vitamin A and Carotenoids: Chemistry, Function and Effects Edited by Victor R Preedy © The Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, www.rsc.org

viii Contents

1.7.5 Retinol Trivial Names 16 1.7.6 Retinol Isomerism 16 1.7.7 Retinol from Symmetrical Cleavage of

Carotenoids 1.8 Retinoids: Derivatives of Retinol 17

1.8.1 Retinal 18 1.8.2 Retinoic Acid 18 1.8.3 Retinoid Isomers 19

Key Facts 20 List of Abbreviations 21 References 21

Chapter 2 Vitamin A in the Context of Other Vitamins and Minerals 23 Jennifer H. Lin and Kuang- Yu Liu

2.1 Sources of Vitamin A and Other Vitamins and Minerals 23

2.2 Intakes of Vitamin A as well as Other Vitamins and Minerals Around the World 24 2.2.1 In the Malnourished Countries 24 2.2.2 In the USA and Europe 26

2.3 Interaction of Vitamin A with Other Vitamins and Minerals 27 2.3.1 Vitamin A and Zinc 27 2.3.2 Vitamin A and 28 2.3.3 Vitamin A and Vitamin D 29

2.4 Chronic Disease Prevention with Supplementation of Vitamin A or in Combination with Other Vitamins and Minerals 29 2.4.1 Cancer Prevention 31 2.4.2 Prevention of Vascular Events 32 2.4.3 Prevention of Other Diseases 32

2.5 Conclusion 33 Summary Points 33 Key Facts 33 Definition of Words and Terms 34 List of Abbreviations References 35

Chapter 3 The Importance of ß-Carotene in the Context of Vitamin A 39 Hans K. Biesalski and Donatus Nohr

3.1 Introduction 39 3.2 ß-Carotene as Antioxidant and/or Pro-oxidant 41

3.2.1 Antioxidant/Pro-oxidant Activities 41 3.2.2 Radical Scavenging Properties 41 3.2.3 Singlet Oxygen Quenching 41

Contents ix

3.3 Necessity of Vitamin A 42 3.3.1 How Much ß-Carotene is Needed to Ensure

Vitamin A Supply? 44 3.3.2 For Embryonic Development and Pregnant

44 3.4 ß-Carotene as Provitamin A 44

3.4.1 Natural Sources of ß-Carotene 44 3.4.2 Bioavailability of ß-Carotene 45 3.4.3 The of ß-Carotene as Provitamin A for

Vegetarians 46 3.4.4 Supply of the Population with Preformed

Vitamin A 47 3.4.5 Basic Need for ß-Carotene to Ensure a

Sufficient Intake to Meet the Vitamin A Requirement? 48

Summary Points 50 Key Facts 50 Definition of Words and Terms List of Abbreviations References 52

Chapter 4 Vitamin A in the Context of Supplementation 55 Frank T. Wieringa, Marjoleine A. Dijkhuizen and Jacques Berger

The Rational for Vitamin A Supplementation 55 4.2 Vitamin A Supplementation for Children between 6

and 59 Months of Age 56 4.3 Vitamin A Supplementation for And does it

Work? 58 4.3.1 Vitamin A Supplementation of Newborns 58 4.3.2 Vitamin A Supplementation for Women

Directly after Delivery 58 4.3.3 Vitamin A Supplementation of Pregnant

Women 59 4.3.4 Vitamin A Supplementation and HIV Infection 60 4.3.5 Vitamin A Supplementation and Measles

Infection 60 4.4 Time for Reflection 61 4.5 Vitamin A and the Immune System 62 Summary Points 64 Key Facts 64 List of Abbreviations 66 References 66

Contents

Chemistry and Biochemistry

Chapter 5 The Chemistry of Vitamin A 73 Alessandra Gentili

5.1 Introduction 73 5.2 Physicochemical Properties 76

5.2.1 Appearance and Solubility 76 5.2.2 Chemical Stability 76

5.3 Spectral Properties 77 5.4 Mass Spectrometry 82 Summary Points 82 Key Facts 84 List of Abbreviations 86 References 86

Chapter 6 of Vitamin A and Related Metabolites 90 Niketa A.

6.1 Introduction 90 6.2 Nomenclature 91 Summary Points 93 Key Facts 93 Definition of Words and Terms 93 List of Abbreviations 94 Acknowledgements 94 References 94

Analysis

Chapter 7 Structural Analysis of Vitamin A Complexes with DNA and RNA 97

H. A. and P. Bourassa

7.1 Introduction 97 7.2 Analytical Methods 98

7.2.1 Spectroscopy 98 7.2.2 CD Spectroscopy 98 7.2.3 Fluorescence Spectroscopy 99 7.2.4 Molecular 100

7.3 Structural Characterization 7.3.1 FTIR Spectra of Retinoid-DNA and Retinoid-

RNA Complexes 100

Contents xi

7.3.2 CD Spectra of Retinoid-DNA and RNA Complexes 100

7.3.3 Fluorescence Spectra and Stability of Retinoid-DNA and Retinoid-RNA Complexes 102

7.3.4 Docking Studies 107 Summary Points Key Facts List of Abbreviations Acknowledgements References

Chapter 8 Encapsulation of Vitamin A: A Current Review on Technologies and Applications 113 Beatrice Albertini, Marcello Di Sabatino and Nadia Passerini

8.1 Introduction 8.1.1 Vitamin A Supplementation: and

Problems 8.1.2 Why Encapsulate Vitamin A? 114

8.2 Encapsulation Technologies 8.3 Development of Dietary Supplements 117

8.3.1 and Protection 8.3.2 Bioavailability Enhancement 122

8.4 Final Remarks and Future Perspectives Summary Points Key Facts 125 Definition of Words and Terms 125 List of Abbreviations 126 References

Chapter 9 Thermal Degradation of ß-Carotene in Food Oils 129 Zeb

9.1 Introduction 129 9.2 Thermal Degradation of ß-Carotene in Oils 131

9.2.1 Kinetics of ß-Carotene Degradation 131 9.2.2 Thermal Degradation Products of ß-Carotene 132

9.3 of ß-Carotene during Thermal Degradation 134 9.3.1 Antioxidant Action 134 9.3.2 Pro-oxidant Action 134

9.4 Fate of Food Oils 136 Summary Points 137 Key Facts 138 Definition of Words and Terms 138 List of Abbreviations 139 References 139

Contents

Chapter 10 Provitamin A Carotenoids: Occurrence, Intake and Bioavailability 142 Torsten Bohn

10.1 Introduction 142 10.2 Occurrence of Provitamin A Carotenoids in the Diet 145 10.3 Dietary Intake of A Carotenoids 147 10.4 Detection of vitamin A Carotenoids in Food

and Body Tissues 147 10.5 Aspects of Bioavailability of Provitamin A

Carotenoids 149 10.5.1 Overview of Provitamin A Carotenoid

Absorption 149 Summary Points Key Facts Definition of Words and Terms List of Abbreviations 158 References

Chapter Vitamin A - Serum Vitamin A Analysis 162 Ronda F. Greaves

Introduction 162 11.1.2 Definitions, Nomenclature and Terminology 163 of Vitamin A in the Body

Pathophysiology Measurement 166

Overview of Method 11.2.2 Considerations 167

Sample Preparation for Analysis 167 11.2.4 Analysis 168

Standardisation 169 Reference Measurement System

11.3.2 Calibrators 170 Secondary Calibrators

11.4 Interpretation of Results 170 11.4.1 Reference Intervals 170 11.4.2 Biological Variation 172

Additional Analytes Method Validation

Range Imprecision 173

11.5.3 Recovery 173 Interference

Contents xiii

Quality Specifications 174 Internal Quality Control

11.6.2 Quality Assurance 174 11.7 Needs and Opportunities 175 Summary Points Key Facts 178 Definition of Words and Terms List of Abbreviations 181 Acknowledgements References

Chapter 12 Liquid Chromatography-based Assay for Carotenoids in Human 184 Taiki Kiyotaka and Teruo

12.1 Introduction 184 12.2 Occurrence Carotenoids in Human RBC 186

12.2.1 HPLC Analysis of Standard Carotenoids 186 12.2.2 Extraction of Carotenoids from Human RBC 188 12.2.3 HPLC Analysis of RBC Carotenoids 189 12.2.4 Xanthophylls are a Potential Antioxidant in

RBC 193 12.3 Antioxidant Effect of Lutein towards Phospholipid

Oxidation in RBC 194 12.3.1 Lutein Supplementation Study 194 12.3.2 Lutein Inhibits RBC Phospholipid Oxidation 195

12.4 Conclusions 198 Summary Points 199 Key Facts Definition of Words and Terms 199 List of Abbreviations 200 References 200

Chapter 13 Capillary Liquid Analysis of Vitamins and ß-Carotene 204 Sheng Zhang and Li Jia

13.1 Introduction 204 13.2 CLC 205

13.2.1 Features 205 13.2.2 Instrumentation 205 13.2.3 Sample Pre-concentration 208

Applications of CLC 208 13.3.1 Fat-soluble Vitamins 208 13.3.2 ß-Carotene 211

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13.4 Future Prospects of CLC 212 Summary Points Key Facts 215 Definition of Words and Terms 217 List of Abbreviations References

Chapter 14 Assay of Carotenoid Composition and Retinol Equivalents in Plants 221 Sangeetha Ravi and V. Baskaran

14.1 Introduction 221 14.2 Assay Methods for Carotenoids 223

14.2.1 Extraction of Carotenoids 223 14.2.2 Purification by Open

Chromatography 225 14.2.3 TLC for Separation and Isolation of

Carotenoids 225 14.2.4 Spectrophotometric Estimation 225 14.2.5 HPLC Analysis 228 14.2.6 Liquid Chromatography-Mass Spectrometric

Analysis of Carotenoids [LC-MS, Atmospheric Pressure Chemical Ionization

229 14.3 Carotenoid Composition in Plants 229 14.4 Calculation of RE in Plants 231 14.5 Conclusions 245 Summary Points 245 Key Facts 246 Definition of Words and Terms 247 List of Abbreviations 247 Acknowledgements 248 References 248

Chapter 15 LC-NMR for the Analysis of Carotenoids in Foods 250 Chisato Tode and Makiko Sugiura

15.1 Introduction 250 Sample Preparation Techniques for Carotenoids 251

15.2.1 Sample Preparation 251 15.2.2 LC-NMR 252

15.3 Measurement Extracted Samples 253 15.3.1 Analysis of Sample 1 Juice) 253 15.3.2 Analysis of Sample 2 (Palm 254

Analysis of Sample 3 (Satsuma Mandarin Orange Juice) 256

Contents

Summary Points 257 Key Facts 257 Definition of Words and Terms 258 List of Abbreviations 259 References 260

Chapter 16 MS Analysis of Retinoids and Carotenoids: Applications to Bovine Milk 261 Alessandra Gentili and Fulvia Caretti

16.1 Introduction 261 16.2 Practical Details and Techniques 263

16.2.1 Chemicals and Materials 263 16.2.2 Standard Solutions 263 16.2.3 Analytical Techniques 263 16.2.4 Sample 265

Identification and Quantification of Vitamin A and Carotenoids by LC-DAD-MS 266

16.2.6 Identification and Quantification of Retinyl Esters by MS 267

16.2.7 Method Validation 267 16.3 Concentrations of Retinoids and Carotenoids in

Bovine Milk 267 16.4 Methodological Considerations Summary Points 275 Summary Points 276 Key Facts 276 Definition of Words and Terms 278 List of Abbreviations 279 References 279

Chapter 17 HPLC-DAD-MS Determination of Carotenoids in Fruit 282 Pasquale Crupi, Victor R. Preedy and Donato Antonacci

17.1 Introduction to Carotenoids 282 Carotenoids in Foods: Presence and Structural

Features 282 17.1.2 Biosynthesis Carotenoids 284 17.1.3 Physiological and Nutritional Properties of

Carotenoids 285 17.2 Carotenoid Analysis in Fruit 286

17.2.1 General Analytic Procedure 286 17.2.2 HPLC Separation of Carotenoids 287 17.2.3 DAD and Identification and

Quantification of Carotenoids 288

Contents

Summary Points 297 Key Facts 298 Definition of Words and Terms 299 List of Abbreviations 299 References 300

Chapter 18 Analysis of A Carotenoids 303

Zeb

18.1 Introduction 303 18.2 Analysis 305

18.2.1 Stationary Phases 305 18.2.2 Mobile Phases 308 18.2.3 Applications of Scanning Densitometry 308

Advantages of TLC Analysis of Pro-vitamin A Carotenoids 310

Summary Points Key Facts Definition of Words and Terms 312 List of Abbreviations 312 References 313

Chapter 19 Extraction of Carotenoids from Plants: a Focus on Carotenoids with Vitamin A Activity 316 Anita Oberholster

19.1 Introduction 316 19.2 General Properties 317 19.3 Preparation of the Sample 319 19.4 Choice of Solvent and Extraction 320 19.5 Saponification 321 19.6 Supercritical Fluid Extraction 324 Summary Points 327 Key Facts 327 Definition of Words and Terms 328 List of Abbreviations 328 References 329

Contents

Chapter 20 Quantification of Carotenoids, Retinol, and Tocopherols in Milk and Dairy Products 332 Beatrice Duriot and Benoit Graulet

20.1 Introduction 332 20.2 Concentrations in Milk and Dairy products and

Variation Factors 333 20.3 Determination 336

20.3.1 Extraction Procedures 336 20.3.2 Quantification 340

20.4 Conclusion 348 Summary Points 348 Key Facts 349 Definition of Words and Terms 349 List of Abbreviations 350 References 351

Chapter 21 Simultaneous Liquid Chromatography for the Determination of Vitamin A and Other Fat-soluble Vitamins to Assess Nutritional Status 355 Fernando Granado-Lorencio, Inmaculada Blanco-Navarro and Perez-Sacristän

21.1 Introduction 355 21.2 Fat-soluble Vitamins and Related Compounds 356

21.2.1 A 356 21.2.2 Vitamin E 358 21.2.3 Vitamin D 358 21.2.4 359

21.3 Assessment of Nutritional Status 359 Nutritional Status of Vitamin A Clinically Relevant Cut-Off Points for Vitamin

A Markers in Serum 362 21.4 Nutritional Status of Vitamin A and Other Fat-

soluble-related Compounds: a Approach 363

21.4.1 Assessment of Fat-soluble Nutritional Status: Analytical Perspective 363

21.5 Ultra-high-performance Liquid Chromatography (UHPLC) 364

21.5.1 Basic Concepts 364 Analysis of Fat-soluble Status in Biological

Matrices 365 21.6 Concluding Remarks 372 Summary Points 373

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Key Facts 374 Definition of Words and Terms 375 List of Abbreviations 375 References 376

Function and Effects

Chapter 22 Distribution and Concentrations of Vitamin A and their Metabolites in Human Tissue 381 Ewa Czeczuga-Semeniuk, Janusz W. Semeniuk and Adrianna

22.1 Introduction 381 22.2 Vitamin A and Carotenoids in Particular Human

Organs 383 22.2.1 General Reflections 383 22.2.2 Liver 384 22.2.3 Adipose Tissue 384 22.2.4 Skin 386 22.2.5 Eye 386 22.2.6 Female Reproductive System 387 22.2.7 389 22.2.8 Human Milk 389 22.2.9 Prostate 390 22.2.10 390

Summary Points 390 Key Facts 391 Definition of Words and Terms 392 List of Abbreviations 392 References 393

Chapter 23 Vitamin A Deficiency: An Overview 396 Teresa Barber, Guillermo Esteban-Pretel, Maria Marin and Joaquin

23.1 Introduction 396 23.2 Requirements 397 23.3 Transport and

Transformations of Vitamin A 398 23.4 Vitamin A Deficiency 400

23.4.1 Epidemiology and Incidence 401 23.4.2 Vitamin A Deficiency and Tissue 403 23.4.3 Treatment and Prevention of Vitamin A

Deficiency 408 23.5 Perspective and Future Directions 409

Contents

23.6 Conclusions 410 Summary Points Key Facts Definition of Words and Terms List of Abbreviations 413 References

Chapter 24 Retinoic Acid Receptors and their Modulators: Structural and Functional Insights 417 Albane Maire, William Bourguet, Hinrich Gronemeyer and Angel R. de Lera

24.1 Introduction 417 24.2 Retinoid and Rexinoid Receptor Ligand-Binding

Domains: Structure-Function Relationships 24.2.1 Structural Basis of RXR Action and

Modulation by Ligands 24.2.2 Structural Basis of RAR Action and

Modulation by Ligands 421 24.3 RXR and RAR Heterodimers: Structure and Synergy 422

24.3.1 Structural Basis of RAR-RXR LBD Heterodimers 422

24.3.2 Subordination and Synergy in RAR-RXR Heterodimeric Interactions 422

24.3.3 Structural Description of RXR Heterodimers 424

24.4 Selective Retinoid and Rexinoid Receptor Modulators 425 RXR vs. RAR Selectivity as a Function of the

LBP Architectures 425 24.4.2 Modulators of RAR-RXR Heterodimers

Acting at the RAR Site 425 24.4.3 Modulators of RAR-RXR Heterodimers

Acting at the RXR Site 429 24.4.4 Modulation at Both Sites of the

Heterodimer 24.5 Summary and Perspectives 431 Summary Points 432 Key Facts 433 Definition of Words and Terms 433 List of Abbreviations 434 Acknowledgements 434 References 435

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Chapter 25 Retinoic Acid in Development 438 Don Cameron, Pennimpede and Martin Petkovich

25.1 Introduction 438 25.2 RA and Signalling 438 25.3 RA in Development 439

25.3.1 of the Retinoid Receptors 440 25.4 RA Metabolism in the Control of Embryonic

Development 440 25.4.1 CYP26 Blocks RA Exposure to the Early

Embryo 441 25.4.2 CYP26 is Required for Early Head

Development 441 25.4.3 CYP26A1 and Caudal Development 442

25.5 RA Signalling in Organogenesis 444 25.5.1 Heart 444 25.5.2 Eye 445 25.5.3 Limb 446

25.6 RA Signalling and Germ 449 25.7 Concluding Remarks 450 Summary Points 450 Key Facts 450 Definition of Words and Terms 451 List of Abbreviations 451 References 452

Chapter 26 A Signaling and of Embryonic Stern Cells 457 Jaspal S. Khillan, Himanshu Bhatia and Liguo Chen

26.1 Introduction 457 26.2 Regulation of Pluripotency of ES Cells by Retinol 458 26.3 Retinol the Expression of Nanog and

459 26.4 Self-renewal of ES Cells by Retinol is Independent of

Retinoic acid 460 26.5 ES Cells Lack Enzymes that Metabolize Retinol into

Retinoic Acid 461 26.6 Mechanism of Retinol Function in Self-renewal of ES

Cells 462 Retinol Function is Mediated via Activation of

the PI3K/Akt Signaling Pathway 462 26.6.2 Retinol Activates PI3 kinase Signaling

Pathway via Receptor 464

Contents

Summary Points 465 Key Facts 465 Definition of Words and Terms 466 List of Abbreviations 467 References 467

Chapter 27 Retinoic Acids and their Biological Functions 470 Joseph L. Napoli

Introduction 470 27.2 Bioanalytical Analysis of RA Isomers 471 27.3 9cRA as an Endogenous Pancreas Autacoid 472 27.4 Pancreas 9cRA Varies Inversely with Glucose 473 27.5 Pancreas 9cRA 473 27.6 Increased 9cRA in the Mouse 476 27.7 Function of 9cRA in the Pancreas Islet 477 27.8 Conclusions 479 Summary Points 480 Key Facts 481 Definition of Words and Terms List of Abbreviations References 482

Chapter 28 Vitamin A and Cancer Risk 485 Siddhartha Mishra and Mi Kyung Kim

28.1 Introduction 485 28.2 Metabolism and Mechanisms of Action of Vitamin A 486 28.3 Epidemiological Studies on Vitamin A and Cancer

Risk 487 28.3.1 Breast Cancer 487 28.3.2 Gastric Cancer 489 28.3.3 Cervical Cancer 489 28.3.4 Head and Neck Cancer 489 28.3.5 Colorectal Cancer 490 28.3.6 Lung Cancer 490 28.3.7 Prostate Cancer 490

28.4 Genetic Polymorphisms Associated with Vitamin A and Cancer Risk 491

28.5 Conclusions 494 Summary Points 494 Key Facts 495 Definition of Words and Terms 495 List of Abbreviations 496 References 497

Contents

Chapter 29 Vitamin A and Immune Function 501 Charles B. Stephensen

29.1 Introduction and Historical Perspective 501 29.2 Vitamin A Deficiency and Childhood Mortality 502 29.3 The Immune System 503 29.4 Vitamin A and Innate Immunity 504

29.4.1 Epithelial Surfaces 504 29.4.2 Granulocytes 505 29.4.3 Natural Killer Cells 507 29.4.4 Monocytes/Macrophages 507

29.5 Vitamin A and Adaptive Immunity 507 29.5.1 Antigen-presenting Cells 507 29.5.2 Function 509 29.5.3 Peripheral 509 29.5.4 Vitamin A and Mucosal Targeting of Immune

Cells 510 29.5.5 and Antibody Responses 510

29.6 Conclusions Summary Points Key Facts Definition of Words and Terms 512 List of Abbreviations References 514

Chapter 30 Vitamin A and Brain Function 516 Christopher R. and Claudio. V.

30.1 Introduction 516 30.2 Altered Vitamin A Signaling Affects Spatial

in Rodents 30.3 Altered Vitamin A Signaling Affects Learning

in Songbirds 518 30.4 Vitamin A Metabolism is Regulated Within the Brain 521 Summary Points 525 Key Facts 526 Definition of Words and Terms 527 List of Abbreviations 528 Acknowledgements 528 References 529

Contents xxiii

Chapter 31 The Importance of Vitamin A during Prgenancy and Impact on Lung Function 532

Hans K Biesalski and Donatus Nohr

31.1 Introduction 532 31.2 The Vicious 533

31.2.1 Dietary Vitamin A Supply 533 31.3 Vitamin A During Pregnancy and Lactation 536

Concerns Against the Recommendation to Supply Vitamin A or Vitamin A-rich Food During Pregnancy 538

31.3.2 Relevance of the Mother's Vitamin Carotene Intake for the Fetal Vitamin A Status 539

The Influence of Vitamin A on the Maturation and Differentiation of the Lung 540

31.4.1 Vitamin A Kinetics During Fetal Lung Development 541

31.4.2 Consequences of Marginal Deficiency 542 The Influence of Vitamin A Supply for the Postnatal

Development of the Lung in Infants 543 31.5.1 Retinol Serum Levels in Neonatals 544 31.5.2 Relevance of Breastfeeding for the Vitamin

Supply of the Newborn 545 31.6 Supplementation of Newborns with Vitamin A 546 Summary Points 547 Key Facts 548 Definition of Words and Terms 548 List of Abbreviations 549 References 549

Subject Index 555