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Preface

Recently, there have been major advances in our understanding of the chem-
istry and function of nutritional components. This has been enhanced by
rapid developments in analytical techniques and instrumentation. Chem-
ists, food scientists and nutritionists are, however, separated by divergent
skills, and professional disciplines. Hitherto, this transdisciplinary divide
has been difficult to bridge.
The series Food and Nutritional Components in Focus aims to cover in a sin-
gle volume the chemistry, analysis, function and effects of single components
in the diet or its food matrix. Its aim is to link scientific disciplines so that
information becomes more meaningful and applicable to health in general.
The series Food and Nutritional Components in Focus covers the latest knowl-
edge base and has a structured format with major subsections covering.
●● Compounds in context
●● Chemistry
●● Analysis
●● Function and Effects
In some books the section on Chemistry is also linked with Biochemistry.
Each chapter has a novel cohort of features namely by containing:
●● Summary Points
●● Key Facts (areas of focus explained for the lay person)
●● Definitions of Words and Terms
The series covers numerous classes of dietary components including, for
example, minerals, vitamins, food additives, and so on. The chapters are writ-
ten by national or international experts, specialists and leaders in the field.
Betaine has the following coverage. Section 1 Betaine in Context has chap-
ters on betaine in general, sugar beet, food plants, synthesis and content.

Food and Nutritional Components in Focus No. 7

Betaine: Chemistry, Analysis, Function and Effects
Edited by Victor R Preedy
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org

v
vi Preface
In Section 2 Chemistry and Biochemistry there is coverage of the chemistry
of betaine, chemical interactions, folate, biomolecules, uptake, the betaine/
GABA transporter, and betaine-homocysteine s-methyltransferase. Section 3
Analysis has chapters on NMR spectroscopy, CE Tandem Mass Spectrometry,
hydrophilic interaction liquid chromatography, characterization analysis of
seeds and fruits. The final Section 4 Function and Effects has contributions
covering metabolic stress, restraint stress, memory impairment, serum beta-
ine, bariatric surgery, folate, pregnancy, alcohol- and nonalcohol-induced
liver injury, DNA methylation, age-related inflammation, athletic perfor-
mance, body composition, osmoprotection, ocular surfaces, choline and
cancer.
Betaine is specifically designed for chemists, analytical scientists, foren-
sic scientists, food scientists, dieticians, nutritionists, food scientists and
research academics. The series is suitable for lecturers and teachers in food
and nutritional sciences. Additionally, and importantly, the series will be a
valuable resource for college or university libraries as a reference guide.
Professor Victor R Preedy
King’s College London
Contents
Betaine in Context

Chapter 1 Betaine in Context 3

Vinood B. Patel and Kosha Mehta

Summary Points 5
Key Facts of Alcoholic Liver Disease 5
Definitions and Explanations of Key Terms 5
List of Abbreviations 6
References 6

Chapter 2 Betaine in Sugar Beet 9

Teruhiro Takabe, Yoshito Tanaka, and Tetsuko Takabe

2.1 Introduction 9
2.2 Physiologic Function of GB in
Plant Cells 10
2.2.1 GB as Compatible Solute 10
2.2.2 GB as an Osmoprotectant 10
2.3 GB Accumulation in Beta vulgaris 11
2.3.1 Subcellular Localization of GB in Beet
Root Cells 11
2.3.2 Distribution in Whole Plant 11
2.3.3 GB in Storage Root 12
2.3.4 GB in Leaves 13
2.4 Pathway and Sites of GB Biosynthesis in Higher
Plants 14
2.4.1 Choline to GB 14
2.4.2 Ethanolamine to Choline 14

Food and Nutritional Components in Focus No. 7

Betaine: Chemistry, Analysis, Function and Effects
Edited by Victor R Preedy
© The Royal Society of Chemistry 2015
Published by the Royal Society of Chemistry, www.rsc.org

vii
viii Contents
2.4.3 Serine to Ethanolamine 16
2.4.4 Enzymes Involved in Regeneration Cycle of
S-Adenosylmethionine 16
2.4.5 Regulation of Gene Expression 16
2.5 Translocation of GB in Beta vulgaris 17
2.6 Utilization of GB from Sugar Beet 18
2.6.1 Exogenous Application for Crop Production 18
2.6.2 Protective Effects and Risks of GB Application 20
2.7 Genetic Engineering of GB Biosynthesis in Plants 21
Summary Points 24
Key Facts for Betaine in Sugar Beet 24
Definitions of Words and Terms 25
List of Abbreviations 26
References 26

Chapter 3 Betaine in Food Plants: A Focus on Synthesis and

Content 29
Rosario A. Muñoz-Clares

3.1 Introduction 29
3.2 Glycine Betaine is an Important Osmoprotectant in
Plants 30
3.3 Biosynthesis of Glycine Betaine in Plants 31
3.3.1 Betaine Aldehyde Dehydrogenase (BADH) 33
3.3.2 Choline Mono-Oxygenase (CMO) 36
3.3.3 Synthesis and Transport of Choline 37
3.4 Concluding Remarks 38
Summary Points 39
Key Facts 39
Key Facts of Enzyme Catalysis 39
Definition of Words and Terms 40
Abbreviations 41
Acknowledgements 41
References 41

Chemistry and Biochemistry

Chapter 4 The Chemistry of Betaine 47

Panteleimon G. Takis, Konstantinos D. Papavasileiou,
Anastassios N. Troganis, and Vasilios S. Melissas

4.1 Introduction 47
4.2 Nomenclature and Generic Properties 48
4.3 Physical and Chemical Properties – Chemistry of
Important Functions 49
Contents ix
4.4 Chemistry of Important Functions 49
4.5 Spectral Data 54
4.6 Crystal Structure 55
4.7 Handling and Toxicity 56
Summary Points 56
Key Facts for Betaines and Some of Its Derivatives
Function and Utility 56
Definitions of Words and Terms 57
List of Abbreviations 58
References 59

Chapter 5 Chemical Interactions of Betaine with Folate and

Other Biomolecules 62
Michael R. Duff Jr, and Elizabeth E. Howell

5.1 Introduction to Osmolytes and Models of Osmolyte

Action 62
5.2 Osmolytes Function as Chemical Chaperones 63
5.3 Preferential Interactions of Betaine with
Macromolecules 64
5.4 Betaine Association with Folate and Its Derivatives 65
5.4.1 Do These In Vitro Observations Translate
into In Vivo Effects? 69
5.5 Cation–π Interactions Provide a Handle to Bind
Betaine 70
5.6 Conclusions 71
Summary Points 71
Definitions and Explanation of Key Terms 72
Abbreviations 73
References 73

Chapter 6 Betaine Uptake with a Focus on the Betaine/GABA

Transporter 76
Y. Zhou, S.A. Kempson, and N.C. Danbolt

6.1 Introduction 76
6.2 Betaine Acts as a Compatible Osmolyte and as
a Methyl Donor 77
6.3 Identification of the Betaine-GABA Transporter
(BGT1; slc6a12) 77
6.4 BGT1 is Expressed in the Brain, Kidney and Liver 78
6.4.1 The Roles of BGT1 in the Kidney 78
6.4.2 The Role of BGT1 in the Liver 80
6.4.3 The Role of BGT1 in the Brain 82
6.4.4 The Role of Betaine in the Testis 84
x Contents
Summary Points 84
Definitions of Words and Terms 84
List of Abbreviations 85
Acknowledgements 85
References 85

Chapter 7 Betaine-Homocysteine S-Methyltransferase 90

Timothy A. Garrow

7.1 Introduction 90
7.2 Early Studies of Bet-Dependent Methyltransferase
Activity 92
7.3 Studies Using Recombinant BHMT Enzymes 93
7.4 BHMT Structure and Characterization of Ligand
Binding 94
Summary Points 98
Key Facts 99
Definitions of Words and Terms 99
List of Abbreviations 99
References 100

Analysis

Chapter 8 Assays of Betaines using 1H NMR Spectroscopy 105

Panteleimon G. Takis, Konstantinos D. Papavasileiou,
Anastassios N. Troganis, and Vasilios S. Melissas

8.1 Introduction 105

8.2 1H-NMR Detection and Quantification of Betaines
in Biofluids 107
8.2.1 Selected Glycine Betaine Assays by 1H-NMR 109
8.2.2 Selected Other Betaines’ and N-Methylated
Compounds Assays by 1H-NMR 111
Summary Points 113
Key Facts for NMR Contribution to Metabolites Function
Revelation 113
Definitions of Words and Terms 114
List of Abbreviations 115
References 116

Chapter 9 Determination of Betaines in Vegetable Oils by

Capillary Electrophoresis-Ion Trap Mass Spectrometry 120
Laura Sánchez-Hernández, Maria Luisa Marina Alegre, and
Antonio L. Crego Navazo

9.1 Introduction 120

Contents xi
9.2 Capillary Electrophoresis Coupled to Mass
Spectrometry for the Determination of
Betaines 122
9.2.1 Derivatization of Betaines 123
9.2.2 Separation of Betaines by CE/MS 124
9.2.3 Validation of the CE/MS2 Method 126
9.3 Application to the Analysis of Vegetable Oils 129
9.3.1 Sample Preparation 130
9.3.2 Determination of Betaines in
Vegetable Oils 130
Summary Points 133
Key Facts 133
Key Facts for Betaines 133
Key Facts for the Extraction Procedure 134
Key Facts for the Separation Technique 134
Definitions of Words and Terms 134
List of Abbreviations 135
Acknowledgements 136
References 136

Chapter 10 Hydrophilic Interaction Liquid Chromatography for

Determination of Betaine 139
Jonathan M. Curtis and Si Mi

10.1 Introduction 139

10.1.1 Basics of HILIC 139
10.1.2 Summary and Comparison to Other
Analytical Techniques Used for Analysis of
Betaine 143
10.2 The Use of HILIC in the Determination of Betaine
Concentrations 144
10.2.1 Betaine in Standard Mixtures 144
10.2.2 Betaine in Samples of Plant Origin 147
10.2.3 Betaine in Samples of Animal Origin 148
10.2.4 Betaine in Food Samples 150
10.3 Conclusions and Future Perspectives 152
Summary Points 152
Key Facts of Betaine Analysis by HILIC 153
Definitions of Words and Terms 153
List of Abbreviations 154
References 155

Chapter 11 Characterization of Betaine from Seeds 159

Priti Patil and Pratima Tatke

11.1 Introduction 159

xii Contents
11.2 Isolation of Betaine from Achyranthes aspera
seeds 162
11.2.1 Procurement of Plant Material 162
11.2.2 Extraction of Alkaloids from
Achyranthes aspera 163
11.2.3 Isolation of Alkaloids from Seeds of
Achyranthes aspera 163
11.2.4 Thin-Layer Chromatographic Studies 164
11.2.5 Purification of Alkaloid 164
11.2.6 Characterization of Alkaloid as Betaine 165
11.2.7 Analysis of Betaine 165
11.3 Isolation of Betaine from Kancolla Seeds 168
11.3.1 Extraction and Isolation 168
11.3.2 Characterization of Betaine Analogs 168
11.3.3 Betaine Analysis 168
11.4 Isolation of L-(+)-Isoleucine Betaine from Cannabis
Seeds 170
11.4.1 Extraction and Purification of Isoleucine
Betaine 170
11.4.2 Characterization of Isoleucine
Betaine 170
11.4.3 Analysis of Isoleucine Betaine 171
11.5 Conclusion 171
Summary Points 172
Key Facts 172
Key Facts of 1H Correlation Spectroscopy (COSY) 172
Key Facts of Distortionless Enhancement by
Polarization Transfer (DEPT NMR) 173
Key Facts of Electrospray Ionization-Mass
Spectroscopy (ESI-MS) 173
Definition of Words and Terms 173
List of Abbreviations 175
References 175

Chapter 12 Occurrence and Analysis of Betaines in Fruits 178

Luigi Servillo, Alfonso Giovane, Rosario Casale,
Nunzia D’Onofrio, Giovanna Ferrari, Domenico Cautela,
Domenico Castaldo, and Maria Luisa Balestrieri

12.1 Introduction 178

12.2 Biosynthesis of Betaines and QACs 180
12.3 Analytical Methods for Determination of
Betaines and QACs 184
12.4 Identification and Quantification of Betaines and
QACs by ESI-Tandem Mass Spectrometry 187
Contents xiii
12.5 Betaines and QACs Distribution in Fruits 190
12.5.1 Glycine Betaine 191
12.5.2 Betaines and QAC Deriving from Proline 192
12.5.3 γ-Butyrobetaine 192
12.5.4 Pipecolic Acid Betaine and β-Alanine
Betaine 192
12.5.5 Trigonelline and Choline 192
12.5.6 N ε-trimethyllysine 193
12.5.7 Hercynine and Ergothioneine 193
12.6 Conclusions 194
Summary points 194
Key Facts of Betaines 195
Definitions and Explanations of Key Terms 195
List of Abbreviations 196
References 197

Function and Effects

Chapter 13 Betaine and Metabolic Stress in Different Tissues 203

Kaisa Olli and Kirsti Tiihonen

13.1 Introduction 203

13.1.1 Physicochemical Properties of Betaine 203
13.1.2 Digestion, Absorption and Distribution 204
13.2 Betaine and Methylation in the Liver 206
13.2.1 Methylation Functions 206
13.2.2 Betaine and Liver Fat Metabolism 207
13.2.3 Liver Macrophages and the Immunological
Effects of Betaine 208
13.3 Betaine and Osmoregulation in the Kidney 209
13.3.1 Osmoregulation 209
13.3.2 The Role of Betaine in the Kidney 209
13.4 Betaine in Epithelial Cells 211
13.4.1 Betaine in the Gut Epithelium 211
13.4.2 Betaine in Skin and Oral Mucosa 211
13.5 Betaine in Muscle Cells 212
13.5.1 Betaine and Lean Weight Gain 212
13.5.2 Betaine and Carnitine Metabolism in
Muscle 212
13.6 Betaine and Fat Cells 212
13.6.1 Betaine and Hypoxic Stress in Adipose
Tissue 212
13.6.2 Betaine and a High-Fat Diet 214
13.6.3 Betaine and Fat Metabolism 214
xiv Contents
13.7 Concluding Remarks 214
Summary Points 215
Key Facts 215
Definitions of Words and Terms 216
List of Abbreviations 217
Acknowledgements 217
References 218

Chapter 14 Beneficial Effects of Betaine on Water-Immersion

Restraint Stress-Induced Memory Impairment
in Mice 222
Masayuki Hiramatsu, Yukari Takahashi, Anna Amano,
Kiwamu Kido, Takuya Matsukura, Toru Yamanashi,
Yusuke Kakehi, Toshitaka Nabeshima, and Masaya Miwa

14.1 Introduction 222

14.2 Methods 224
14.2.1 Animals 224
14.2.2 Drugs 224
14.2.3 Experimental Schedules 225
14.2.4 Water-Immersion Restraint Stress
(WIRS) 225
14.2.5 Spontaneous Alternation Behavior in
Y-Maze Test 225
14.2.6 Step-Down-Type Passive Avoidance Test 226
14.2.7 Responses to Electric Shock 226
14.2.8 Corticosterone Assay 226
14.2.9 Real-Time RT-PCR 227
14.2.10 Determination of Lipid Peroxidation
Level 228
14.2.11 Protein Assay 228
14.2.12 Data Analysis 228
14.3 Results 229
14.3.1 Onset of Memory Impairment Induced by
Water-Immersion Restraint Stress 229
14.3.2 Effects of Repeated Administration of
Betaine on Learning and/or Memory
Impairment after Water-Immersion
Restraint Stress 230
14.3.3 Effects of Subacute Administration of
Betaine or Catechin on Learning and/or
Memory Impairment after Water-Immersion
Restraint Stress 231
14.3.4 Effects of Acute Administration of Betaine
on Learning and/or Memory Impairment
after Water-Immersion Restraint Stress 231
Contents xv
14.3.5 Effects of Acute Administration of Betaine
on Plasma Corticosterone Level after
Water-Immersion Restraint Stress 231
14.3.6 Effects of Acute Administration of Betaine on
Interleukin-1β mRNA Level in the Hippocam-
pus and Frontal Cortex after Water-Immersion
Restraint Stress 232
14.3.7 Effects of Acute Administration of Betaine
on MDA Level in the Hippocampus after
Water-Immersion Restraint Stress 234
14.3.8 Effects of Acute Administration of Betaine
on the Expression of GABA Transporter
mRNA Levels in the Hippocampus after
Water-Immersion Restraint Stress 234
14.4 Discussion 235
14.5 Conclusions 238
Competing Interests 238
Authors’ Contributions 238
Summary Points 238
Key Facts 239
Key Facts of Delayed Neurodegeneration 239
Definitions of Words and Terms 239
Abbreviations 240
Acknowledgements 241
References 241

Chapter 15 Serum Betaine Concentrations and the Effects of

Bariatric Surgery 245
Julian Swierczynski, Areta Hebanowska, and
Tomasz Sledzinski

15.1 Introduction 245

15.2 The Role of Betaine in Pathological
Conditions 249
15.3 Serum Betaine and Dimethylglycine Concentrations
in Health and Disease 250
15.4 Human Plasma Betaine Concentration after Betaine
Supplementation 254
15.5 Betaine and Body Composition 255
15.6 Serum Betaine Concentrations in Obese Patients
after Bariatric Surgery 257
15.7 Directions of Future Research 259
Summary Points 260
Definitions of Words and Terms 260
Key Facts of Bariatric Surgery 261
xvi Contents
List of Abbreviations 262
Acknowledgements 262
References 262

Chapter 16 Folate and Betaine Interactions during Pregnancy 267

Michelle M. Murphy

16.1 One-Carbon Metabolism 267

16.1.1 Folate and Betaine and One-Carbon
Metabolism 267
16.2 Early Development 270
16.2.1 Betaine, BHMT, Embryo and Fetal
Development 270
16.3 Pregnancy and Fetal Development 271
16.3.1 One-Carbon Metabolism, Pregnancy and
Fetal Development 271
Summary Points 278
Key Facts 279
Definitions of Words and Terms 279
Abbreviations 280
References 280

Chapter 17 Multiple Roles of Betaine in Protecting Against Alcohol-

Induced Liver Injury 285
Paul G. Thomes, Sarah M. Bligh, and Kusum K. Kharbanda

17.1 Introduction 285

17.2 Mechanisms of Alcohol-Induced Liver Injury 286
17.3 Methionine Metabolism 286
17.4 Effect of Ethanol Consumption on Methionine
Metabolism 288
17.5 Functional Consequences of Ethanol-Induced
Alteration in Methionine Metabolism 288
17.5.1 Defects in Crucial Methylation Reactions 289
17.5.2 Homocysteine Toxicity 289
17.6 Protective Role of Betaine in Alcoholic Liver Injury 290
17.6.1 Betaine Attenuates Alcohol-Induced
Steatosis 291
17.6.2 Betaine Attenuates Alcohol-Induced
Apoptosis 295
17.6.3 Betaine Prevents Accumulation of
Ethanol-Induced Damaged Proteins 295
17.6.4 Betaine Prevents Impairments in
PRMT-Catalyzed Reactions 297
17.6.5 Betaine Affects Histone Methylation and
Mallory–Denk Body Formation 297
Contents xvii
17.6.6 Betaine Prevents Blood-Alcohol Cycling 298
17.6.7 Betaine Treatment Attenuates Alcohol-Induced
Alterations to the Mitochondrial Respiratory
Chain Proteome 298
17.6.8 Betaine Treatment Attenuates Oxidative
Stress and Inflammation 298
17.7 Future Directions 299
Summary Points 300
Key Facts of Alcohol and Liver Injury 300
Definition and Explanations of Key Terms Used 301
List of Abbreviations 301
Acknowledgements 302
References 302

Chapter 18 Betaine, DNA Methylation and Nonalcoholic

Fatty Liver Disease 311
Zhu Huilian and Wang Lijun

18.1 Epidemiologic Character and Nutritional

Risk Factors of NAFLD 311
18.2 Experimental and Clinical Evidence for Betaine
Treatment of NAFLD 313
18.3 The Underlying Genetic Role of Betaine in
the Treatment of NAFLD 318
18.4 Regulation of DNA Methylation by Betaine in
the Treatment of NAFLD 319
18.4.1 Epigenetic Profile of NAFLD 319
18.4.2 DNA Methylation Connects Methyl Donors
and NAFLD 319
Summary Points 322
Key Facts of Nutriepigenomics 322
Definitions of Words and Terms 323
List of Abbreviations 324
References 325

Chapter 19 The Beneficial Role of Dietary Betaine in the Suppression

of Age-Related Inflammatory NF-κB 329
Hae Young Chung, Eun Kyeong Lee, and Byung Pal Yu

19.1 Introduction 329

19.2 Modulation of NF-κB by Betaine in the Aging
Process 330
19.2.1 Betaine as a Redox Mediator 330
19.2.2 Sensitivity of NF-κB to Redox Changes 332
19.2.3 Changes in NF-κB by Thiol Status 333
19.2.4 Activation of NF-κB during Aging 335
xviii Contents
19.3 Protective Roles of Betaine Against Age-Related
Changes 335
19.3.1 Attenuation of Oxidative Stress-Induced
NF-κB Pathway in the Aged Kidney 335
19.3.2 Suppression of Adhesion Molecule
Expression 336
19.3.3 Enhancement of Thiol Status in Attenuating
Age-Related NF-κB 337
19.4 Summary 337
Summary Points 338
Key Facts in the Development of Betaine as an
Antiaging Agent 339
Definition of Words and Terms 339
List of Abbreviations 340
Acknowledgements 341
References 341

Chapter 20 Betaine in Athletic Performance and Body

Composition 344
Stuart A. S. Craig

20.1 Introduction 344

20.2 Human Performance Studies 345
20.2.1 Acute Dose Studies 345
20.2.2 Chronic Dose Studies 347
20.3 Mechanism Studies 355
20.3.1 In Humans 355
20.3.2 In Animals 357
20.3.3 In Vitro 359
20.4 Conclusions 361
Summary Points 362
Key Facts 362
Key Facts on Betaine as a Nutrient 362
Definitions of Words and Terms 363
List of Abbreviations 364
References 364

Chapter 21 Betaine, Osmoprotection, and Health of the Ocular

Surface in Dry-Eye Disease 368
Qian Garrett and Mark D. P. Willcox

21.1 The Ocular Surface and Tear Film 368

21.2 Dry-Eye Disease and Tear-Film Hyperosmolarity 369
21.2.1 Hyperosmolarity, Inflammation and
Apoptosis 370
21.2.2 Osmoprotection – Organic Osmolytes 371