Isoflavones: Chemistry, Analysis, Function and Effects

Cover......Page 1
Copyright......Page 5
Contents......Page 8
Isoflavones in Context......Page 28
1.1 Introduction......Page 30
1.2 Absorption, Metabolism and Excretion of Isoflavones......Page 31
1.3 Mechanisms of Action of Isoflavones......Page 32
1.4.2 The Brain......Page 33
1.4.4 Breast Cancer......Page 34
1.5 Areas in Dispute......Page 35
Key Facts......Page 36
References......Page 37
2.1 Characterization of Phytoestrogens......Page 41
2.2.2 Isoflavones......Page 42
2.3 Chemical Features of Plant Isoflavones......Page 44
2.4 Biosynthesis of Isoflavones......Page 45
2.5 Localisation of Isoflavones in Plants......Page 46
2.6.2 Isoflavones as Phytoalexins and Phytoanticipins......Page 49
Summary Points......Page 50
Definitions of Words and Terms......Page 51
List of Abbreviations......Page 52
References......Page 53
3.1 Introduction......Page 55
3.2.2 Analysis......Page 56
3.4 Growth, Variety, Environmental and Post-harvestStorage Conditions Affecting Isoflavone Composition in Soybeans......Page 58
3.5 Isoflavone Composition as Affected by Processing......Page 63
Definitions of Words and Terms......Page 68
List of Abbreviations......Page 69
References......Page 70
Chemistry and Biochemistry......Page 74
4.1 Introduction......Page 76
4.2 Bioconversion of Isoflavones from Glycosidesto Aglycones......Page 80
4.3 Enzymatic Transformation of Isoflavone Isomersin Fermented Soymilk......Page 81
4.4 b-Glycosidase Reaction during Bioconversionof Isoflavones......Page 83
Definitions of Word and Terms......Page 84
List of Abbreviations......Page 85
References......Page 86
5.1 Introduction......Page 88
5.2.1 Synthesis of Daidzein: BF3 . OEt2-catalyzed Friedel–CraftsAcylation and Ring Closure......Page 90
5.2.3 Synthesis of Daidzein: I2-Mediated Cyclization......Page 91
5.3 Synthesis of Formononetin (2)......Page 94
5.3.1 Carbonyls as One-carbon Electrophiles......Page 96
5.3.2 Activated Aldehyde Surrogates as One-carbonSurrogates......Page 97
5.4.1 Selective Methylation of Daidzein (1)......Page 100
5.5 Synthesis of Dimethyldaidzein (4)......Page 101
5.5.2 Synthesis of Dimethyldaidzein: Organolead-mediatedArylation......Page 103
Summary Points......Page 105
List of Abbreviations......Page 106
References......Page 107
6.2 Phenylpropanoid and Isoflavonoid Pathways......Page 110
6.4.1 Semi-synthesis of Non-natural Isoflavonoids......Page 112
6.4.3 ER Assay......Page 113
6.5 Structural and Functional Studies of IFS......Page 116
Key Facts......Page 117
List of Abbreviations......Page 118
References......Page 119
7.1 Introduction......Page 121
7.2 Structure Elucidation: Establishing SpectralCorrelations......Page 123
7.3 Chromatography-NMR......Page 128
7.4 Conformation and NMR......Page 129
7.6 Isoflavone Metabolites......Page 130
7.7 Solvent Effects......Page 134
Key Facts......Page 137
Definitions of Words and Terms......Page 138
References......Page 139
8.1 Biotransformation of Genistein Compounds in theGastrointestinal Tract......Page 142
8.1.1 Deglycosylation of Genistin in the Small Intestine......Page 143
8.1.2 Glucuronidation and Sulfation of Genistein......Page 144
8.1.4 Breakdown of Genistein and Luminal Excretion......Page 146
8.1.5 Transfer of Genistein in Placenta......Page 148
8.2 A Comparison with Other Xenoestrogens......Page 149
8.2.2 Biotransformation of Xenoestrogens......Page 150
8.2.3 Placenta Transfer......Page 151
Summary Points......Page 152
List of Abbreviations......Page 153
References......Page 154
9.1 Genistein and its Biological Activities......Page 158
9.1.1 Oestrogenic Activity......Page 159
9.1.2 Anticancer Effects......Page 160
9.1.4 Anti-inflammatory Activity......Page 161
9.2 Intracellular Formation of the Genistein Metabolite5,7,30,40-Tetrahydroxyisoflavone (THIF)......Page 162
9.3 THIF and Cancer......Page 164
9.4 THIF and Endothelial Function......Page 166
9.5 Summary......Page 167
Key Facts......Page 168
References......Page 169
10.1 Introduction......Page 175
10.2 Chemical Structure and Interactionwith Estrogen Receptors......Page 176
10.3 Metabolism......Page 179
Summary Points......Page 180
Definitions of Words and Terms......Page 181
References......Page 182
11.1 Introduction......Page 184
11.2 From Plant Biosynthesis to MammalianBiosynthesis......Page 185
11.2.1 Biosynthesis of Isoflavonoids in Leguminous Cells......Page 186
11.3 Interaction of Isoflavonoids with ERs......Page 190
11.4 Mammalian Metabolism and Bioavailability......Page 192
11.5 Biochemical and  Physiological Functionsof Isoflavonoids......Page 194
11.5.1 Estrogenic-related Effects......Page 195
11.5.2 Non-estrogenic-related Effects......Page 196
Summary Points......Page 197
Key Facts......Page 198
Definitions of Words and Terms......Page 199
List of Abbreviations......Page 200
References......Page 201
Analysis......Page 204
12.1 Introduction......Page 206
12.2 Microwave Extraction System Designs......Page 208
12.4 Oil Separation and Isoflavone Purification......Page 210
12.5.1 Isoflavones (and Oil) Yields......Page 211
12.5.2 Influence of Time and Temperature on the Oil and Isoflavones Extraction Yield – Reaction Kinetics......Page 213
12.6 Conclusion......Page 216
Key Facts......Page 217
Definitions of Words and Terms......Page 218
References......Page 219
13.1 Introduction......Page 223
13.2.1 Selective Enzymatic Hydrolysis......Page 225
13.2.2 Fractionation by Ion-exchange Chromatography......Page 230
13.2.3 Direct Assay......Page 231
13.3 A Simple Direct Assay of Conjugated MetabolitesUsing HPLC-UV......Page 232
13.3.1 Reference Compounds......Page 233
13.3.2 SPE......Page 234
13.3.3 Chromatographic Conditions......Page 236
13.3.4 Application......Page 237
Summary Points......Page 239
Definitions of Words and Terms......Page 240
List of Abbreviations......Page 242
References......Page 243
14.1 Introduction......Page 245
14.2.1 High-throughput HPLC Methods using UVDetection......Page 249
14.2.2 High-throughput HPLC Methods using MS......Page 251
Summary Points......Page 265
Definitions of Words and Terms......Page 266
References......Page 267
15.1 Introduction......Page 271
15.2.1 Direct Extraction......Page 272
15.2.2 Hydrolysis......Page 282
15.2.3 Internal Standards......Page 284
15.4 Conclusion......Page 285
Key Facts......Page 286
References......Page 287
16.1 Introduction......Page 290
16.2 Isoflavone Isolation......Page 293
16.3 Techniques for the Analysis of Isoflavonesin Supplemented Food......Page 295
16.3.1 Liquid Chromatography (LC)......Page 296
16.3.3 Capillary Electrophoresis (CE)......Page 298
16.3.4 Mass Spectrometry (MS)......Page 299
16.4 Conclusions......Page 300
Key Facts......Page 301
Definition of Words and Terms......Page 302
References......Page 303
17.1 Introduction......Page 307
17.3 Mass Spectrometry (MS) as a Tool forIdentification of Isoflavone Glycoconjugates......Page 308
17.4 Sources of Structural Variability of FlavonoidCompounds......Page 310
17.5 Differentiation of Isoflavone and FlavoneGlycoconjugates with Instrumental Methods......Page 312
17.6 Differentiation of C-Glycosides and O-Glycosidesof Isoflavonoids......Page 314
17.7 Differentiation of Acylated Glycoconjugatesof Isoflavonoids......Page 315
Definitions of Word and Terms......Page 318
References......Page 319
18.1 Introduction......Page 321
18.3 Chemical Composition......Page 323
18.4.1 Anti-tumor Activity......Page 325
18.4.3 Anti-hypertension......Page 329
18.4.4 Anti-atherosclerosis......Page 330
18.4.5 Neuroprotection......Page 331
18.4.6 Anti-allergy......Page 332
18.4.7 Anti-hyperglycemic Effect......Page 333
Conclusions......Page 334
Key Facts......Page 335
Definitions of Words and Terms......Page 336
References......Page 337
19.1 Introduction......Page 343
19.2.2 Osteogenic Herbal Fractions and Compoundsof Butea monosperma......Page 344
19.3.1 Chromatographic Conditions......Page 346
19.3.2 Mass Spectrometric Conditions......Page 348
19.3.3 Validation of the LC-MS/MS Method......Page 349
19.4 Conclusion......Page 352
Summary Points......Page 353
Definition of Words and Terms......Page 354
References......Page 356
20.1 Introduction......Page 360
20.3.2 HPLC Analysis of Isoflavones......Page 361
20.3.4 Content of a Novel Isoflavone in Groundnuts......Page 362
20.4.1 Isoflavone Profile of Groundnuts......Page 363
20.4.2 Influence of the Extraction Temperature on the IsoflavoneComposition of Groundnut Extract......Page 364
20.4.3 Purification of a Novel Isoflavone (Peak-1) from theGroundnut Extract......Page 366
20.4.4 Structural Analysis of a Novel Isoflavone from theGroundnut Extract......Page 367
20.4.5 Content of a Novel Isoflavone from the Groundnut Extract......Page 368
20.5 Conclusion......Page 369
Key Facts......Page 370
Definitions of Words and Terms......Page 371
References......Page 372
Function and Effects......Page 374
21.1 Introduction......Page 376
21.2.1 Australia and the UK......Page 377
21.2.2 Brazil......Page 378
21.2.4 China and Hong Kong......Page 381
21.2.5 Italy......Page 382
21.2.7 Korea......Page 383
21.2.8 Singapore and Indonesia......Page 384
21.2.10 USA......Page 385
Summary Points......Page 386
Definitions of Words and Terms......Page 387
References......Page 388
22.1 Introduction......Page 392
22.2 Isoflavone Sources......Page 393
22.2.1 Beverages as Isoflavone Sources......Page 394
Summary Points......Page 403
Definitions of Words and Terms......Page 404
References......Page 405
23.1 General Introduction......Page 408
23.2.1 Clinical Information, Genetics and Biochemistry......Page 409
23.2.2 Pathophysiology......Page 410
23.3.1 GAGs: Structure, Function and Life Cycle......Page 411
23.4 Use of Isoflavones for Substrate ReductionTherapy (SRT)......Page 414
23.4.2 Isoflavones and Analogs are Potent Agents for SRT......Page 415
23.4.3 Isoflavone Action on GAG Synthesis and GAGAccumulation......Page 418
23.5 Conclusions and Perspectives for the Clinic......Page 419
Definitions of Words and Terms......Page 421
References......Page 422
24.1 Introduction......Page 426
24.1.1 Delivery of Isoflavone Dosage without Compromising Palatability......Page 427
24.1.2 Processing Effects on Soy Isoflavones......Page 428
24.1.3 Relevance of Isoflavone Chemical Composition......Page 429
24.2.2 Soy-almond Bread (SAB) Preparation......Page 430
24.2.3 Isoflavone Analysis......Page 431
24.2.4 Physicochemical Experiments......Page 432
24.2.5 Characterization of Organoleptic Properties......Page 433
24.3.1 Process of Selecting the Optimal Phytochemical Delivery Vehicle......Page 434
24.3.2 Isoflavone Analysis......Page 436
24.3.3 Physicochemical Properties......Page 437
24.3.4 Characterization of Organoleptic Properties......Page 440
24.4 Conclusions......Page 443
Key Facts......Page 444
Definitions of Words and Terms......Page 445
List of Abbreviations......Page 446
References......Page 447
25.1 Introduction......Page 450
25.2 The Case of Genistein......Page 452
25.2.1 Genistein and Thyroid Function......Page 453
25.3 Conclusions......Page 457
Summary Points......Page 458
Key Facts......Page 459
List of Abbreviations......Page 460
References......Page 461
26.1 Introduction......Page 465
26.2 Absorption, Metabolism, and Excretion......Page 466
26.3.1 Anti-bacterial Effects......Page 468
26.3.3 Anti-inflammation Effect......Page 469
26.3.5 Inhibition of Angiogenesis......Page 471
26.3.7 Evidence from Population Studies......Page 472
Definitions of Words and Terms......Page 474
References......Page 475
27.1 Introduction......Page 478
27.2 Pre-clinical Studies of the Deleterious, Endocrinedisrupting Effects of Dietary Isoflavones on Learning and Memory......Page 479
27.3 Pre-clinical Studies of the Beneficial Effects of Dietary Isoflavones in Rodent Models of Age-associated Cognitive Deficits......Page 481
27.4 Pre-clinical Studies of Beneficial Effects of Dietary Isoflavones in Ovariectomized Rats......Page 482
27.5 Human Clinical Studies of Beneficial Effects of Dietary Isoflavones on Learning and Memory......Page 484
Summary Points......Page 486
Definition of Words and Terms......Page 487
References......Page 488
28.1 Introduction......Page 492
28.2 Absorption......Page 493
28.4 Glycitein and Cancer......Page 494
28.5 Glycitein and Cardiovascular Health......Page 497
28.7 Glycitein and Memory and Mood......Page 498
28.8 Glycitein and Oxidative Stress......Page 499
Summary Points......Page 500
Definitions of Words and Terms......Page 501
List of Abbreviations......Page 502
References......Page 503
29.1 Background: Polyphenols and Isoflavonoids......Page 507
29.2 Isoflavonoid Metabolism in Mammals:Postnatal Development......Page 508
29.3 Equol: Biosynthesis (Plants and Mammals),Antioxidant Activity, and Safety Data in Postnatal Development......Page 509
29.4 Comparison between Human and Rat:Newborn and Adult Parameters......Page 512
29.5.1 Isoflavonoids: Perinatal Rodent Studies......Page 514
29.5.2 Equol: Perinatal Rodent Studies......Page 515
29.5.3 Isoflavonoids: Perinatal Human Studies......Page 517
29.6 Summary and Considerations......Page 519
Summary Points......Page 520
Key Facts......Page 521
Definition of Words and Terms......Page 522
References......Page 523
30.1 Introduction......Page 527
30.2.1 GABAA Receptor Function......Page 528
30.2.2 GABAA Receptor Structure......Page 529
30.3.1 Genistein as an Inhibitor of Protein Tyrosine Kinases (PTKs)......Page 530
30.3.2 Direct Inhibition of GABAA Receptors......Page 531
30.4.1 NMDA Receptor Function......Page 532
30.4.2 NMDA Receptor Structure......Page 533
30.5.1 Genistein as an Inhibitor of Protein Tyrosine Kinases(PTKs)......Page 535
30.6 Genistein Modulation of GABAA and NMDA Receptors via the Estrogenic Pathway......Page 536
30.8 Conclusion......Page 538
Definitions of Words and Terms......Page 539
References......Page 540
31.1 Introduction......Page 545
31.2 Animal Studies......Page 546
31.3 Mechanisms of the Toxic Action......Page 547
31.4 Human Studies......Page 548
31.5 Interpretation of Data in Relation to Human Exposure......Page 551
Key Facts......Page 552
References......Page 553
32.1 Introduction......Page 556
32.2 Genistein may have Anti-diabetic Effects......Page 557
32.3 Genistein at Physiological ConcentrationsAugments Glucose-stimulated Insulin Secretion(GSIS) in Beta-cells and Pancreatic Islets......Page 559
Definitions of Words and Terms......Page 564
References......Page 565
33.1 Introduction......Page 568
33.2.1 Introduction to Soy Phytochemicals and Isoflavones......Page 570
33.2.2 Population-based Studies......Page 571
33.2.3 Animal Studies......Page 572
33.2.4 Laboratory Studies......Page 573
33.3.1 Modulation of Fat Deposition and Adipogenesisby Soy Isoflavones......Page 574
33.3.2 A Facile Strategy for the Identification of Soy Isoflavoneswith Potential for Regulating Visceral Fat......Page 576
33.3.3 Discovery of Proteins Targeted by Soy Isoflavoneswith a Regulatory Role in Adipogenesis......Page 578
33.3.4 Candidate Molecular Targets and Mechanisms ofAnti-obesity Isoflavones: Interplay Between NQO1and p53 in Regulation of Adipogenesis......Page 579
33.3.5 Role of PPARa, PPARc, C/EBPa and Other CandidateMolecular Sensors/Effectors of Adipogenesis......Page 580
Key Facts......Page 582
List of Abbreviations......Page 583
References......Page 584
34.1 Introduction......Page 589
34.3 Hormonal Regulation of Reproductive Tract Development......Page 590
34.4 Regulation of Gonadal Function......Page 592
34.5 Isoflavone Action in Testicular Cells......Page 593
34.5.1 Effects on Steroidogenesis......Page 594
34.5.2 Effects on Sperm Production......Page 595
34.5.3 Effects on Developing versus Mature Stages of Development......Page 596
34.6 Mechanisms of Isoflavone Action......Page 597
34.7 Isoflavone Action in the Human Testis......Page 599
34.8 Conclusion......Page 600
Definitions of Words and Terms......Page 601
References......Page 602
35.1 Introduction......Page 607
35.2.2 Estrogenic Activity and Breast Cancer......Page 608
35.2.3 Equol and Prostate Cancer......Page 610
35.3.1 Equol and Pancreatic Cancer......Page 613
35.4 Equol and CVDs......Page 614
35.6 Equol and Genotoxicity......Page 615
35.8 Equol and Cancer Chemoprevention......Page 616
35.9 Equol and Drug Metabolism......Page 617
Summary Points......Page 618
Definitions of Words and Terms......Page 619
References......Page 620
36.1 Introduction......Page 624
36.2 Bone and Estrogen......Page 625
36.3 Bone and Soy Isoflavones......Page 626
36.4 Bone and Purified Genistein, Daidzein and Equol......Page 627
36.5 Conclusion......Page 632
Definition of Words and Terms......Page 633
References......Page 634
37.1 An Introduction to Inflammation inAdipose Tissue......Page 638
37.2 An Overview of Isoflavones as Anti-inflammatoryAgents......Page 642
37.2.1 Isoflavones can Modulate Proinflamatory Factors inMacrophages and Adipocytes and Down-regulate Gene Expression of Proinflammatory Mediators......Page 643
37.2.2 Isoflavones can Modulate Proinflamatory Factorsin Adipose Tissue by a Decrease in AdiposeTissue Mass and/or Number......Page 644
37.3.1 The Effects of Isoflavones in Animal Models ofObesity: Effect of Isoflavones in Rats with High-fatDiet (HFD)-induced Obesity/Insulin Resistance and theAnalysis of Inflammatory Factors......Page 646
37.4.2 Studies with Genistein (Gen) in Human CellInflammation......Page 648
Key Facts......Page 649
Definitions of Words and Terms......Page 650
References......Page 651
38.1 Pharmacology Aspects......Page 654
38.2 Clinical Evidence......Page 657
Key Facts......Page 667
References......Page 668
Subject Index......Page 673