Isoflavones: Chemistry, Analysis, Function and Effects: Volume 5 (Food and Nutritional Components in Focus) - Hardcover

Hardcover

ISBN 10: 1849734194 ISBN 13: 9781849734196

Publisher: Royal Society of Chemistry, 2012

Synopsis

Isoflavones is an extensive and detailed book which will appeal across the disciplines providing a snapshot of this fascinating scientific subject.

About this title

About the Author

Victor Preedy is currently Professor of Nutritional Biochemistry and Director of Genomics Centre, King's College London and Professor of Clinical Biochemistry at King's College Hospital London. After graduating with a BSc degree in Physiology with Pharmacology and Biology, Professor Preedy carried out a period of research on protein metabolism in the Department of Nutrition at the London School of Hygiene and Tropical Medicine. After the successful award of his PhD he studied aspects of cardiac protein metabolism at the National Heart Hospital. After 4 years, he then moved to the MRC Clinical Research Centre in Harrow, which was followed by his appointment as a lecturer to Kings College in 1988. He was promoted to Reader in 1995 and Professor in 2003. Professor Preedy has published over 550 articles, which includes over 160 peer-reviewed manuscripts based on original research and 90 reviews as well as 35 books.

From the Back Cover

Isoflavones remain the subject of many scientific studies most of which reveal them to have some health benefits. Coverage within this book begins with an overview of phytoestrogens in health and plants with specific reference to isoflavones, how isoflavones are found in the diet and novel compounds in nuts. Expert accounts of the chemical and biochemical research on this topic are provided followed by analytical and bioanalytical assessments. Rounding up the book are the chapters on function and effects of isoflavones which provide details on isoflavones in beverages, soy and soy products and other food delivery systems and how their function effects the thyroid, menopause, prostate, breast, bone and cardiovascular disease to name but a few. Delivering high quality information, this extensive and detailed book provides a fascinating insight into this area of health and nutritional science. It will bridge scientific disciplines so that the information is more meaningful and applicable to health in general. Part of a series of books, it is specifically designed for chemists, analytical scientists, forensic scientists, food scientists, dieticians and health care workers, nutritionists, toxicologists and research academics. Due to its interdisciplinary nature it could also be suitable for lecturers and teachers in food and nutritional sciences and as a college or university library reference guide.

Excerpt. © Reprinted by permission. All rights reserved.

Isoflavones

Chemistry, Analysis, Function and Effects

By Victor R. Preedy

The Royal Society of Chemistry

Copyright © 2013 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-419-6

Contents

Isoflavones in Context, 
Chapter 1 Phytoestrogens in Health: The Role of Isoflavones Rodney J. Baber, 3, 
Chapter 2 Phytoestrogens in Plants: With Special Reference to Isoflavones Franz Bucar, 14, 
Chapter 3 Isoflavones in Foods and Ingestion in the Diet Baskaran Stephen Inbaraj and Bing Huei Chen, 28, 
Chemistry and Biochemistry, 
Chapter 4 The Chemistry/Biochemistry of the Bioconversion of Isoflavones in Food Preparation Kashif Ghafoor, Fahad Y. Al-Juhaimi and Jiyong Park, 49, 
Chapter 5 Chemistry and Synthesis of Daidzein and its Methylated Derivatives: Formononetin, Isoformononetin, and Dimethyldaidzein Vincent M. Carroll, Jeffrey D. St. Denis, Kyle F. Biegasiewicz and Ronny Priefer, 61, 
Chapter 6 Non-natural Isoflavonoids Namita Bhan and Mattheos Koffas, 83, 
Chapter 7 The Structure of Isoflavones by 1D and 2D Homonuclear and Heteronuclear NMR Spectroscopy Kristiina Wähälä, Somdatta Deb and Tapio Hase, 94, 
Chapter 8 Biotransformation and Transfer of Genistein: a Comparison with Xenoestrogens and a Focus on the Human Placenta Hsiu-Wen Chan, Greg E. Rice and Murray D. Mitchell, 115, 
Chapter 9 The Biological Effects of Genistein and its Intracellular Metabolite, 5,7,3',4'-Tetrahydroxyisoflavone Giulia Corona and Jeremy P. E. Spencer, 131, 
Chapter 10 Genistein Chemistry and Biochemistry Francesco Squadrito and Alessandra Bitto, 148, 
Chapter 11 Isoflavones and Human Estrogen Receptor: When Plants Synthesize Mammalian Hormone Mimetics Patricia de Cremoux and Yves Jacquot, 157, 
Analysis, 
Chapter 12 Continuous Microwave-assisted Isoflavone Extraction Dorin Boldor and Cristina Mirela Sabliov, 179, 
Chapter 13 Isoflavones: High-performance Liquid Chromatographic Analysis of Glucuronic Acid-and Sulfuric Acid-conjugated Metabolites of Daidzein and Genistein in Human Plasma and Urine Kazuo Ishii, Kaori Hosoda and Takashi Furuta, 196, 
Chapter 14 High-throughput Quantification of Pharmacologically Active Isoflavones using LC-UV/PDA and LC-MS/MS Wahajuddin and Sumit Arora, 218, 
Chapter 15 Methods for Isoflavones: A Focus on Beverage Analysis Rita C. Alves and M. Beatriz P. P. Oliveira, 244, 
Chapter 16 The Determination of Isoflavones in Supplemented Foods: An Overview Alberto Zafra-Gómez, Sonia Capel-Cuevas and Noemí I. Dorival-García, 263, 
Chapter 17 Isoflavones: LC-MS/MS Profiling of Isoflavone Glycosides and Other Conjugates Piotr Kachlicki and Maciej Stobiecki, 280, 
Chapter 18 Puerariae radix Isoflavones Lei Wan and Chia-Hung Lin, 294, 
Chapter 19 Pattern Profiling and Quantitative Determination of Isoflavones in Herbal Chemotypes using Liquid Chromatography Tandem Mass Spectrometry Lakshmi Manickavasagam, Smriti Mishra and Girish Kumar Jain, 316, 
Chapter 20 Analysis of Novel Isoflavone Digycoside in Nuts Kazuhiro Nara, 333, 
Function and Effects, 
Chapter 21 Isoflavone Ingestion by Multiethnic Populations: Implications for Health Baskaran Stephen Inbaraj and Bing Huei Chen, 349, 
Chapter 22 Isoflavones in Beverages Rita C. Alves and M. Beatriz P. P. Oliveira, 365, 
Chapter 23 Use of Isoflavones in Inherited Metabolic Diseases: A Focus on Mucopolysaccharidoses Daniel Scherman, Audrey Arfi and Corinne Marie, 381, 
Chapter 24 Optimizing Isoflavone-rich Food Delivery Systems for Human Clinical Trials Jennifer Ahn-Jarvis, Steven Schwartz and Yael Vodovotz, 399, 
Chapter 25 Isoflavones and Thyroid Function: An Overview Francesco Squadrito and Alessandra Bitto, 423, 
Chapter 26 Isoflavones against Gastric Cancer: Function and Effects Sue K. Park and Kwang-Pil Ko, 438, 
Chapter 27 Dietary Isoflavones and Learning and Memory Craige C. Wrenn, 451, 
Chapter 28 Glycitein in Health Brian R. Stephens and Joshua A. Bomser, 465, 
Chapter 29 Isoflavones and Prenatal Exposure to Equol Edwin D. Lephart, 480, 
Chapter 30 Genistein: GABAA and NMDA Receptors Renqi Huang and Glenn H. Dillon, 500, 
Chapter 31 Estrogenic Activity and Molecular Mechanisms of Coumestrol-induced Biological Effects Kenneth Ndebele, Barbara Graham and Paul Tchounwou, 518, 
Chapter 32 Genistein and Insulin Secretory Function Dongmin Liu, 529, 
Chapter 33 Prevention and Management of Obesity by Isoflavones Barbara B. Doonan, Erxi Wu and Joseph M. Wu, 541, 
Chapter 34 Soy Isoflavones and Testicular Function Benson T. Akingbemi, 562, 
Chapter 35 Equol and Cell Proliferation Zhong Li, Caiyun Zhong and Chunyan Hu, 580, 
Chapter 36 Bone, Genistein, Daidzein and Equol Marina Komrakova, Ewa Klara Stuermer, Klaus Michael Stuermer and Stephan Sehmisch, 597, 
Chapter 37 Isoflavones and Inflammation in Adipose Tissue and Implications for Health Maria Teresa Blay, Montserrat Pinent and Anna Ardévol, 611, 
Chapter 38 Isoflavones for Menopausal Vasomotor Syndrome Rafael Bolaños Diaz and Juan Carlos Zavala Gonzales, 627, 
Subject Index, 646, 

CHAPTER 1

Phytoestrogens in Health: The Role of Isoflavones

RODNEY J. BABER

Medical Suites, Level 3, North Shore Private Hospital, Westbourne St., St Leonards, NSW 2065, Australia

Email: rbaber@med.usyd.edu.au

1.1 Introduction

Phytoestrogens are diphenolic, non-steroidal estrogen-like substances found in all plants, the highest concentrations being in legumes (Baber 2010; Nelson 2008), and are classified according to their chemical structure. The greatest estrogenic activity is found in flavones, flavonols, flavanones, lignans, chalcones and isoflavones. The most common of these are the isoflavones and lignans, which are found mainly in fruit, vegetables and whole grains (Lethaby et al. 2007). These compounds have a steric structure similar to that of steroidal estrogens, allowing them to bind to the human estrogen receptor (ER) and they are therefore capable of exerting various estrogenic or anti-estrogenic effects (Duncan et al. 2003). Isoflavones bind with a greater affinity to ERβ than to ERa (Kuiper et al. 1996). The binding affinity of isoflavones for ERs has been estimated to be between 10-2 and 10-4 of that of 17β-estradiol (Collins et al. 1997; Miksicek 1994), however, these substances can be present in the blood at levels up to 10 000 times that of steroidal estrogens (Adlercreutz et al. 1991).

Over 10 000 peer-reviewed papers have been published on the role of isoflavones in health. Amongst commonly consumed foods, isoflavones are found in physiologically relevant amounts in soybeans and foods derived from soy (Adlercreutz and Mazur 1997). The greater reliance on vegetables and particularly legumes such as soy for dietary protein in Asian and Central American communities means that those communities typically have substantially higher dietary isoflavone intake than those found in Western countries (Goldin et al. 1986).

Soybeans contain three primary isoflavones in their glycoside form: genistin, daidzin and glycitin. Digestion leads to the cleavage of the sugar moiety and the formation of the respective aglycones: genistein, daidzein and glycitein. Red clover has also been used to manufacture supplements for human use. Red clover contains four isoflavones: formononetin, biochanin, daidzein and genistein. At physiological concentrations, formononetin does not bind to the ER but is metabolized to daidzein and then by intestinal bacteria to equol, both of which have been shown to have estrogenic properties (Baber 2010).

Interest in these compounds began over 20 years ago with research by the US National Cancer Institute exploring possible chemo-preventive properties for phytoestrogens, especially in regard to breast cancer. Ongoing research led to further investigation of these compounds in relation to cardiovascular and skeletal health, cognitive function and the alleviation of menopausal symptoms.

Despite continuing research, the role of isoflavones in health remains controversial, with concerns expressed that the estrogen-like effects of these compounds may pose a risk to certain individuals, especially women with breast cancer or at high risk of that disease. Clinical trials, although numerous, have typically been small, short, of variable quality, have tested different (and often impure) substances and have chosen different endpoints to measure usefulness, efficacy and safety.

There are substantial inconsistencies between results from Asian epidemiologic studies, which are generally viewed as supportive of health benefits, and Western clinical trials, which are much less so. The epidemiologic data are based on the intake of traditional soy foods, such as tofu, miso and soymilk, whereas the intervention trials have usually utilized isolated soy protein and soy or isoflavone supplements. The outcome differences may be due to differences between traditional isoflavone-rich foods and prepared isoflavone supplements, to individual differences in absorption of isoflavones, the timing and duration of exposure to isoflavones and ethnic differences or to a healthy user effect.

1.2 Absorption, Metabolism and Excretion of Isoflavones

Isoflavone aglycones are absorbed in the upper small intestine by passive diffusion, peaking in the blood within 1 h of being ingested (Sfakianos et al. 1997). In contrast, the β-glucosides are not passively absorbed. They are hydrolyzed by β-glucosidases from intestinal bacteria or an intestinal enzyme, lactase-phlorizin hydrolase. Isoflavone aglycones are converted into their β-glucuronides by UDP-glucuronyltransferases in gut mucosal cells (King et al. 1996) and to a lesser extent to sulfate esters catalyzed by 3'-phosphoadenosine 5'-phosphosulfate (PAPS)-sulfotransferases (Ronis et al. 2006). Glucuronidation and sulfation also occur in the liver. These phase II metabolites are excreted in the bile and are deconjugated in the lower bowel, allowing them to be reabsorbed again, creating an enterohepatic circulation (Sfakianos et al. 1997). Daidzein is metabolized to dihydrodaidzein, which is further metabolized to equol and O-desmethylangolensin (O-DMA). Genistein is transformed to dihydrogenistein and then metabolized to 6-hydroxy-O-DMA. Human urinary excretion of these metabolites is variable, and only approx. 30–40% of subjects excrete significant quantities of equol after isoflavone consumption (Kurzer et al. 1997). The same is not true of animals in which equol excretion appears quite consistent. Based on many studies, the consensus is that only 25–30% of the adult population of Western countries excrete equol when fed soy foods. This is significantly lower than the reported 50–60% frequency of equol-producers in adults from Japan, Korea or China, or in Western adult vegetarians. This regional or ethnic difference in equol production has led to the hypothesis that equol production is necessary for an individual to derive the predicted health benefits from isoflavone consumption (Setchell and Clerici 2010).

1.3 Mechanisms of Action of Isoflavones

The ability of Isoflavones to bind to to mammalian ERs has been known for over 40 years, although, compared with 17β-estradiol, isoflavones have approx. 100 times weaker affinity (Kuiper et al. 1997).

A greater understanding of estrogen action began in 1996 with the discovery of ERβ (Kuiper et al. 1996). Although related to ERα, which is located on chromosome 6, ERβ is located on chromosome 14. The ligand-binding sites are highly homologous between ERα and ERβ. However, the few amino acid differences result in isoflavones exerting preferential binding affinity to ERβ. ERα and ERβ are expressed at various concentrations in different organs and different cell types. This has led to the development of compounds, known as selective estrogen receptor modulators (SERMs), which selectively target receptors and which may be antagonistic in some and agonistic in others. Some have suggested that isoflavone binding to ERβ is an antagonistic process, not an agonistic one, and that hence isoflavones may be 'natural SERMs' (Matthews and Gustafsson 2003). The mechanism of action of isoflavones may thus be estrogenic or anti-estrogenic in different tissues depending upon the concentrations of ERα and ERβ, the concentration of the isoflavone and the concentration of endogenous sex hormones. Isoflavones also have non-genomic activity. Genestein, in vitro, will inhibit the activity of tyrosine protein kinase (Akiyama et al. 1987). Genistein also affects genes involved in the control of cell growth via effects on natural killer cell function, as well as enzyme inhibition and the peroxisome proliferator regulator (Sarkar and Li 2003).Overall, evidence suggests that many pathways, not just estrogen-dependent events, mediate the biological effects of isoflavones and their metabolites. Future studies may utilize data that have been obtained in DNA microarray experiments. Lastly, studies have suggested that some of the benefits of dietary isoflavones observed in other populations may depend on early life exposure (Korde et al. 2009), which may involve their impact on gene expression at an epigenetic level.

1.4 Clinical Effects of Isoflavones

1.4.1 Cardiovascular Health

Isoflavones may exert an effect on the cardiovascular system by three major mechanisms:

(1) directly through ER-mediated effects;

(2) through ER-independent effects directly on cardiovascular risk factors and putative atherogenic risk factors;

(3) indirectly through the displacement of animal protein intake.

Isoflavones exert estrogenic and anti-estrogenic effects (Kuiper et al. 1998). In animal models, isoflavones have been shown to require the presence of the ER to exert anti-atherogenic efffects. The vascular endothelium is a rich site of ERβ expression and the preferential binding of isoflavones for ERβ suggests they may exert anti-atherogenic effects in vascular tissue (Makela et al. 1999). However, binding affinities for the ER do not explain the functional complexity of isoflavones. For example, although genistein and equol have a 20-fold greater affinity for ERβ than ERa, the transcriptional expression is greatest for equol relative to all other isoflavones. The contribution of the protein portion of soy versus the isoflavone portion to the cardiovascular effects reported also remains unclear.

At present any cardiovascular effects of isoflavones are thought to be related to their effects on lipid metabolism. Results are awaited from trials examining the effects of isoflavones on progression of atherosclerosis and whether the capacity to convert daidzein into equol confers greater cardiovascular benefits. No randomized clinical trials examining clinical endpoints of cardiovascular health are available. Therefore, although there is some evidence of a beneficial effect of isoflavones on lipids and vascular function, and while a healthy diet should be encouraged as a general health measure, it is not appropriate to recommend phytoestrogen supplements or diets as a primary cardiovascular disease preventive intervention.

1.4.2 The Brain

Both ERα and ERβ are abundantly expressed in brain and exhibit a pattern of distribution consistent with their roles in reproductive and cognitive function (Spencer et al. 2008). As expected, ERα occurs in brain regions involved in regulation of reproduction but both occur, particularly ERβ, in brain regions involved in cognition. The expression and localization of ERs are dynamic and can vary depending upon brain region, cell type, hormonal status and neurological condition. The effects of isoflavones in the brain may be due to genomic or non-genomic actions. Some clinical trials also point to different effects on cognition in women depending on the age since the menopause, a situation analogous to the 'critical window' hypothesis for the effects of postmenopausal estrogens on the cardiovascular and cognitive health of women.

1.4.3 Bone Health

A number of genomic and non-genomic mechanisms exist by which phytoestrogens may affect bone metabolism. Isoflavones increase the synthesis of vitamin D in a number of non-renal cell types, have been shown to stimulate calcium uptake in bone and to increase bone cell proliferation and differentiation in animal studies. These effects may lead to improved bone health consistent with data on postmenopausal estrogen therapy and bone health (Writing Group for the Women's Health Initiative Investigators 2002). More than 25 studies have examined the effects of isoflavones on bone mineral density (BMD) in postmenopausal women most, as usual, being small and short. A 2-year trial in postmenopausal osteopenic women given 54 mg day-1 genistein found that spinal and hip BMD increased significantly compared with placebo (Marini et al. 2008). However, two long-term trials (Brink et al. 2008; Vupadhyayula et al. 2009) showed no significant effect. Possible explanations for this inconsistency include chronological differences in exposure (Asian adult soy intake assessed in the epidemiologic studies may reflect lifelong intake) and the ability to convert daidzein into equol. There may be a critical dose of isoflavones required to achieve an effect on BMD, and there may be differences in bioavailability between various supplements, foods and purified compounds. Consequently, it remains unclear whether isoflavones have a beneficial effect on BMD and, importantly, no randomized trials have demonstrated efficacy of phytoestrogens on fracture prevention (Baber 2010).

1.4.4 Breast Cancer

Isoflavones have been identified as putative chemopreventives (Messina 2010). Most research interest has focused on breast and prostate cancer because of the difference in incidence of these cancers in Western and Asian communities. Isoflavones may alter the metabolism of endogenous estrogens, potentially producing indirect effects on estrogenic pathways. Other mechanisms by which isoflavones may be cancer protective include antiproliferative effects, tyrosine kinase inhibition, modulation of steroid hormone-metabolizing enzyme activity, induction of apoptosis and inhibition of angiogenesis. Dietary isoflavones also reduce circulating and intra-breast estradiol concentrations in monkeys, with a corresponding decrease in uterine and breast tissue proliferation (NAMS 2011).

(Continues...)

Excerpted from Isoflavones by Victor R. Preedy. Copyright © 2013 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2012
• Language: English
• ISBN 10: 1849734194
• ISBN 13: 9781849734196
• Binding: Hardcover
• Number of pages: 710
• Editor: Victor R. Preedy