Phd Thesis, Wageningen University, Wageningen, NL (2016) with References, with Summary in English

The influence of phase II conjugation on the biological activity of flavonoids Karsten Beekmann Thesis committee Promotors Prof. Dr Ivonne M.C.M. Rietjens Professor of Toxicology Wageningen University Prof. Dr Peter J. van Bladeren Professor of Toxicokinetics and Biotransformation Wageningen University Co-promotor Dr Lucas Actis-Goretta Senior Research Scientist, Nutrition and Health Research Nestlé Research Center, Lausanne, Switzerland Other members Prof. Dr Gary Williamson, Leeds University, England Prof. Dr Aalt Bast, Maastricht University Prof. Dr Sander A.H. Kersten, Wageningen University Dr Rob Ruijtenbeek, PamGene International B.V., Den Bosch This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences) The influence of phase II conjugation on the biological activity of flavonoids Karsten Beekmann Thesis at Wageningen University submitted in fulfilment of the requirements for the degree of doctor Prof. Dr A.P.J. Mol, by the authority of the Rector Magnificus in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Wednesday 18 May 2016 at 11 a.m. in the Aula. Karsten Beekmann 172 pages. The influence of phase II conjugation on the biological activity of flavonoids, PhD thesis, Wageningen University, Wageningen, NL (2016) With references, with summary in English ISBN 978-94-6257-764-0 table of contents Chapter 1 7 - 21 General introduction Chapter 2 A state-of-the-art overview of the effect of metabolic conjugation on 22 - 45 the biological activity of flavonoids Chapter 3 Flavonoid conjugate biosynthesis and identification using the 46 - 65 Metabolite Identification Database (MetIDB) Chapter 4 The effect of quercetin and kaempferol aglycones and glucuronides 66 - 85 on peroxisome proliferator-activated receptor-gamma (PPAR-γ) Chapter 5 The effect of glucuronidation on isoflavone induced estrogen receptor 86 - 107 (ER)α and ERβ mediated coregulator interactions Chapter 6 The effect of glucuronidation on the potential of kaempferol to inhibit 108 - 127 serine/threonine protein kinases Chapter 7 128 - 159 General discussion Summary 163 - 165 Acknowledgements 167 - 168 About the author 169 List of publications 170 Overview of completed training activities 171 Chapter 1 General introduction, aim and outline of the thesis Chapter 1 General introduction General introduction Flavonoids are a class of polyphenolic chemicals ubiquitously present in the plant kingdom where they occur as secondary metabolites fulfilling a range of functions such as pigmentation and UV protection [1]. In food, flavonoids contribute to the coloring and 1 wine and cocoa. Flavonoids attract attention as supposedly bioactive food constituents taste [2]. The most important dietary sources of flavonoids are fruits, vegetables, tea, such as the prevention of cardiovascular diseases [3, 4], neurodegenerative diseases [5] - consumption of a diet high in flavonoids is correlated to a wide range of health effects, and diabetes [6, 7]. A vast amount of scientific publications on the supposed mechanisms kinases, of other enzymes, and/or of transport proteins [8-12]. of action of flavonoids report flavonoids to act as ligands for receptors, inhibitors of Flavonoids commonly consist of two aromatic rings (i.e. A- and B-ring) which are linked by the C-ring consisting of an additional three carbons and one oxygen (Figure 1.1). 3' 2' 4' 8 1' B 7 O 2 5' 6' 6 A C 3 5 4 Figure 1.1 Basic flavonoid skeleton structure with conventional numbering of carbons and naming of rings. More than 5,000 different flavonoids have been identified [13] and they are divided into the following six main subclasses of flavonoids: flavonols, isoflavones, flavanols, saturation and oxygenation of the C-ring, as well as positioning of the B-ring. Most flavanones, flavones, and anthocyanidins [14, 15]. These subclasses show distinct flavonoid subclasses are diversely distributed throughout the plant kingdom and flavonoids often occur in several different food sources (see Table 1.1). Bioavailability in Europe [16, 17] and 190 to 345 mg/day in the USA [18, 19]. The intestinal uptake Recent studies estimate the mean dietary intake of flavonoids to be 370– 428 mg/day reported to be only a few percent of the ingested dose ranging from not detectable to of flavonoids is low and the systemic bioavailability for most types of flavonoids is 30% [20, 21]. Flavonoids occur nearly exclusively as conjugated metabolites in plasma normal dietary intake usually do not exceed the low micromolar range [20]. The plasma [22-25], and maximum concentrations of these flavonoid metabolites in plasma from half-life of flavonoid conjugates is reported to be mostly around a few hours, ranging 8from 1h to 28 h depending on the flavonoid type (see Table 1.1 for details). 9 General introduction Absorption, distribution, metabolism and excretion of flavonoids The low systemic bioavailability and high rate of metabolism are generally considered to oppose the biological activity of flavonoids. In the following sections, the absorption, distribution, metabolism and excretion of flavonoids are described; Figure 1.2 depicts the pharmacokinetics and pharmacodynamics of microbial metabolites and their 1 a compartmentalized overview of the pharmacokinetics of flavonoids. The study of conjugates is outside the scope of this thesis and will not be described in further detail. Ingested flavonoids Compartments involved in (mostly glycosides) metabolism and biological activity Compartments involved in transport and excretion Bile Direction of transport - transport of larger flavonoid conjugates Small intestine Liver Other tissues - deconjugation of flavonoid - (de)conjugation of - (de)conjugation of glucosides flavonoid conjugates, flavonoid conjugates, - uptake and first pass microbial metabolites, microbial metabolites, conjugation of flavonoids and their conjugates and their conjugates Hepatic portal - biological activity - biological activity - biological activity circulation - transport of flavonoid conjugates, microbial Colon metabolites, and their Kidney - deconjugation of flavonoid conjugates Systemic circulation - (de)conjugation of - transport of flavonoid glycosides (disaccharides, flavonoid conjugates, conjugates, microbial rutinosides, etc.) microbial metabolites, metabolites, and their - microbial metabolism of and their conjugates conjugates flavonoids - excretion of flavonoid - uptake and first pass conjugates, microbial conjugation of flavonoids metabolites and their and microbial metabolites Endothelium conjugates - biological activity - (de)conjugation of - biological activity flavonoid conjugates, microbial metabolites, and their conjugates Feces - biological activity Urine - flavonoid aglycones - flavonoid conjugates - microbial metabolites - microbial metabolites and their conjugates Figure 1.2 Schematic representation of major routes of absorption, distribution, metabolism and excretion of flavonoids. Absorption In plants, flavonoids occur as monomers, oligomers or polymers and are mostly present as glycosides (i.e. conjugated to sugar molecules); flavanols constitute an exception as they mostly occur in nonglycosylated form [26], as well as leaf surface flavonoids of certain herbs [27]. The glycosidic bonds of the majority of flavonoid glycosides resist food processing; however, during microbial fermentation of soy-based foods isoflavone aglycones (i.e. the unconjugated form) are released [28-32]. Therefore, apart from the exceptions named above, flavonoids are usually ingested as glycosides. 9 Chapter 1 General introduction Due to their size and hydrophilicity, flavonoid glycosides are not readily absorbed in aglycones before they can be further metabolized and become systemically available. the gastrointestinal tract; the glycosides need to be deconjugated to their respective Table 1.1 Chemical structures of flavonoid subclasses, common flavonoid members, main dietary sources and plasma kinetics [14, 15, 33-35] 1 Flavonoid subclass Common and chemical flavonoids in Main dietary sources Plasma kinetics structure subclass Flavonol Quercetin Vegetables (e.g. onion, kale, broccoli), Tmax 0.5-5.5 h Kaempferol fruits (e.g. apple), tea T1/2 2-11h Myricetin [36-39] (one study reporting T1/2 up to 28h [40]) Daidzein Legumes (especially soy bean) Tmax 4.5-6 h Genistein T 3-8.5 h Isoflavone 1/2 Glycitein [41-44] Flavanol Catechin Cocoa, tea, fruits (e.g. apricot, apple) Tmax 0.5-4 h Epicatechin T1/2 1-6 h [45-49] Flavanone Hesperetin Citrus fruits (e.g. orange, grapefruit, Tmax 4.5 h Naringenin lemon) T1/2 3.6-3.8 h Eriodictyol [50] Anthocyanidin Cyanidin Berries (e.g. blackberry, black Tmax 1 h Pelargonidin currant), fruits (e.g. cherry, black T1/2 2 h Peonidin grape), [51, 52] Delphinidin vegetables (e.g. aubergine) Malvidin Flavone Apigenin Leaf vegetables (e.g. celery), No data available Luteolin herbs (e.g. parsley) The type of glycosylation determines at which site in the gastrointestinal tract the flavonoid glycosides can be deconjugated to the respective aglycone. Especially deglycosilation in the small intestine by two major pathways. The glucosides can be flavonoid glucosides (i.e. flavonoids conjugated to glucose) are subject to enzymatic deglycosylated by the brush-border enzyme lactase-phlorizin hydrolase (LPH) before the aglycone produced can diffuse passively into the enterocytes. Another route of uptake is through transport of the glycoside into the enterocytes

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