http://informahealthcare.com/dmr ISSN: 0360-2532 (print), 1097-9883 (electronic) Drug Metab Rev, Early Online: 1–16 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/03602532.2014.1003649 REVIEW ARTICLE Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure–activity/property relationship-based approach in the study of bioavailability and bioactivity Gerard Bryan Gonzales 1,2,3 , Guy Smagghe 2 , Charlotte Grootaert 1 , Moises Zotti 2,4 , Katleen Raes 3 , and John Van Camp 1 1 Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Gent, Belgium, 2 Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, Gent, Belgium, 3 Department of Industrial Biological Science, Faculty of Bioscience Engineering, Ghent University, Kortrijk, Belgium, and 4 Department of Crop Protection, Laboratory of ChemoGenomics and Bioinformatics, Federal University of Santa Maria, Santa Maria, Brazil Abstract Flavonoids are a group of polyphenols that provide health-promoting benefits upon consumption. However, poor bioavailability has been a major hurdle in their use as drugs or nutraceuticals. Low bioavailability has been associated with flavonoid interactions at various stages of the digestion, absorption and distribution process, which is strongly affected by their molecular structure. In this review, we use structure–activity/property relationship to discuss various flavonoid interactions with food matrices, digestive enzymes, intestinal transporters and blood proteins. This approach reveals specific bioactive properties of flavonoids in the gastrointestinal tract as well as various barriers for their bioavailability. In the last part of this review, we use these insights to determine the effect of different structural characteristics on the overall bioavailability of flavonoids. Such information is crucial when flavonoid or flavonoid derivatives are used as active ingredients in foods or drugs. Keywords ABC transporters, amylase, flavonoids, glucuronidation, lipase, mucus layer, protein–flavonoid interaction, QSAR, sulfation History Received 10 October 2014 Revised 22 December 2014 Accepted 22 December 2014 Published online 30 January 2015 Introduction Flavonoids are a large group of secondary plant metabolites. They are the most widespread and diverse group of polyphe- nols and occur as either aglycones or conjugates with glycosides and acyl groups, wherein around 8000 different types have been identified so far (Gonzales et al., 2014a). They exert a variety of biological activities, including anti- oxidative (Fiol et al., 2012; Pietta, 2000), anti-hypertensive (Al Shukor et al., 2013; Balasuriya & Rupasinghe, 2012), anti-obesity (Hsu & Yen, 2008), anti-viral, hepatoprotective and immune-regulatory activities (Middleton et al., 2000). Albeit their health-promoting benefits, their poor oral bioavailability has been regarded as a major hurdle in using these compounds as health-promoting ingredients (Manach et al., 2004, 2005; Scalbert & Williamson, 2000; Thilakarathna & Rupasinghe, 2013). Generally, factors such as food matrix interactions, food processing, host (human)- related factors (e.g. age, occurrence of certain diseases and lifestyle) and the flavonoids’ chemical structure cause their poor oral bioavailability (D’Archivio et al., 2010). Many reviews discuss the relationship of flavonoid structure to their oral bioavailability; however, they tend to focus on a single aspect of digestion. In this article, we will follow the fate of flavonoids throughout the entire gastro-intestinal tract and in the circulation and discuss the structure–activity relationship (SAR) at every stage of this process. By investigating the stepwise interactions of flavonoids with enzymes and matrix compounds using qualitative and quantitative SAR (QSAR), we will be able to estimate the chance of survival of the compounds in the circulation and the reasons for their non- survival. In addition, we will compare various in vitro and in vivo studies and discuss certain discrepancies in flavonoid bioavailability between the two approaches. Flavonoid structure Flavonoids consist of a 15-carbon skeleton consisting of two benzene rings attached via a heterocyclic pyrane ring, labeled as rings A, B and C, in a C6-C3-C6 arrangement, as depicted in Figure 1. They are divided into several groups depending on the degree of hydroxylation, methoxylation, prenylation, glycosylation or even the attachment of the B ring (in the case of isoflavones). Flavonoids occur either as glycosides, methylated derivatives or aglycones (the basic structure). The position of the B ring may be at the C2-position in the case of most flavonoids or in the C3-position in the case of isoflavones. Common hydroxylation points are at positions 5, 7 (A ring), 3 0 ,4 0 ,5 0 (B ring), 3 and 2 (C ring). Differences also depend on the presence of the C2¼C3 double bond and Address for correspondence: Prof. John Van Camp, Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Gent 9000, Belgium. Tel: +32-(0)9 264 62 08. E-mail: John.VanCamp@UGent.be Drug Metabolism Reviews Downloaded from informahealthcare.com by Universiteit Gent on 02/03/15 For personal use only.