Chiou 2014

JOURNAL OF FUNCTIONAL FOODS x x x ( 2 0 1 3 ) x x x –x x x
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journal homepage: www.elsevier.com/locate/jff
Metabolic and colonic microbiota transformation

may enhance the bioactivities of dietary
polyphenols
Yi-Shiou Chioua, Jia-Ching Wua, Qingrong Huangb, Fereidoon Shahidic

Ying-Jan Wanga, Chi-Tang Hob,*, Min-Hsiung Pand,e,*
a
Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 704, Taiwan
b
Department of Food Science, Rutgers University, New Brunswick, NJ 08901-8520, USA
c
Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL, Canada
d
Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan
e
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
A R T I C L E I N F O A B S T R A C T
Article history: Epidemiological evidences throughout the years have indicated that consumption of phy-
Available online xxxx tochemicals may play important functions in the regulation of pathological and normal
biological processes. Polyphenols are one of the large and ubiquitous groups of phyto-
Keywords: chemicals. Dietary polyphenols are naturally present in a wide variety of fruits and vegeta-
Bioactive metabolites bles, and potentially contribute to the maintenance of human health. However, growing
Dietary polyphenols information has indicated that the bioactive compounds from polyphenols may exert ben-
Biotransformation eficial effects in part by their metabolites. The bioactive metabolites were converted by the
Chemopreventive agents gut microflora, liver microsomes and hepatocytes, and identified in intestinal, plasma,
feces, and urine after dietary ingestion. Surprisingly, recent studies suggested that many
metabolites possess more active biological functions than their precursors. In order to
explore the possibilities of metabolites in food bioactive compounds, more clear under-
standing of the metabolic pathways and the molecular targets responsible for health pro-
motion and diseases prevention are needed. In this review, we first summarize the
distribution and beneficial health activities of metabolites from dietary polyphenols. We
also discuss the available evidence on the relationship between metabolites bioefficacy
and bioavailability of their parent polyphenol compounds. We hope that this knowledge
will lead to future research to discover and develop new bioactive compounds as possible
chemopreventive agents.
2013 Elsevier Ltd. All rights reserved.
* Corresponding authors. Addresses: Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, NJ 08901, USA.
Tel.: +1 848 932 5553; fax: +1 732 932 6776 (C.-T. Ho), Institute of Food Science and Technology, National Taiwan University, No. 1,
Section 4, Roosevelt Road, Taipei 10617, Taiwan. Tel.: +886 2 33664133 (M.-H. Pan).
E-mail addresses: ho@aesop.rutgers.edu (C.-T. Ho), mhpan@ntu.edu.tw (M.-H. Pan).
1756-4646/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jff.2013.08.006
Please cite this article in press as: Chiou, Y.-S. et al., Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary
polyphenols, Journal of Functional Foods (2013), http://dx.doi.org/10.1016/j.jﬀ.2013.08.006
2 JOURNAL OF FUNCTIONAL FOODS x x x ( 2 0 1 3 ) x x x –x x x
1. Introduction Bioavailability is a complex process involving multiple

stages of liberation, absorption, distribution, metabolism
Plant polyphenols are secondary metabolites found abun- and excretion (Rein et al., 2013). The healthful properties of
dantly in a wide variety of foods, such as fruits, vegetables, bioactive polyphenol compounds depend on their bioavail-
herbs, seeds and cereals and in beverages, such as coffee, ability for intestinal absorption, metabolism, and subsequent
tea cocoa and wine (Vinson, Su, Zubik, & Bose, 2001). In recent interaction with target tissues (Stahl et al., 2002). However,
years, polyphenols have been shown to have the capacity to dietary polyphenols are mostly poorly absorbed and exten-
influence pathological and physiological processes via multi- sively biotransformed, which lead to a reduction in their bio-
ple mechanisms, including free-radical scavenging, metal availability. However, it is interesting that even with low
chelation, regulation of enzymatic activity, inhibition of cellu- bioavailability, most polyphenols still exhibit biological func-
lar proliferation and alteration of signaling transduction path- tions. Recent research has demonstrated that metabolites
ways (Liu, 2004; Vanden, 2012). Epidemiological and from dietary polyphenols might have more profound biologi-
experimental studies have highlighted the association be- cal activities than their precursors (Delmas et al., 2011; Mon-
tween the consumption of polyphenol-rich foods and their agas et al., 2010). The present review focuses on the potential
beneficial health effects (Kussmann, Affolter, Nagy, Holst, & health effects and bioactivities of metabolites from dietary
Fay, 2007). Other evidences have also indicated that dietary in- polyphenols, including resveratrol, daidzein, genistein, 6-sho-
take of polyphenols contributes to the prevention of chronic gaol, rutin, apigenin, quercetin, theaflavin-3,3 0 -digallate
diseases, such as cancers, diabetes, ulcer, cardiovascular, (TFDG), curcumin and nobiletin, and discuss molecular mech-
and other degenerative disorders in humans (Pan, Lai, & Ho, anisms on the modulation of cellular signaling events by their
2010). bioactive metabolites.
Abbreviations: AA, arachidonic acid; AD, Alzheimer’s disease; AMPK, AMP-activated protein kinase; AP-1, activator protein-1; ASCVD,
atherosclerotic cardiovascular disease; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; BID, BH3 interacting-domain;
BMD, bone mineral density; C3, complement protein 3; CAT, catalase; CDKs, cyclin-dependent kinases; CDKIs, Cdk inhibitors; C/EBP,
CCAAT/enhancer binding protein; C4HE, cis-4-hydroxyequol; CML, Ne-carboxymethyllysine; CNS, central nervous system; COX-2,
cyclooxygenase-2; CpG, cytosine phosphate guanine; CREB, cAMP response element binding protein; CV, capillary vascularity; Cx-43,
connexin-43; CYP-450, cytochrome P-450; DA, dopamine; DAT, dopamine transporter; 3,4-DHPAA, 3,4-dihydroxyphenylacetic acid; 3,4-
DHT/4MC, 3,4-dihydroxytoluene/4-methylcatechol; DHT, dihydrotestosterone; DMBA, 7,12-dimethylbenz(a)anthracene; 3 0 -DMN, 3 0 -
demethylnobiletin; 4 0 -DMN, 4 0 -demethylnobiletin; EGF, endothelial growth factor; EPCs, endothelial progenitor cells; ER, estrogen
receptor; ERK, extracellular-signal-regulated kinase; ET, endothelin; EZH2, enhancer of zeste homolog 2; FASN, fatty acid synthase; GCL,
glutamate–cysteine ligase; GDNF, glial cell line-derived neurotrophic factor; GFAP, glial fibrillary acidic protein; GI, gastrointestinal; GM,
gentamicin; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GSK-3-3b, glycogen synthase kinase-3b; GST,
glutathione S-transferases; GSTT2, glutathione S-transferase T2; 3 0 -HD, 3 0 -hydroxydaidzein; 6-HD, 6-hydroxydaidzein; 8-HD, 8-
hydroxydaidzein; HEK, human embryonic kidney; HFA, human flora associated; 3 0 -HG, 3 0 -hydroxygenistein; 6-HG, 6-hydroxygenistein;
8-HG, 8-hydroxygenistein; HMGB1, high mobility group box 1 protein; HMG-CoA, hydroxy methylglutaryl coenzyme A; HO-1, heme
oxygenase-1; H2O2, hydrogen peroxide; Homovanillic acid, 3-methoxy-4-hydroxyphenylacetic acid; HPP, 3-(4-hydroxyphenyl)-propionic
acid; HSL, hormone sensitive lipase; HUVECs, human umbilical vein endothelial cells; IBMX, isobutylmethylxanthine; ICAM-1,
intercellular adhesion molecule-1; IgE, immunoglobulin E; IGF-1, insulin-like growth factor 1; IL-1-3b, interleukin-1b; iNOS, inducible
nitric oxide synthase; JNK, c-Jun N-terminal kinases; LC3, light chain 3; LDL, low-density lipoprotein; LLC, Lewis lung carcinoma; LPL,
lipoprotein lipase; LDLr, low density lipoprotein receptor; LPO, lipid peroxidation; LPS, lipopolysaccharide; MAPK, mitogen-activated
protein kinase; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MDR, multidrug resistance; MIP-2, macrophage
inflammatory protein 2; MKK4, mitogen-activated protein kinase kinase 4; MMP, matrix metalloproteinase; mPHAA, 3-hydroxypheny-
lacetic acid; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide; NASH, non-alcoholic steatohepatitis;
NF-jB, nuclear factor-kappa B; NGF, nerve growth factor; NIK, NF-jB-inducible kinase; NO, nitric oxide; Nrf2, nuclear factor (erythroid-
derived 2)-like 2; NSAIDs, non-steroidal anti-inflammatory drugs; O-DMA, O-desmethylangolensin; OX-LDL, oxidized low-density
lipoprotein; OVA, ovalbumin; PCA, passive cutaneous anaphylaxis; PCNA, proliferating cell nuclear antigen; PD, Parkinson’s disease;
PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3-kinase; PKA, cyclic AMP-dependent protein kinase; PMN, polymorphonuclear
leukocyte; p75NTR, p75 neurotrophin receptor; PPAR-c, peroxisome proliferator-activated receptor c; PR, progesterone receptor; p70S6K,
p70 ribosomal protein S6 kinase; PTEN, phosphatase and tensin homolog deleted on chromosome ten; PUD, peptic ulcer disease; Q-3G,
quercetin 3-O-glucoside; RANTES, regulated on activation, normal T cell expressed and secreted; RASSF1, Ras association (RalGDS/AF-6)
domain family members; Rb, retinoblastoma protein; RES, resveratrol; ROS, reactive oxygen species; 6S, 6-shogaol; SIRT-1, sirtuin-1; SOD,
superoxide dismutase; SR-A, scavenger receptors-A; SRC-3, steroid receptor coactivator-3; SREBP-2, sterol regulatory element-binding
protein-2; STZ, streptozotocin; SULT, sulfotransferases; TBARS, thiobarbituric acid reactive substances; t-BHP, tert-butylhydroperoxide; t-
BOOH, tert-butyl hydroperoxide; TF(s), theaflavin(s); TFDG, theaflavin-3,3 0 -digallate; TF3G, theaflavin-3 0 -gallate; Th1, T-helper 1; THC,
tetrahydrocurcumin; 6,7,4 0 -THI, 6,7,4 0 -trihydroxyisoflavone; 7,3 0 ,4 0 -THI, 7,3 0 ,4 0 -trihydroxyisoflavone; 7,8,4 0 -THI, 7,8,4 0 -trihydroxyisofla-
vone; 5,6,7 0 ,4 0 -TEHI, 5,6,7,4 0 -tetrahydroxyisoflavone; 6,7,3 0 ,4 0 -TEHI, 6,7,3 0 ,4 0 -tetrahydroxyisoflavone; 6,7,8 0 ,4 0 -TEHI, 6,7,8,4 0 -tetrahydrox-
yisoflavone; 7,8,3 0 ,4 0 -TEHI, 7,8,3 0 ,4 0 -tetrahydroxyisoflavone; TIMPs, tissue inhibitor of metalloproteinases; TNF-a, tumor necrosis factor-
a; TNF-jB, tumor necrosis factor-jB; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TrkA, tyrosine receptor kinase A; t-
R-3,4 0 DS, trans-resveratrol-3,4 0 -disulfate; t-R-3,5DS, trans-resveratrol-3,5-disulfate; t-R-3G, trans-resveratrol-3-O-glucuronide; t-R-4 0 G,
trans-resveratrol-4 0 -O-glucuronide; TXA2, thromboxane A2; TXB2, thromboxane B2; TYR, tyrosinase; UGT, UDP-glucuronosyltrans-
ferases; VCAM-1, vascular CAM-1; VEGF, vascular endothelial growth factor; VLDL, very low-density lipoprotein; VMAT2, vesicular
monoamine transporter 2.
JOURNAL OF FUNCTIONAL FOODS x x x ( 2 0 1 3 ) x x x –x x x 3
2. Health effects of bioactive metabolites from affecting their activities and functional effects on the mam-
dietary polyphenols malian tissues (Landete, 2012; Selma, Espin, & Tomas-Barber-
an, 2009). Different studies have been carried out to
2.1. Absorption and metabolism of dietary polyphenols understand gut microbiota transformations of particular pol-
yphenol types and identify the responsible microorganisms.
About 10% of dietary polyphenols can be absorbed in the small The gut microbiota consists of a diverse collection of micro-
intestine and reach the plasma (Clifford, 2004). It has been bial species that are mostly bacterial and are commonly de-
reported that over 90% of polyphenol glucosides accumulated tected in human or animals feces. Most of the in vitro and
in the colon need to be hydrolyzed in small intestine by passive ex vivo studies on the metabolic fate of dietary polyphenols
transport after brush border membrane-bound b-glucosidases have been performed using human fecal bacteria (diluted to
(e.g., lactase phlorizin hydrolase (LPH)-dependent deglucosi- physiological cecal concentration), rat cecal contents or pig
dation) or by gut bacterial b-glucosidases which converted to cecum model.
aglycones in order to be absorbed (van et al., 2011). Once
absorbed, polyphenol aglycones are metabolized by phase I 2.1.1.1. Rutin and quercetin. Rutin (quercetin-3-O-rutinoside)
and phase II biotransformation enzymes in the gut epithelium and quercetin (3,5,7,3 0 ,5 0 -pentahydroxyflavonol) are common
and liver, such as cytochrome P-450 (CYP-450), glutathione dietary flavonoids of natural origin that are present in most
S-transferases (GST), UDP-glucuronosyltransferases (UGT) fruits, vegetables and plant-derived beverages. Several candi-
and sulphotransferases (SULT), and excreted in the urine and date bacteria for rutin metabolism have been suggested; for
bile or back into the intestine through the enterohepatic cycle example, Bacillus sp., Veillonella sp., Baceroides distasonis, Bacte-
(van et al., 2011). Subsequently, some remaining polyphenol roides uniformis and Bacteroides ovatuis (Scalbert & Williamson,
aglycones and/or metabolized derivatives enter the vascular 2000; Winter, Moore, Dowell, & Bokkenheuser, 1989; Yang
systemic circulation where they may be distributed to the et al., 2012) metabolized rutin to quercetin, quercetin 3-O-glu-
peripheral tissues, perhaps even across the blood–brain bar- coside (Q-3G), and leucocyanidin. Colonic Eubacterium ramulus
rier, or urinary excreted. Thus, each of these conversions and transformed Q-3G into 3,4-dihydroxyphenylacetic acid (3,4-
conjugations are often essential for absorption and facilitate DHPAA), acetate, and butyrate with the formation of querce-
their urinary and biliary excretion which can explain their ra- tin and phloroglucinol (1,3,5-trihydroxybenzene) as interme-
pid elimination. On the other hand, phenolic compounds can diates in human fecal samples, and germ-free and human
also interact with the gut microbiota, producing a variety of flora associated rats (Schneider, Schwiertz, Collins, & Blaut,
bioactive metabolites by carrying out ring-cleavage, reduction, 1999; Schneider, Simmering, Hartmann, Pforte, & Blaut,
decarboxylation, demethylation, and dehydroxylation reac- 2000). It has been reported that other bacteria from the fecal
tions, which varies depending on the microbial population of microbiota of humans or pig cecum microflora (Labib, Erb,
the gastrointestinal (GI) tract. Recent studies have indicated Kraus, Wickert, & Richling, 2004), including Butyrivibrio spp.
the relevance of the intestinal microbial activation of polyphe- (Krishnamurty, Cheng, Jones, Simpson, & Watkin, 1970), Clos-
nols in human health. Gut bacteria can hydrolyze glycosides, tridium orbiscindens (Winter et al., 1989) and Eubacterium oxido-
glucuronides, sulfates, amides, esters, and lactones. The reducens (Krumholz & Bryant, 1988) strains, could degrade
hydrolysis of glycosides and conjugated aglycones results in quercetin to 3,4-DHPAA, phloroglucinol and 3,4-dihydroxytol-
the formation of bioactive metabolites that are potentially uene/4-methylcatechol (3,4-DHT/4MC). Additionally, oral
more biologically active within the cells, as well as in the blood administration of rutin, 3,4-DHPAA, 3,4-DHT, 3-(m-hydroxy-
stream than their parent compounds. In fact, the process of phenyl)propionic acid, 3-hydroxyphenylacetic acid (mPHAA),
bioactive metabolites distribution is a complex interplay be- 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid,
tween the chemistry of polyphenol glycosides, metabolism of HVA) and beta-m-hydroxyphenylhydracrylic acid were also
their aglycones and the rates of transport of each form, which detected in the urine and plasma of human and rats (Baba,
may contributed to the production of the similar and/or differ- Furuta, Fujioka, & Goromaru, 1983; Baba, Furuta, Horie, &
ent metabolite profiles (Day et al., 2000). A list of the main Nakagawa, 1981; Gross et al., 1996; Sawai, Kohsaka, Nishiy-
bioactive metabolites found in gut microbiota/feces, liver ama, & Ando, 1987). However, unchanged rutin and quercetin
microsomes, plasma, urine and brain tissue is provided in were not present in the urine. Hence, the biological effects of
Tables 1–4 and discussed below. dietary polyphenols may depend on the substrate being
metabolized and the products formed.
2.1.1. Main bioactive metabolites identified from microbiota
and feces 2.1.1.2. Apigenin. Apigenin (5,7,4 0 -trihydroxyflavone) is a nat-
Most dietary polyphenols are transformed into their respec- ural flavonoid found in many foods consumed by humans.
tive aglycones and lead to the production of more or less Previous reports have shown that pig cecum model was a
active compounds. Biotransformation is an important factor suitable ex vivo model for simulating the flavonoids’ meta-
in regulating the biological activity of dietary polyphenols. bolic events taking place in the human large intestine (Labib
As mentioned above, the biological effects of polyphenol et al., 2004). In the case of apigenin, the B-ring has to be
compounds greatly rely on further degradation and transfor- hydroxylated to enable flavone degradation and yielded two
mation by specific components of the gut microbiota via metabolites 3-phenylpropionic acid and 3-(4-hydroxy-
esterase, glucosidase, hydrogenases, dehydroxylase, demeth- phenyl)-propionic acid (HPP) by the pig gut microbiota (Labib,
ylase, isomerase and decarboxylase activities, thereby Hummel, Richling, Humpf, & Schreier, 2006). Another study
modifying their bioavailability and positively or negatively indicated that apigenin 7-O-glucoside could be deglycosylated
to 3-(3,4-dihydroxyphenyl)propionic acid and HPP by a new en, Wahala, & Adlercreutz, 1999). So far, in vitro studies
species of the Lachnospiraceae (strain CG19-1) (Braune & Blaut, suggest that equol, O-DMA and 6 0 -H-O-DMA are more biolog-
2011). In addition, Karlsson et al. (2005) also identified three ically active than their precursor and/or other intermediate
phenolic compounds (3-phenylpropionic acid, 3-hydroxyphe- metabolites, such as dihydrodaidzein and tetrahydrodaidzein
nylacetic acid, and HPP) in human fecal water. (Hedlund, van, Johannes, Nordeen, & Ogden, 2006; Hwang
et al., 2006; Shinkaruk, Carreau, Flouriot, netau-Pelissero, &
2.1.1.3. Daidzein and genistein. It is believed that isoflavones Potier, 2010). These metabolites have specially been detected
have abundant health-promoting properties (Yuan, Wang, & in a variety of body fluids, including blood, urine, prostatic
Liu, 2007). However, isoflavone glucosides genistin (4 0 ,5,7-tri- fluid and breast tissue (Yuan et al., 2007). Therefore, these
hydroxyisoflavone-7-O-glucoside) and daidzin (7,4 0 -dihydr- findings show a good correlation between the manifestation
oxyisoflavone-7-O-glucoside) have higher hydrophilicity and of the daidzein/genistein-metabolizing phenotypes and the
molecular weights, which may influence their bioavailability health effects.
and physiological activity. Their bioavailability requires the
conversion of glucosides into the principal bioactive agly- 2.1.1.4. Theaflavin-3,3 0 -digallate (TFDG). Black tea, one of the
cones (daidzein and genistein) via the action of intestinal most popular beverages worldwide, is fully fermented and de-
enzymes (e.g., b-glucosidase) from bacteria. The aglycones rived from the leaves of Camellia sinensis. To date, the major
are either absorbed intact or further metabolized by intestinal bioactive theaflavins (TFs) in black tea are theaflavin (TF),
microbiota (Setchell et al., 2002; Zubik & Meydani, 2003). The theaflavin-3-gallate (TF3G), theaflavin-3 0 -gallate (TF3 0 G) and
human intestinal bacteria catalyzing the bioactivation of theaflavin-3,3 0 -digallate (TFDG) (Setchell et al., 2002). How-
daidzein (7,4 0 -dihydroxyisoflavone) via dihydrodaidzein to ever, it has been reported that theaflavin and TFDG have poor
equol (7,4 0 -isoflavandiol) have been identified: Adlercreutzia systemic bioavailability in tissue samples (small and large
equolifaciens, Slackia isoflavoniconvertens, Slackia equolifaciens, intestine, liver, and prostate), plasma and urine from mice
Eggerthella sp. and Lactococcus garvieae (Jin, Kitahara, Sakamot- and humans, respectively (Henning et al., 2006; Mulder, van
o, Hattori, & Benno, 2010; Maruo, Sakamoto, Ito, Toda, & Ben- Platerink, Wijnand Schuyl, & van Amelsvoort, 2001). Chen
no, 2008; Schroder, Matthies, Engst, Blaut, & Braune, 2013; et al. (2012) demonstrated that fecal microbiota from healthy
Yokoyama & Suzuki, 2008). The corresponding pathway of human volunteers involved in the metabolism of TFDG, and
genistein (5,7,4 0 -trihydroxyisoflavone) conversion via dihy- found two specific strains of bacteria capable of producing
drogenistein to 5-hydroxyequol has also been reported for primary and secondary metabolites through cleaving the
the human intestinal S. isoflavoniconvertens and S. equolifaciens mono- and digallate groups. Both Lactobacillus plantarum
and for Enterorhabdus mucosicola isolated from the mouse 299v and Bacillus subtilis exhibited galloylesterase, decarboxyl-
intestine (Clavel et al., 2009; Matthies, Loh, Blaut, & Braune, ase and esterases activities which have the capacity to metab-
2012). Coldham et al. (2002) reported that incubation of hu- olize TFDG into TF3G and TF3 0 G and then both TF3G and
man and rat gut microflora with [3H] and [14C] genistein TF3 0 G can be further degraded to TF, gallic acid and pyrogallol.
yielded similar radiolabelled metabolites, intermediates dihy-
drogenistein and 6 0 -hydroxy-O-desmethylangolensin (6 0 -H-O- 2.1.1.5. Curcumin. Curcumin [1,7-bis(4-hydroxy-3-methoxy-
DMA) and end-product 4-hydroxyphenyl-2-propionic acid. phenyl)-1,6-heptadiene-3,5-dione] is the major yellow pig-
Furthermore, the strain Mt1B8, rod-shaped bacterium as a ment in turmeric, derived from the rhizome of the herb
member of the Coriobacteriaceae., have been reported to be Curcuma longa Linn. Studies have found that curcumin pres-
able to transform dihydrodaidzein and dihydrogenistein to ent a low oral bioavailability in human, suggesting that the
equol and 5-hydroxyequol, respectively (Matthies et al., chemopreventive activities perhaps attributable to intestinal
2008). In contrast, the microbiota of human flora associated metabolism (Ireson et al., 2001; Sharma et al., 2001). Early re-
(HFA) rats uniformly produce equol and O-desmethylangolen- search of Pan, Huang, and Lin (1999) investigated the pharma-
sin (O-DMA) from daidzein (Bowey, Adlercreutz, & Rowland, cokinetic of curcumin in mice, and found that curcumin was
2003). Eubacterium ramulus and strain CG19-1, a flavonoid- first biotransformed to dihydrocurcumin and tetrahydrocurc-
degrading anaerobic bacterium from the human gastrointes- umin (THC). Orally administered curcumin was absorbed
tinal tract has also been reported as being responsible for from the alimentary tract and present in the general blood
cleaving the C ring of genistein and daidzein, and degraded circulation after largely being metabolized to the form of cur-
to dihydrogenistein, 6 0 -H-O-DMA, 2-(4-hydroxyphenyl)propi- cumin glucuronide, curcumin sulfate, THC, hexahydrocurcu-
onic acid and O-DMA, respectively (Braune & Blaut, 2011; Bra- min, and hexahydrocurcuminol (Asai & Miyazawa, 2000;
une, Maul, Schebb, Kulling, & Blaut, 2010; Schoefer, Mohan, Ireson et al., 2001). Curcumin sulfate was the first curcumin
Braune, Birringer, & Blaut, 2002). In a similar way, Hur et al. metabolite that identified in rat gut sacs and patient feces,
(2002) isolated a gram-positive anaerobic bacterium Clostrid- and its generation have been catalyzed by human phenol sul-
ium sp. HGH 136 from human feces capable of cleaving the photransferase isoenzymes SULT1A1 and SULT1A3 (Ireson
C-ring of daidzein to O-DMA. In addition, Yokoyama, Niwa, et al., 2002; Sharma et al., 2001). In fact, curcumin glucuronide
Osawa, and Suzuki (2010) isolated a new strain SY8519 that was identified in intestinal and hepatic microsomes, and cur-
could convert daidzein to O-DMA. Some daidzein and geni- cumin sulfate, THC, and hexahydrocurcumin were found as
stein reductive metabolites such as cis-4-hydroxyequol curcumin metabolites in intestinal and hepatic cytosol from
(C4HE), 4-ethylphenol, 2-dehydro-O-DMA, 1,3,5-trihydroxy- humans and rats. Moreover, THC was more stable than curcu-
benzene and 3-(4-hydroxyphenyl)-benzopyran-4,7-diol were min, and possessed more potent biological activities (Lai
also isolated and characterized (Coldham et al., 2002; Heinon- et al., 2011; Wu et al., 2011). Thus, it has been suggested that
the intestinal tract plays a critical role in the metabolic dispo- play a critical role in altering dietary polyphenols biological
sition of curcumin. properties. Therefore, the formation of hydroxylated metabo-
lites of polyphenol compounds may represent a metabolic acti-
2.1.2. Main bioactive metabolites identified from liver vation process in some cases.
microsomes
Most dietary polyphenols are deconjugated and transformat- 2.1.3. Main bioactive metabolites identified from plasma
ed by hydrolyzing and conjugating enzymes into phase II con- Resveratrol (3,5,4 0 -trihydroxystilbene; RES) is a secondary
jugates including methyl ethers, glucuronides and sulfates in plant metabolite found in a variety of natural foods. RES is
the liver, which are often essential for reabsorption and considered to be a preventive food compound due to its
excretion (van et al., 2011). Thereafter, increasingly reports fo- acknowledged healthy benefits such as antioxidative,
cused on the formation of oxidative metabolites, and identify anti-inflammatory and antiageing properties. Although the
what kinds of the hepatic enzymes involve in metabolism. systemic bioavailability of RES is very low, but its bioconver-
The human liver microsomes (HLM) can predominantly sion can lead to metabolites with significantly different
metabolize numerous isoflavones through hepatic cyto- chemical and biological activities. RES is absorbed and rapidly
chrome P450 (CYP) superfamily isoforms, which could modu- conjugated to yield mainly glucuronide and sulfate deriva-
late the biological activity of these dietary isoflavones. More tives through the action of UGT and SULT (e.g., aryl sulfatase)
recently, it has been demonstrated that daidzein was readily at the enterocyte and hepatocyte, respectively (Henry-Vitrac,
metabolized by rat and human hepatic microsomes (CYP1A2, Desmouliere, Girard, Merillon, & Krisa, 2006; Marier et al.,
CYP1A1, CYP2E1, CYP1A1 and CYP 1B1) to major mono- 2002). Recently, main RES metabolites, trans-resveratrol-3-O-
hydroxylated oxidative products 6 0 -hydroxy-daidzein (6-HD), sulfate (R-3S), trans-resveratrol-3-O-glucuronide (t-R-3G),
3 0 -hydroxy-daidzein (3 0 -HD), 8-hydroxy-daidzein (8-HD), trans-resveratrol-4 0 -O-glucuronide (t-R-4 0 G), trans-resveratrol-
7,3 0 ,4 0 -trihydroxyisoflavone (7,3 0 ,4 0 -THI), 6,7,4 0 -trihydroxyisof- 3,4 0 -disulphate (t-R-3,4 0 DS), trans-resveratrol-3,5-disulphate
lavone (6,7,4 0 -THI), 7,8,4 0 -trihydroxyisoflavone (7,8,4 0 -THI), (t-R-3,5DS) and t-RES-C/O-conjugated diglucuronides have
6,7,3 0 ,4 0 -tetrahydroxyisoflavone (6,7,3 0 ,4 0 -TEHI), 5,6,7,4 0 -tetra- been isolated from human plasma (Burkon & Somoza, 2008;
hydroxyisoflavone (5,6,7 0 ,4 0 -TEHI), 7,8,3 0 ,4 0 -tetrahydroxyisof- Ruotolo et al., 2013). Besides these metabolites, resveratrol
lavone (7,8,3 0 ,4 0 -TEHI) and 6,7,8,4 0 -tetrahydroxyisoflavone monoglucuronide (M1), dihydroresveratrol monosulphate
(6,7,8 0 ,4 0 -TEHI) (Atherton, Mutch, & Ford, 2006; Kulling, Leh- (M2), resveratrol monosulfate (M3) and dihydroresveratrol
mann, & Metzler, 2002; Lehmann, Esch, Wagner, Rohnstock, (M4) have also been identified and quantified in urine and fe-
& Metzler, 2005; Peng et al., 2003). Like daidzein, genistein cal samples (Walle, Hsieh, DeLegge, Oatis, & Walle, 2004;
can be metabolized by rats or human liver microsomes to Wang, Hang, Wu, & Liu, 2005). Bode et al. (2013) in vitro and
hydroxylated metabolites 3 0 -hydroxygenistein (3 0 -HG), in vivo studies with human gut microbiota demonstrated that
8-hydroxygenistein (8-HG), 6-hydroxygenistein (6-HG), two strains, Slackia equolifaciens and Adlercreutzia equolifaciens
5,6,7,4 0 -tetrahydroxyisoflavone, 5,7,8,4 0 -tetrahydroxyisoflav- are able to convert RES to 3,4 0 -dihydroxy-trans-stilbene and
one, 5,7,3 0 ,4 0 -tetrahydroxyisoflavone, 2,5,7,4 0 -tetrahydroxyi- 3,4 0 -dihydroxybibenzyl (lunularin), but their biological activ-
soflavone, 5,7,8,3 0 ,4 0 -pentahydroxyisoflavone and 5,6,7,3 0 ,4 0 - ity are not known.
pentahydroxyisoflavone (Kulling, Honig, & Metzler, 2001; Kul-
ling, Honig, Simat, & Metzler, 2000). In both human and rat 2.1.4. Main bioactive metabolites identified from urine
hepatocyte incubations, genistein was converted to glucuron- Nobiletin (5,6,7,8,3 0 ,4 0 -hexamethoxyflavone; NOB) a major
o- and sulpho-conjugates (genistein 4 0 -O-sulfate 7-O-glucuro- polymethoxyflavone found in sweet orange (Citrus sinensis)
nide, genistein 7-O-glucuronide, genistein 4 0 -O-glucuronide, peel, is currently recognized as a promising chemopreventive
genistein 7-O-sulfate and genistein 4 0 -O-sulfate) (Bursztyka agent. Bioactive metabolites of NOB are closely associated
et al., 2008). Several CYP isoforms are found in the hydroxyl- with the biological properties. It has been shown that
ation of genistein in position 3 0 and position 8 including demethyl and di-demethyl NOB hydroxylated products, such
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively. as 4 0 -demethylnobiletin (4 0 -DMN), 3 0 -demethylnobiletin
However, this phenomenon is also well established for other (3 0 -DMN) and 3 0 ,4 0 -didemethylnobiletin (3 0 ,4 0 -DDMN) were
recombinant human CYP isoforms CYP1A1, CYP1A2 and identified in rodent urine (Li, Wang, Sang, Huang, & Ho,
CYP1B1, which were predominantly involved in the produc- 2006; Yasuda et al., 2003). Other four phase II products (glucu-
tion of orobol, 6-OH and 8-OH (Breinholt, Rasmussen, Brosen, ronide and sulfate conjugates) of NOB were found in bile, ur-
& Friedberg, 2003; Roberts-Kirchhoff, Crowley, Hollenberg, & ine and serum of rats (Xu et al., 2011). It is believed that, by
Kim, 1999). undergoing metabolic biotransformation in vivo, NOB is
Other study using liver microsomes from mouse, rat, dog, extensively demethylated by hepatic CYP450 enzymes (Wang
monkey, and humans, found that 6-shogaol (6S) was metabo- et al., 2006), yielding multiple hydroxylated metabolites, that
lized to three major reductive metabolites 1-(4 0 -hydroxy-3 0 - played a predominant role in health-related effects. Thus,
methoxyphenyl)-4-decen-3-ol (M6), 1-(4 0 -hydroxy-3 0 -methoxy- the toxic effect of nobiletin bioactive metabolites should be
phenyl)-decan-3-ol (M9), and 1-(4 0 -hydroxy-3 0 -methoxy- paid more attention in further development.
phenyl)-decan-3-one (M11), as well as two new oxidative
metabolites (1E,4E)-1-(4 0 -hydroxy-3 0 -methoxyphenyl)-deca- 2.1.5. Main bioactive metabolites identified from brain tissue
1,4-dien-3-one (M14) and (E)-1-(4 0 -hydroxy-3 0 -methoxy- The role of dietary polyphenols in the regulation of neurode-
phenyl)-dec-1-en-3-one (M15) in all species (Chen, Soroka, generative/age-related diseases is an emergent topic of inves-
Zhu, & Sang, 2013). It is generally believed that CYP isoforms tigation. How phenolic compounds to cross blood–brain
barrier (BBB) and affect brain function is an interesting ques- element-binding protein-2 (SREBP-2)-mediated cholesterol
tion. Latest studies have reported that some microbial metab- biosynthesis and reducing lipid peroxidation (Soundararajan
olites formed in the feces and colon have been detected in et al., 2008). Thus, several lines of evidence clearly demon-
brain tissues. Moreover, researcher also explained the rela- strate that bioactive metabolites could help limit the oxida-
tionship between interactive roles of polyphenol metabolites tive damage.
and central nervous system (CNS). Ho et al. (2013) reported
that a phase II conjugate metabolites, Q-3G, identified in the 2.2.1.2. Anti-inflammatory effects. Chronic inflammation and
rat brain following oral dosage with a Cabernet Sauvignon infection are causally linked to multistage carcinogenic pro-
red wine, improved Alzheimer’s disease (AD)-type deficits in cess, especially in the promotion and progression stages.
hippocampal formation basal synaptic transmission and The inflammation processes lead to up-regulation of a series
long-term potentiation through mechanisms associated with of enzymes and signaling proteins in the immune or inflam-
activation of the c-Jun N-terminal kinases (JNK), extracellular- matory cells. Recent data pointed out that bioactive metabo-
signal-regulated kinase (ERK) and cAMP response element lites (3,4-DHPPA, HPP, phloroglucinol, 3 0 -DMN, 4 0 -DMN, 3 0 ,4 0 -
binding protein (CREB) signaling pathways. Quitschke, Stein- DDMN and TF) can act as modifiers of proinflammatory signal
hauff, and Rooney (2013) also evidenced that intravenous transduction pathways by inhibiting proinflammatory
intake of curcuminoids may result in more effective proce- enzymes expression such as inducible forms of nitric oxide
dures for plaque prevention and elimination, which might synthase (iNOS) and cyclooxygenase (COX-2), responsible for
be dependent on their conjugated and reductive metabolites. elevated levels of nitric oxide (NO) and prostaglandins
Data from C57BL/CH3and CV-1 mice found that curcuminoids (PGE2), respectively, and several pivotal cytokines such as
(curcumin, demethoxycurcumin and bisdemethoxycurcu- interleukin-1b (IL-1b), IL-6 and tumor necrosis factor-a (TNF-
min) and their conjugated and reductive metabolites a), mainly by acing through nuclear factor-kappa B (NF-jB),
(sulfate/glucuronide conjugates, hexa- and octahydrocurc- TNF-jB, AP-1 and mitogen-activated protein kinases (MAPK)
uminoids) can be detected in plasma and brain. Therefore, signaling (Bae, 2012; Kang, Eom, & Kim, 2013; Karlsson et al.,
the brain has to be considered as a target site of bioactive 2005; Kim & Joo, 2011; Kim & Kim, 2010; Kim, Ku, Lee, &
metabolites and deserves further research. Bae, 2012, Li et al., 2007; Miene, Weise, & Glei, 2011; Monagas
et al., 2009; Morikawa et al., 2003). Recent evidence also exhib-
2.2. Biological functions of bioactive metabolites ited that phloroglucinol and daidzein metabolite (7,3 0 ,4 0 -THI)
provided photoprotective effect and prevention of skin cancer
2.2.1. Cancer prevention and therapeutic activities (Fig. 2) via inhibiting Cot and MKK4 kinase activity directly, activator
2.2.1.1. Detoxification, antioxidant and cytoprotection. Many protein-1 (AP-1)-mediated matrix metalloproteinases (MMP)-1
recent studies have demonstrated the role of oxidative stress expression, and elevated SOD and CAT levels, as well as sup-
in carcinogenesis. Oxidative stress can result in injury to all pressed COX-2 expression in UVB-induced keratinocytes and
the important cellular components like proteins, DNA and mouse epidermal cells (Kim, Piao, Cho, Lee, & Hyun, 2012; Lee
lipids, which compromises cell viability and functions (Wein- et al., 2011a; Piao, Zhang, Lee, & Hyun, 2012). Collectively,
berg & Chandel, 2009). Sources of oxidative stress include these results suggest that bioactive metabolites may poten-
detoxifying enzymes, reactive oxygen species (ROS), nicotin- tially be useful for the treatment of inflammation associated
amide adenine dinucleotide (NADPH), UV radiation, chemical with diseases and cancer.
compounds (e.g., environmental pollutants, smoking and
alcohol), and exercise (Sosa et al., 2013). In tert-butyl hydro- 2.2.1.3. Anti-proliferative, apoptosis and autophagy
peroxide (t-BOOH)-stimulated human HepG2 cells, radiation- effects. Uncontrolled cell proliferation is characteristic of
exposed mice and high cholesterol-fed rats, quercetin and transformed and malignant cells. Therefore, the regulation
apigenin metabolites (phloroglucinol and HPP) could protect of cell cycle progression, induction of apoptosis and autoph-
against oxidative stress/damage and cell death by reducing agy are important strategies for chemoprevention in the
ROS production and restoring glutathione reductase (GR), multistage carcinogenesis. The progression of the cell cycle
reduced glutathione (GSH), glutathione peroxidase (GPx), is comprised of five sequential stages: G0, G1, S, G2 and M,
erythrocyte superoxide dismutase (SOD) and catalase (CAT) which are regulated by cyclin-dependent kinases (CDKs) and
levels (Kang et al., 2010; Lee et al., 2003; Queguineur et al., cyclins, Cdk inhibitors (CDKIs), and check point kinases
2012; Kim et al., 2012a). Equol also inhibited apoptosis and (Chk 1 and Chk 2) (Malumbres & Barbacid, 2009). Apoptosis
ROS generation that prevented oxidized low-density lipopro- (type I programmed cell death) and autophagy (type II pro-
tein (OX-LDL)-stimulated damage in human umbilical vein grammed cell death) are multi-step, multipathway and highly
endothelial cells (HUVECs) (Kamiyama, Kishimoto, Tani, Uts- ordered processes that are a necessary part of the develop-
unomiya, & Kondo, 2009). Besides blocking the production of ment and homeostasis of multicellular organisms. Studies
ROS, 3,4-DHTwere shown to inhibit hepatocellular cholesterol have demonstrated that autophagy and apoptosis are tumor
biosynthesis (Glasser, Graefe, Struck, Veit, & Gebhardt, 2002) suppressors that may be initiated by a variety of stimuli and
and exerting excellent antilipoperoxidant activity (Pavlica & triggered by common upstream signals including phosphati-
Gebhardt, 2010) that prevented tert-butylhydroperoxide (t- dylinositol 3-kinase (PI3K)/mammalian target of rapamycin
BHP), hydrogen peroxide (H2O2) and iron (FeSO4)-induced (mTOR) Ser/Thr kinase and tumor necrosis factor receptor
damage. In oxidative stress model, rutin metabolite, Q-3G (TNFR) superfamily, such CD95/Fas, TNFR or TRAILR (Maiuri,
protected neuroblastoma (SH-SY5Y) cells against H2O2-in- Zalckvar, Kimchi, & Kroemer, 2007). Equol, 7,3 0 ,4 0 -THI, 6,7,4 0 -
duced oxidative stress by inducing sterol regulatory THI and M14 are produced from daidzein and 6-shogaol via
the actions of gut bacteria or hepatic enzymes, respectively. MMP-9 activities by upregulation of tissue inhibitor of
These metabolites (equol, 7,3 0 ,4 0 -THI, 6,7,4 0 -THI and M14) metalloproteinases (TIMPs) level and downregulation of AP-
have been reported to induce apoptosis and cell cycle arrest 1 transcription activity (Kong et al., 2008; Magee, Allsopp,
in a variety of cancer cells by activation of tumor necrosis Samaletdin, & Rowland, 2013; Zheng et al., 2012). Likewise,
factor-related apoptosis-inducing ligand (TRAIL) (extrinsic numerous laboratories have illustrated that vascular endo-
pathway) and mitochondria (intrinsic pathway) signaling thelial growth factor (VEGF) plays a pivotal role in cancer
pathways and inhibition of Akt/glycogen synthase kinase-3b and endothelial cell growth, migration, angiogenesis, and also
(GSK-3b)/AP-1 pathway through binding to CDK2, CDK4 and increases vessel permeability (Eichholz, Merchant, & Gaya,
phosphatidylinositol 3-kinase (PI3K) kinase (Atherton et al., 2010). Kwon et al. (2012) and Yoysungnoen, Wirachwong,
2006; Kim & Kim, 2013; Lee et al., 2010; Liu, Suzuki, Santosh Changtam, Suksamrarn, and Patumraj (2008) have reported
Laxmi, Okamoto, & Shibutani, 2012; Lo, Wang, & Ho, 2012). that quercetin and curcumin metabolites (phloroglucinol
The antiandrogenic and estrogenic properties of equol are and THC) could attenuate tumor growth and angiogenesis
unique in that equol specifically binds 5a-dihydrotestosterone by disrupting VEGF-dependent migration and capillary-like
(DHT) and estrogen receptor (ER) b with high affinity, and is tube formation of endothelial progenitor cells (EPCs). Overall,
beneficial for preventing growth of reproductive tumor tissues it is suggested that bioactive metabolites represent a common
(Lehmann et al., 2005; Lund et al., 2004; Rannikko et al., 2006). potential mechanism for their anti-cancer actions.
In addition, equol presented breast cancer inhibitory capacity
through modification of epigenetic mechanisms such as DNA 2.2.2. Chronic human diseases prevention (Fig. 3)
methylation, histones demethylation, and acetylation 2.2.2.1. Obesity, atherosclerotic cardiovascular disease
(Bosviel, Durif, Dechelotte, Bignon, & Bernard-Gallon, 2012; (ASCVD), and metabolic disorders. Majority of obese individu-
Dagdemir, Durif, Ngollo, Bignon, & Bernard-Gallon, 2013). als develop many metabolic disorders. The metabolic syn-
According to a previous report, THC may be more effective drome is a constellation of metabolic risk factors that
than its precursor curcumin in preventing tumor cell prolifer- consist of hypercholesterolaemia, hypertension and hyper-
ation through inhibition of connexin-43 (Cx-43) expression glycaemia. Numerous studies indicate that the presence of
and Wnt-1/b-catenin signaling pathways activation (Lai metabolic syndrome is associated with increased risk of car-
et al., 2011), and induction of autophagy signaling pathway diovascular disease, type 2 diabetes, hypertension and fatty
(Wu et al., 2011). The effects of genistein and rutin metabo- liver disease (Nikolopoulou & Kadoglou, 2012). In addition, it
lites (6 0 -H-O-DMA, 3,4-DHT and 3,4-DHPAA) on the inhibition is clear that inflammation participates in the link between
of cell growth by downregulation of anti-apoptotic protein obesity and metabolic disease. Lasa, Churruca, Eseberri,
Bcl-2 as well as pro-survival Akt signaling, arresting cells ndres-Lacueva, and Portillo (2012) reported that the anti-obes-
cycle at G2/M phase and inducing apoptosis that is mediated ity effects of resveratrol metabolites (R-3S, t-R-3G and t-R-4 0 G)
by activation of the caspase-3 apoptotic cascade (Gao et al., are elicited through the inhibition of CCAAT/enhancer bind-
2006; Hedlund et al., 2006; Morita, Arimochi, & Ohnishi, ing protein (C/EBP)-a and -3b, peroxisome proliferator-acti-
2003; Payton, Bose, Alworth, Kumar, & Ghosh, 2011). Further- vated receptor c (PPAR-c), fatty acid synthase (FASN) and
more, Polycarpou et al. (2013) also reported that resveratrol lipoprotein lipase (LPL) expression and induction of sirtuin
metabolites (t-R-3G and t-R-4 0 G) induced G1 arrest in human (SIRT-1) and hormone sensitive lipase (HSL) mRNA levels. In
colorectal cancer cells via cyclin D1 depletion, AMP-activated ovariectomized (OVX) mice, daidzein metabolites, O-DMA
protein kinase (AMPK) phosphorylation and A3 adenosine and equol slightly inhibited bone and lipid metabolism and
receptor activation. However, in the case of R-3S, but not might be helpful to human health (Ohtomo et al., 2008). More
other metabolites, it is endowed with anti-estrogenic activity recently, daidzein, genistein, quercetin, nobiletin and TFDG
by interacting with human receptors (hER-a and -b) that result metabolites (6-HD, O-DMA, 3 0 -HG, phloroglucinol 4 0 -DMN,
in suppression of cell growth (Ruotolo et al., 2013). These 3 0 ,4 0 -DDMN and TF) with strong anti-inflammatory and anti-
results clearly demonstrated the suppressive effects of oxidant activities, have been shown to be effective in amelio-
metabolites from dietary polyphenols on tumor proliferation. rating metabolic syndrome and preventing atherosclerosis
and cardiovascular diseases in in vitro and in vivo models
2.2.1.4. Anti-angiogenesis and anti-metastasis (Chang et al., 2012; Eguchi, Murakami, Li, Ho, & Ohigashi,
effects. Metastasis, or the spread of cancer from its primary 2007; Lo et al., 2010; Mueller, Hobiger, & Jungbauer, 2010;
site to a distant organ, is not only promoting cancer progres- Mueller & Jungbauer, 2008; Ohtomo et al., 2008; Wang et al.,
sion but also the major cause of morbidity and mortality for 2012). In addition, 3,4-DHT was shown to reduce plasma glu-
cancer patients (Duffy, McGowan, & Gallagher, 2008). Tradi- cose and prevent apoptosis by significant inhibition of Ras
tionally, metastatic steps include dissociation of tumor cells association (RalGDS/AF-6) domain family members (RASSF1
in the primary tumor, local invasion, angiogenesis, intravasa- and NORE1) expression and regulation of nerve growth factor
tion of invading cells into the vasculature or lymphatic (NGF)/tyrosine receptor kinase A (TrkA) system which may
systems, survival in these channels, extravasation, and prolif- block NGF/p75 neurotrophin receptor (p75NTR) activation in
eration at a distant site (Nguyen & Massague, 2007). At each pancreatic b cells of hyperglycemic rats (Gezginci-Oktayoglu
metastatic step, tumor cells can be modulated by microenvi- & Bolkent, 2011; Gezginci-Oktayoglu & Bolkent, 2012).
ronmental factors, including interactions with variety mole- Moreover, lipid peroxidation and glycation product formation
cules like proteolytic enzymes (e.g., MMPs), growth factors also contribute to an increased risk for developing diabetes
and angiogenic factors. Rutin and daidzein metabolites mellitus. Indeed, rutin metabolites 3,4-DHT, 3,4-DHPAA,
(Q-3G and equol) have been shown to inhibit MMP-2 and quercetin and Q-3G have been shown in antidiabetic and
8
Table 1 – Molecular targets of bioactive metabolites from microbiota and feces.
Chemical structure
Experimental models Molecular mechanism(s) of targets (refs)
Original compound Metabolites
Human intestinal Rutin 3, 4-DHPAA Lipopolysaccharide (LPS)-stimulated Blocks tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β
(Winter et al., peripheral blood mononuclear cells production (Monagas et al., 2009)
1989; Yang et al., (PBMC)
2012; Monagas et tert-butylhydroperoxide (t-BHP), Cytoprotection and antilipoperoxidant activity by reducing reactive
al., 2009) 3, 4-DHT hydrogen peroxide (H2O2) and iron oxygen species (ROS) and malondialdehyde (MDA) production
(FeSO4)-induced neuronal PC12 cells (Pavlica & Gebhardt, 2010)
JOURNAL OF FUNCTIONAL FOODS

Glucose-induced collagen-linked Inhibits the formation of pentosidine, argpyrimidine histone H1 and
fluorescent adduct Nε-carboxymethyllysine (CML) adducts, glucose autoxidation and
Quercetin glycation of collagen I (Cervantes-Laurean et al., 2006; Pashikanti et
al., 2010)
t-BHP-stimulated liver parenchymal and Increases antioxidative activity and inhibits hepatocellular cholesterol
human hepatocellular carcinoma HepG2 biosynthesis (Glasser et al., 2002)
cells
Carrageenan-induced inflammation in Reduces prostaglandin E2 (PGE2), TNF-α, regulated on activation,
Q-3G rats normal t cell expressed and secreted (RANTES), macrophage
inflammatory protein 2 (MIP-2) contents and cyclooxygenase-2
(COX-2) mRNA level (Morikawa et al., 2003)
Ovalbumin (OVA)/aluminum hydroxide Suppresses neutrophil and mononuclear cell numbers and IL-5 level
challenged BALB/c mice (Rogerio et al., 2007; Joskova et al., 2011)
Alloxan-induced hyperglycemia and Inhibits hepatic glucose-6-phosphatase activity and increases
lipid peroxidation (LPO) in rats antioxidative enzymes activities, such as catalase (CAT), superoxide
x x x ( 2 0 1 3 ) x x x –x x x
dismutase (SOD) and glutathione (GSH) content (Panda & Kar, 2007)
Leucocyanidin 12-O-tetradecanoylphorbol-13-acetate Reduces activator protein-1 (AP-1), matrix metalloproteinases
(TPA)-induced human fibrosarcoma (MMP)-9 and MMP-2 activities and enhances tissue inhibitor of
HT1080 cells metalloproteinase-1 (TIMP-1) level (Kong et al., 2008)
Calpeptin-stimulated neurite retraction Stimulates neuronal differentiation via reducing multiple Rho GTPase
in NG108-15 cells mechanisms (Palazzolo et al., 2012)
Ear passive cutaneous anaphylaxis Antiallergic effect (Makino et al., 2013)
(PCA) reaction in OVA-tread mice
H2O2-induced oxidative stress in Promotes sterol regulatory element-bindingprotein-2 (SREBP-2)
SH-SY5Y cells activation and inhibiting low density lipoprotein receptor (LDLr)
expression (Soundararajan et al., 2008)
Aspirin-induced gastric mucosa erosions Anti-ulcer activity (Lewis & Shaw, 2001; Prabha et al., 2011)
in Wistar rats
Pig caecum Apigenin HPP High cholesterol-fed rats Increases erythrocyte SOD and CAT activities, and GSH level, reduces
(Labib et al., 2006) hepatic thiobarbituric acid reactive substances (TBARS) level and
glutathione peroxidase (GSH-Px) (Lee et al., 2003)
Melanin synthesis in human embryonic Inhibits tyrosinase (TYR) activity (Kim et al., 2011)
kidney (HEK) 293 cells
TNF-α-stimulated human colon cancer Decreases COX-2 protein expression (Karlsson et al., 2005)
HT-29 cells
Pig caecum and Quercetin 3, 4-DHPAA LNCaP prostate cancer and colon cancer Antiproliferative activity (Gao et al., 2006)
human intestinal HCT-116 cells
(Krumholz & Detoxification and inflammation in Increases glutathione S-transferase T2 (GSTT2) expression and
Bryant, 1988; human colorectal adenoma cells LT97 reduces COX-2 expression (Miene et al., 2011)
Labib et al., 2004) Phloroglucinol Radiation-induced cell damage in Protects oxidative damage by decreasing intracellular ROS and
Chinese hamster lung fibroblasts (V79-4) restores GSH level and glutamate-cysteine ligase (GCL) protein
cells and γ-rays exposed BALB/c mice expression. Anti-apoptotic effects via inhibition of mitogen-activated
protein kinase kinase 4 (MKK4), c-Jun N-terminal kinase (JNK) and
AP-1cascades, reversion of mitochondrial membrane action potential,
3, 4-DHT reduction of the caspase-9 and -3 activities, and induction of Bcl-2

expression (Kang et al., 2010)
Lymphocytes were isolated from mice Enhances immune responses by inciting the lymphocytes proliferative
spleens activity and IL-2 secretion through activation of extracellular-
signal-regulated kinase (ERK), JNK, p38, and nuclear factor-kappa B
(NF-κB) pathways (Ahn et al., 2010)
LPS-induced RAW264.7 or HepG2 cells Blocks TNF-α,IL-6, IL-1β, PGE2 and ROS levels, MMPs activities,
and TPA or H2O2- stimulated human and increases GSH level via inhibition of NF-κB-inducible kinase
fibrosarcoma HT1080 cells (NIK), AP-1 and ERK signaling pathways (Kim & Kim, 2010; Kang et
al., 2013)
LPS or high mobility group box 1 protein Inhibits cellular permeability, monocytes adhesion, and migration by
(HMGB1)-induced HUVECs and THP-1 suppression of adhesion molecules expression intercellular adhesion
monocyte cells molecule-1 (ICAM-1) and vascular CAM-1 (VCAM-1), E-selectin,
p38 phosphorylation and NF-κB and tumor necrosis factor-κB
(TNF-κB) release (Bae, 2012; Kim et al., 2012c)
Endothelial progenitor cells (EPCs) and Inhibits vascular endothelial growth factor (VEGF)-induced tumor
x x x ( 2 0 1 3 ) x x x –x x x
Lewis lung carcinoma (LLC)-tumor- growth and angiogenesis (Kwon et al., 2012)
bearing mice
H2O2-induced neurotoxicity in murine Reduces ROS, lipid peroxidation, Ca2+ release,8-isoprostane, protein
hippocampus neuronal HT22 and carbonylation, and 8-hydroxy deoxyguanine (8-OhdG) levels and
neuroblastoma SH-SY5Y cells or raises cell viability (Kang et al., 2012; Kim et al., 2012a; Ahn et al.,
amyloid beta peptide (Aβ) oligomers- 2012)
induced toxicity in PC12 cells
tert-butylhydroperoxide (t-BOOH) Represses ROS, MDA and Glutathione-S-transferase (GST) contents
-stimulated HepG2 cells and enhances GSH, glutathione peroxidase (GPx) and glutathione
reductase (GR) levels (Queguineur et al., 2012)
UVB-induced human HaCaT Protects cell viability and damage via inhibiting MMP-1 and AP-1
keratinocytes activities, ROS, 8-isoprostane and Ca2+ levels and mitogen-activated
protein kinases (MAPK s) activation, and elevating SOD and CAT
activities (Piao et al., 2012; Kim et al., 2012b)
Arachidonic acid (AA)-induced rabbit Attenuates ROS, COX, thromboxane A2 (TXA2) and PGE2 production
platelets aggregation and thromboxane and bates ERK and p38 phosphorylation (Chang et al., 2012)
9
10
B2 (TXB2) production ; TPA-stimulated

polymorphonuclear leukocyte (PMN) or
IL-1β-induced pulp fibroblasts
Ionizing radiation-caused small intestinal Augments antiapoptotic protein Bcl-2 and Bcl-XS/L expression and
damage in mice reduces proapoptotic protein p53, Bax, and Bak levels (Ha et al., 2013)
Sciatic nerve was crushed injury in mice Promotion of cutaneous nerve regeneration through increasing the
or gentamicin (GM)-treated mice expression of nerve growth factor (NGF) and glial cell lineY derived
neurotrophic factor (GDNF) (Kimura et al., 1999; Hsieh et al., 2009)
H2O2-induced neural stem/progenitor Neuroprotective effect by induction of heme oxygenase-1(HO-1)
cells (NS/PCs) expression and activation of ERK and phosphatidylinositol 3-kinase
(PI3K) /Akt signaling pathways (Furukawa et al., 2010)
Streptozotocin (STZ)-triggered Blocks plasma glucose, β cell apoptosis, caspase-8/-3 activation and
hyperglycemic rats Ras-association domain family (RASSF/NORE) 1expression and

increases NGF+, tyrosine receptor kinase A (TrkA)+ p75 neurotrophin
receptor (p75NTR)+ and TNF-α+ pancreatic β cell numbers
(Gezginci-Oktayoglu & Bolkent, 2012; Gezginci-Oktayoglu &
Bolkent, 2011)
Brain-derived neurotrophic factor Augments BDNF production and normalizes ERK activation
(BDNF)-caused pain–emotion (Fukuhara et al., 2012)
Human melanoma cells (Sbcl2 and Arrests cell cycle G2/M phase and induces apoptosis through
1205Lu) or murine tumor cells (PC12, upregulation of Bax and caspases-3 expression and cytochrome C.
B16, C6 and LL/2) release, and inhibition of Bcl-2 and Akt levels (Payton et al., 2011;
Morita et al., 2003)

Human and rats Genistein 6'-H-O-DMA Human prostate cancer LNCaP cells Reduces cell growth by induction of caspase-3 activation (Hedlund et
intestinal al., 2006)
(Matthies et al.,
2008; Matthies et
al., 2009)
x x x ( 2 0 1 3 ) x x x –x x x
Human, SIA rats Daidzein Equol Ovariectomized (OVX) SD rats Increases uterine insulin-like growth factor 1 (IGF-1), progesterone
(Matthies et al., receptor (PR) and complement protein 3 (C3) mRNA levels and
2012) promotes proliferating cell nuclear antigen (PCNA)-positive cells in
the uterine stroma (Rachon et al., 2007)
Mt1B8 mice O-DMA OVX mice and 1α,25(OH)2D3 induced a Maintains bone mineral density (BMD) and inhibits whole body fat
(Matthies et al., co-culture system of mouse bone-marrow mass, plasma lipids and osteoclast formation (Ohtomo et al., 2008)
2008) cells with primary osteoblastic cells
Oxidized low-density lipoprotein Inhibited apoptosis and ROS generation by decreasing NAD (P) H
(OX-LDL)-stimulated apoptosis in oxidase and increasing NO production (Kamiyama et al., 2009)
HUVECs
Human breast cancer cell lines Decreases in the methylation of the cytosine phosphate guanine (CpG)
(MDA-MB-231 and MCF-7) and islands and histone (H3K27me3, H3K9me3, H3K4me3), and promotes
mammary epithelial MCF-10A cells histone acetylation (H4K8ac and H3K4ac), leading to increase breast
Table 1 (continued)
cancer susceptibility (BRCA1and BRCA2), enhancer of zeste homolog

2 (EZH2), ERα, ERβ, steroid receptor coactivator-3 (SRC-3) and P300
genes expression (Bosviel et al., 2012; Dagdemir et al., 2013)
OVA-specific T cell and B cell responses Elevates immunoglobulin E (IgE) and IL-13 production (Sakai et al.,
in BALB/c mice 2010)
Human prostate cancer DU145 and Decreases cell migration and invasion via activating phosphatase and
human breast cancer MDA-MB-231 cells tensin homologue deleted on chromosome ten (PTEN), SOD and
nuclear factor (erythroid-derived 2)-like 2 ( (Nrf2) and reducing
malondialdehyde (MDA), urokinase-type plasminogen activator,
MMP-2 and -9 levels (Magee et al., 2013; Zheng et al., 2012)
Human breast cancer MCF-7 cells Suppresses tumor growth by inducing caspase-3 expression (Liu et al.,
xenograft in nude mice and 2012)
7,12-dimethylbenz(a)anthracene

(DMBA)-induced mammary tumors
Human endometrial carcinoma Ishikawa Antiandrogenic and estrogenic properties via binding
cells and prostate cancer patients 5α-dihydrotestosterone (DHT) and estrogen receptor (ER)
β (Rannikko et al., 2006; Lund et al., 2004; Lehmann et al., 2005)
Human TFDG TF Rat pheochromocytoma PC12 cells Inhibits toxic amyloid-β and α-synuclein fibrils formation (Grelle et
(Chen et al., 2012) al., 2011)
Homocysteine-induced injury in human Increases the cell viability and alleviates DNA damage through
umbilical vein endothelial cells reducing MDA and endothelin (ET)-1 and raising GSH-PX, SOD,
(HUVECs) nitric oxide (NO) and nitric oxide synthase (NOS) (Wang et al., 2012)
1-methyl-4-phenyl-1,2,3,6-tetrahydropyri Reduces IL-1β, IL-6, TNF-α, IL-4, IL-10, glial fibrillary acidic protein
dine (MPTP)-induced dopaminergic (GFAP), COX-2 and Bax levels, improves motor behavior and
neurodegeneration and neurotoxicity in expression of nigrostriatal dopamine transporter (DAT), vesicular
TF3G mice monoamine transporter 2 (VMAT2), and Bcl-2 (Anandhan et al.,
2012b; Anandhan et al., 2012a)
Ischemia-reperfusion (I/R) injury in a Abates hepatic steatosis, oxidative stress, inflammation and hepatocyte
x x x ( 2 0 1 3 ) x x x –x x x
mouse fatty liver model, primary apoptosis by decreasing ROS and TNF-α production (Luo et al., 2012)
hepatocytes and LPS-stimulated
RAW264.7 cells
LPS-bone marrow cells were isolated Blocks IL-6, monocyte chemoattractant protein-1 (MCP-1), and
from ICR mice ICAM-1 expression through blockade of NF-κB and MAPK signaling
TF3'G pathways (JNK, p38 and ERK) (Kim & Joo, 2011)
11
antiperoxidative effects by decreasing glycation products for-

mation and activating antioxidative enzymes content, such
as CAT, SOD and GSH (Cervantes-Laurean et al., 2006; Panda
and hyper-permeability) and capillary vascularity (CV) (Yoysungnoen

& Kar, 2007; Pashikanti, de Alba, Boissonneault, & Cervan-
synthase kinase-3β (GSK -3β) proteins expression and downregulates
Induces autophagy through exalting light chain 3 (LC3) II, beclin-1,

Increases dopamine (DA) and DOPAC (3,4-dihydroxyphenyl acetic
Reduces blood glucose, plasma insulin, serum and liver cholesterol,
E R K and Wnt-1/β-catenin signaling pathways activation (Lai et al.,

Attenuates pathologic features (microvascular dilatation, tortuosity,
PI3K/Akt/mammalian target of rapamycin (mTOR), p70 ribosomal

triglycerides, free fatty acids, phospholipids, HMG CoA reductase
tes-Laurean, 2010). In another study, the antidiabetic and
acid) contents and inhibits monoamine oxidase (MA O-B ) activity
Decreases iNOS, COX-2, connexin-43 (Cx-43) and p- glycogen
p-ERK and p-JNK expression and bolcking phosphorylation of

activity, very low-density lipoprotein (VLDL) and low-density
antihyperlipidemic effects of THC were found to be more po-

lipoprotein (LDL) cholesterol levels (Pari & Murugan, 2007)
protein S6 kinase (p70S6K) and p38 levels (Wu et al., 2011)

tent than its precursor curcumin. THC could significantly
attenuate serum and liver cholesterol, triacylglycerols, free
fatty acids, phospholipids, hydroxy methylglutaryl coenzyme
A (HMG-CoA) reductase activity, very low-density lipoprotein
(VLDL) and low-density lipoprotein (LDL) cholesterol levels
(Pari & Murugan, 2007). A recent report revealed that most
chronic liver diseases are characterized by the presence of
inflammatory and oxidative stress processes with enhanced
(R ajeswari & Sabesan, 2008)
expression of various pro-inflammatory cytokines and lipid

mediators (Ferre & Claria, 2006). In the non-alcoholic steato-
hepatitis (NASH) model, TF as metabolite of TFDG has been
found to relieve liver steatosis, oxidative stress, inflammation
and hepatocyte apoptosis by down-regulation of TNF-a and
et al., 2008)
ROS production (Luo et al., 2012). Therefore, we conclude that

2011)
bioactive metabolites have protective effects against obesity

and metabolic disorders-related diseases by antioxidant,
anti-inflammatory, and anti-apoptotic mechanisms.
STZ-nicotinamide-induced diabetic rats
Human promyelocytic leukemia HL-60

Azoxymethane (AOM)-induced colon
MPTP-induced Parkinson's disease in
2.2.2.2. Neurodegenerative diseases. Recent studies have dem-

HepG2 cells and xenograft model in
onstrated that the severity of cerebrovascular diseases,

including amyloid diseases such as Alzheimer’s and Parkin-
son’s disease (PD) and other nervous system pathologies, cor-
carcinogenesis in mice
relate with inflammation-mediated responses in neural cells

BALB/c nude mice
(Britschgi & Wyss-Coray, 2007). Moreover, microglia activation

is one of the causative factors in neuroinflammation, which
results in brain damage during neurodegenerative disease.
In vitro and in vivo studies have shown that nobiletin and
mice
cells
TFDG metabolites (4 0 -DMN, 3 0 ,4 0 -DDMN, TF, TF3G, and TF3 0 G)

and THC can prevent PD and Alzheimer’s disease by inhibit-
ing monoamine oxidase (MAO-B) activity, oxidative stress
and amyloid synuclein fibrils formation and upregulating
anti-apoptosis and anti-inflammation signaling pathways
and thereby exerting memory-enhancing actions (Al et al.,
2009; Anandhan, Janakiraman, & Manivasagam, 2012a;
Anandhan et al., 2012b; Grelle et al., 2011; Rajeswari & Sabe-
san, 2008; Su et al., 2012). Previous studies have also shown
THC
that quercetin metabolites (3,4-DHT and phloroglucinol) and

Q-3G possess neuroprotective properties and ameliorate neu-
ropathic pain by promoting neurite elongation, differentia-
tion and regeneration, and augmenting brain-derived
neurotrophic factor (BDNF) production, respectively (Ahn,
Moon, Kim, Jung, & Choi, 2012; Fukuhara et al., 2012; Furuka-
wa et al., 2010; Hsieh, Lin, Lue, Chang, & Hsieh, 2009; Kang
et al., 2012; Kim, Lee, Kang, Lee, Hyun, & Kim, 2012; Kimura,
Curcumin
Nishizaki, Orita, & Masuda, 1999; Palazzolo, Horvath, & Zeno-

bi-Wong, 2012). These results obtained in manifold models
highlight the potential of bioactive metabolites to finely regu-
lated neurological function that may delay the onset of age
Sharma et al., 2001;
(Ireson et al., 2001;
Asai & Miyazawa,

Ireson et al., 2002;
related amyloid diseases.

2000; Pan et al.,
Human and rats
2.2.2.3. Peptic ulcer disease (PUD). Major causes of PUD are

1999)
stressful lifestyle, alcohol consumption, use of steroidal and

nonsteroidal anti-inflammatory drugs (NSAIDs), infections,
smoking, lower socioeconomic status and family history
Table 2 – Molecular targets of bioactive metabolites from liver microsomes (LM).
Chemical structure
Human Daidzein 6-HD Human colon cancer HCT-116 and Reduces cell growth by inhibiting of cyclin-dependent kinase
(Atherton et al., DLD1 cells (CDK)1 and CDK2 activities and activating of caspase 3 (Lee et al.,
2006; Peng et al., 2011b)
2003; Pfeiffer et al., LPS-induced macrophages RAW 264.7 Reduces PPAR γ and PPARα activities and IL-6 and TNF-α levels,
2005) cells and GAL4-peroxisome proliferator increases IL-10 secretion (Mueller & Jungbauer, 2008; Mueller et
7, 3', 4'-THI -activated receptor (PPAR)α and γ al., 2010)
Rats transfected-NIH-3T3 cells
(Kulling et al., 2000; Human breast cancer MCF-7 cells and Induces apoptosis through the ROS-dependent suppression of
Kulling et al., 2002) human cervical cancer HeLa cells multidrug resistance (MDR) transporters and the upregulation of
p53, Bax, and caspase-9 (Lo et al., 2012; Atherton et al., 2006)
Endothelial growth factor Decreases neoplastic transformation and cell cycle progression by

6, 7, 4'-THI
(EGF)-induced JB6 P+ mouse epidermal inhibiting G1 phase-regulatory proteins expression, including cyclin
cells D1, CDK4, cyclin E, and CDK2 and retinoblastoma protein (Rb)
phosphorylation (Ser-795 and Ser-807/Ser-811) and binding to
CDK2, CDK4 and PI3K and thereby blocking its kinase activity and
the Akt/GSK -3β/AP-1 pathway (Lee et al., 2010)
UVB-induced JB6 P+ mouse epidermal Inhibits COX-2 expression through inhibiting NF-κB transcription
cells and UVB-induced tumors in activity and blocking mitogen-activated MKK4 and Cot activity via
hairless mouse skin docking to the ATP binding site of Cot and MKK4, thereby
suppressing UVB-induced MAPK phosphorylation, including JNK
and p38 (Lee et al., 2011a)
Human and rats Genistein 3'-HG GAL4-PPARα and γ transfected- Resists PPARγ and PPARα activities (Mueller & Jungbauer, 2008;
(Kulling et al., 2001; NIH-3T3 cells Mueller et al., 2010)
Bursztyka et al.,
2008)
x x x ( 2 0 1 3 ) x x x –x x x
Mouse, rat, dog, 6-shogaol M14 Human colon cancer HCT-116 and Inhibits cell growth and induces apoptosis (Chen et al., 2013)
monkey and human human nonsmall lung cancer H-1299
(Chen et al., 2013) cells
13
Fig. 1 – Schematic represents of health promotion efficiency of metabolites from food bioactive compounds.
(Bandyopadhyay, Biswas, Bhattacharyya, Reiter, & Banerjee, and equol may exert potent inhibitory activities through
2001). Peptic ulcer is a sore that forms in the lining of the suppression of immune cell number and IL-5 level and
stomach, duodenum or both, caused by local inflammation, heightening IgE and IL-13 production (Joskova, Franova, &
which leads to a well-defined mucosal defect. Therefore, res- Sadlonova, 2011; Makino et al., 2013; Rogerio et al., 2007; Sakai
toration of the balance between offensive factors like acid, et al., 2010). Additionally, phloroglucinol markedly enhanced
pepsin and defensive factors like NO and growth factor may the immune responses by stimulating the lymphocytes prolif-
be a promising strategy for the treatment of PUD. It has been eration and IL-2 secretion through activation of MAPKs-med-
reported (Lewis & Shaw, 2001; Prabha, Karpagam, Var- iated NF-jB signaling pathways (Ahn et al., 2010). Thus,
alakshmi, & Packiavathy, 2011) that rutin metabolite leucocy- evidence is now emerging that allergic disease may be regu-
anidin markedly increases gastric pH, mucus thickness, sialic lated by bioactive metabolites of polyphenols.
acid, hexosamine and NO contents and serum hemoglobin le-
vel that could contribute to its anti-ulcer activities. In another 3. Summary
study, it was confirmed that phloroglucinol, one of the quer-
cetin metabolite, protects against intestinal damage effects In this review, we have detailed the absorption, metabolism
via enhancing anti-apoptosis-related molecules expression and bioavailability of dietary polyphenols (Tables 1–4 and
such as Bcl-2 and Bcl-X(S/L) (Ha et al., 2013). Taken together, Fig. 1) as well as the action of bioactive metabolites from poly-
these data suggest that bioactive metabolites specifically pro- phenolic compounds, with a special focus on metabolites’
mote the regeneration of intestinal crypts and might be ben- health effects and disease prevention properties resulting
eficial for the development of new PUD therapeutic agents. from its biotransformation (Figs. 2 and 3). There are many
studies demonstrating that polyphenolic compounds are
2.2.2.4. Immunomodulatory effect. Asthma and allergy are poorly absorbed and rapidly cleared from the circulation, thus
inflammatory diseases, caused by dysregulation of T-helper leading to a reduction in their bioavailability. However, it has
1 (Th1) and Th2-driven immune responses, which promote been established that intestinal microfloral metabolism of
immunoglobulin E (IgE) production, eosinophilic inflamma- dietary polyphenolic compounds can alter their biological
tion, activation and survival, and enhance airway smooth activities, which in turn could potentially influence host’s
muscle contractility (Busse & Rosenwasser, 2003). Impor- health. The above mentioned research findings further show
tantly, balance of Th1-Th2 cytokines secretion has been sug- that the biological effects of bioactive metabolites are as var-
gested as being necessary for maintaining healthy immune ied as their cellular targets and exhibit better bioefficacy than
homeostasis. Besides, clinical and experimental investiga- their precursors. In addition these bioactive metabolites may
tions suggest that eosinophils are not only playing important also show different bioavailability and/or bioefficacy as com-
roles in the pathogenic process, but are also the source of var- pared to their precursors. For example, 6,7,4 0 -THI and 7,3 0 ,4 0 -
ious cytokines (e.g., interleukins, ILs), which have pro-inflam- THI, are major metabolites of daidzein that effectively inhibit
matory and immunoregulatory functions and properties the CDK1, CDK2, Cot and MKK4 kinase activities by directly
(Corren, 2012). According to recent reports, quercetin, Q-3G docking to the ATP binding sites, but daidzein itself does
Table 3 – Molecular targets of bioactive metabolites from plasma.
Chemical structure
Human Resveratrol R-3S Estrogenic and anti-estrogenic activity assays Inhibits estrogenic activity by interact with human oestrogen
(Ruotolo et al., 2013; in yeast and 17β-estradiol-induced human receptors (hER-α and -β) (Ruotolo et al., 2013)
Burkon & Somoza, breast cancer MCF-7 cells
2008) Insulin, isobutylmethylxanthine (IBMX), and Reduces CCAAT/enhancer binding protein (C/EBP)-α and -β,
dexamethasone induced 3T3-L1 PPAR-γ, lipoprotein lipase (LPL) expression and fatty acid
pre-adipocytes differentiation synthase (FASN) mRNA levels, increased hormone sensitive
lipase (HSL) and sirtuin-1 (SIRT-1) mRNA levels (Lasa et al.,
t-R-3G 2012)
Human colorectal cell lines (Caco-2, Induces G1 phase cell cycle arrest by cyclin D1 depletion,
HCT-116 and CCL-228) AMP-activated protein kinase (AMPK) phosphorylation and A3
adenosine receptor activation (Polycarpou et al., 2013)

t-R-4'G
SIA rats Daidzein Equol Human cervical cancer HeLa cells Enhances tumor necrosis factor-related apoptosis-inducing
(Matthies et al., ligand (TRAIL)-induced apoptosis through activation of
2012) caspase-3, -8, -9, and cleavage of BH3 interacting-domain death
agonist (BID) (Kim & Kim, 2013)
x x x ( 2 0 1 3 ) x x x –x x x
15
16
Table 4 – Molecular targets of bioactive metabolites from urine.

Chemical structure Experimental models Molecular mechanism(s) of
targets (Refs.)
Rats and mice Wang Nobiletin 3 0 ,4 0 -DDMN • LPS-stimulated RAW264.7 • Inhibits LPS-induced NO pro-
et al. (2006); Yasuda cells duction, iNOS and COX-2 pro-
et al. (2003); Xu et al. • TPA- or OX-LDL-induced tein expression Li et al. (2007)
(2011); Li et al. (2006) THP-1 human monocyte- • Suppresses CD36, CD11b,
like cells scavenger receptors-A (SR-A)
and lectin-like oxidized LDL
receptor-1 (LOX-1) mRNA lev-
els by blocking NF-jB and
4 0 -DMN AP-1 transcriptional activi-

ties, and attenuates DiI-
oxLDL uptake Eguchi et al.
(2007); Lo et al. (2010)
• MK-801-induced memory • Activates phosphorylation of
impairment in mice brain ERK and cAMP response ele-
and primary hippocampal ment binding protein (CREB)
neurons in acyclic AMP-dependent
3 0 -DMN • TPA- or TNF-a-stimulated protein kinase (PKA)/MAPK/
human lens epithelial cell ERK kinase (MEK)/ERK path-
line SRA01/04 way Al et al. (2009)
• Serum withdrawal- and • Decreases proMMP-9 expres-
H2O2-caused PC12 cell sion Oshitari et al. (2011)
death • Mediates antiapoptotic
x x x ( 2 0 1 3 ) x x x –x x x
actions and cytoprotective
effects via modulation of
PI3K/Akt signaling, induction
of Nrf2 activation, and upreg-
ulation of intracellular GSH,
GCL and HO-1 levels Su et al.
(2012)
Fig. 2 – Schematic represents of chemopreventive targets and efficiency of metabolites of polyphenols on cancer
development.
Fig. 3 – Schematic represents of chemopreventive targets and efficiency of metabolites of polyphenols on chronic human
diseases.
not affect the activity of any of these proteins (Lee et al., production of more active components. Instead, the biological
2011a; Lee et al., 2011b). Although the metabolite may have metabolic biotransformation of parental compounds may re-
higher biological activities, direct ingestion of metabolites sult in products with higher bioefficacy available to the target
might not be the best way of getting most of the physiological sites of action. Given these occasions, several approaches
and therapeutic benefits. This is due to the fact that further have been developed to improve the bioavailability of dietary
bacterial degradation and liver microsomal oxidation of polyphenols, such as chemical modifications, delivery formu-
bioactive metabolites cannot be promised to lead to the lation and combination with other food ingredients (Rein
et al., 2013). Moreover, identifying the naturally occurring or induced by oxygen-derived reactive species: Protection by
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JOURNAL OF FUNCTIONAL FOODS x x x ( 2 0 1 3 ) x x x –x x x

journal homepage: www.elsevier.com/locate/jff

Metabolic and colonic microbiota transformation

Yi-Shiou Chioua, Jia-Ching Wua, Qingrong Huangb, Fereidoon Shahidic

1. Introduction Bioavailability is a complex process involving multiple

Table 1 – Molecular targets of bioactive metabolites from microbiota and feces.

JOURNAL OF FUNCTIONAL FOODS

JOURNAL OF FUNCTIONAL FOODS

B2 (TXB2) production ; TPA-stimulated

JOURNAL OF FUNCTIONAL FOODS

cancer susceptibility (BRCA1and BRCA2), enhancer of zeste homolog

JOURNAL OF FUNCTIONAL FOODS

antiperoxidative effects by decreasing glycation products for-

and hyper-permeability) and capillary vascularity (CV) (Yoysungnoen

synthase kinase-3β (GSK -3β) proteins expression and downregulates

Induces autophagy through exalting light chain 3 (LC3) II, beclin-1,

E R K and Wnt-1/β-catenin signaling pathways activation (Lai et al.,

PI3K/Akt/mammalian target of rapamycin (mTOR), p70 ribosomal

tes-Laurean, 2010). In another study, the antidiabetic and

acid) contents and inhibits monoamine oxidase (MA O-B ) activity

Decreases iNOS, COX-2, connexin-43 (Cx-43) and p- glycogen

p-ERK and p-JNK expression and bolcking phosphorylation of

antihyperlipidemic effects of THC were found to be more po-

protein S6 kinase (p70S6K) and p38 levels (Wu et al., 2011)

expression of various pro-inflammatory cytokines and lipid

ROS production (Luo et al., 2012). Therefore, we conclude that

bioactive metabolites have protective effects against obesity

Human promyelocytic leukemia HL-60

2.2.2.2. Neurodegenerative diseases. Recent studies have dem-

onstrated that the severity of cerebrovascular diseases,

relate with inflammation-mediated responses in neural cells

(Britschgi & Wyss-Coray, 2007). Moreover, microglia activation

TFDG metabolites (4 0 -DMN, 3 0 ,4 0 -DDMN, TF, TF3G, and TF3 0 G)

that quercetin metabolites (3,4-DHT and phloroglucinol) and

Nishizaki, Orita, & Masuda, 1999; Palazzolo, Horvath, & Zeno-

Asai & Miyazawa,

related amyloid diseases.

2.2.2.3. Peptic ulcer disease (PUD). Major causes of PUD are

stressful lifestyle, alcohol consumption, use of steroidal and

Table 2 – Molecular targets of bioactive metabolites from liver microsomes (LM).

JOURNAL OF FUNCTIONAL FOODS

Table 3 – Molecular targets of bioactive metabolites from plasma.

JOURNAL OF FUNCTIONAL FOODS

Table 4 – Molecular targets of bioactive metabolites from urine.

JOURNAL OF FUNCTIONAL FOODS

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