Bioactive substances of plant origin in food - impact on genomics
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Reprod. Nutr. Dev. 42 (2002) 461–477 461
© INRA, EDP Sciences, 2002
DOI: 10.1051/rnd:2002034
Review
Bioactive substances of plant origin
in food – impact on genomics
Arkadiusz ORZECHOWSKI, Piotr OSTASZEWSKI*, Michal JANK,
Sybilla Jacqueline BERWID
Department of Physiological Sciences, Faculty of Veterinary Medicine,
Warsaw Agricultural University, Poland
Abstract — In the past decade, substantial progress has been made concerning our knowledge of bioac-
tive components in plant foods and their links to health. Human diets of plant origin contain many hun-
dreds of compounds which cannot be considered as nutrients, but appear to play a role in the main-
tenance of health. These substances are called nutraceuticals. In some cases where the disease process
is at least partially understood, elements of protection can be related to a single compound or struc-
turally related group of compounds in the diet. Bioactive components of food which are of special inter-
est include the following groups: polyphenols, phytoestrogens, phytosterols, phytates and polyun-
saturated fatty acids. Most of them are featured by antioxidant properties. In the first part of this
review, we indicate the main groups of bioactive compounds giving a description of their localisation,
chemical properties and biological actions. Recently, it was shown, however, that the bioavailabil-
ity of potential antioxidants from plant foods is generally too low to have any substantial direct
effect on reactive oxygen species. As a result of that it is postulated that dietary compounds, even in
very low concentrations, may have a far greater impact than previously appreciated on the regulation
of gene expression. The second part of this paper concerns the action of the literally most important
bioactive substances on the molecular mechanisms of the control of genes which in turn affect cel-
lular metabolism. A few current studies on the action of selected nutraceuticals on the activity of tran-
scription factors such as AP-1, NF-kB, SREBPs, PPARs as final targets in the signal transduction cas-
cade and gene regulation are included. A detailed analysis of numerous factors of dietary origin
with their targets is far beyond the scope of this paper. However, continuing research on the effects
of nutraceuticals on gene expression should provide insight into the mechanisms of prevention of dis-
eases such as obesity, diabetes, atherosclerosis, hypertension and cancer by dietary manipulations.
bioactive compounds / antioxidants / transcription factors / AP-1 / NF-kB / PPARs / SREBPs /
gene expression
* Correspondence and reprints
E-mail: ostaszewski@alpha.sggw.waw.pl462 A. Orzechowski et al.
1. INTRODUCTION 2.1. Polyphenols
Wild primates, close relatives to humans, Polyphenolic compounds are mainly
consume as a rule diets high in fiber, vita- found in fruits and vegetables and are one of
mins, minerals, and with variable levels of the most important sources of bioactive
proteins and fatty acids [66]. Even in cap- components of the human diet [76] Over
tivity but more in the wild, they sponta- 8000 polyphenols have been identified and
neously have plenty of exercise. In turn, the among them more than 2000 are found in
current lifestyles of humans almost every- nature. Plants need them for pigmentation,
where in the world are in sharp contrast, and growth, reproduction, resistance to pathogens
as a consequence, humans suffer from a and for many other functions. One of the
large number of chronic diseases. In the most important groups of polyphenols is
past, infectious diseases killed our ances- flavonoids. They can be divided into the
tors early on, often younger than age 40, so following subgroups: flavones/flavonones,
they did not display the current epidemic of anthocyanins and catechins/flavonols. In
chronic diseases that arise in older ages. plants, flavonoids usually form complexes
Now medical status has been improved. The with various sugars which are called glyco-
problem of infectious diseases has been sides. Flavones/flavonones have been iso-
solved due to the amelioration of medical lated from almost all fruits and vegetables
care (vaccination programs, antibiotics). with their highest concentrations being
Nowadays, people live longer and therefore found in the outer layers. Therefore flavonoid
express symptoms of chronic diseases asso- consumption can be dramatically reduced
ciated with senescence and lifestyle (also if the peel of an apple is removed. How-
called civilisation diseases) such as obesity, ever, there are fruits like oranges for exam-
diabetes, hypertension, coronary heart dis- ple that have high amounts of flavonoids
ease, and cancer. also present in the pulp. In most European
countries, the average daily consumption of
flavones/flavonones does not exceed 25 mg
2. NATURAL BIOACTIVE per day. Anthocyanins are the largest group
COMPOUNDS OF PLANTS of water-soluble pigments in plants. They
are widely distributed in the human diet
through crops, beans, fruits, vegetables and
Bioactive components of food which are red wine [31]. Tsuda et al. [98] showed that
of special interest include the following anthocyanins can inhibit the formation of
groups: polyphenols, phytoestrogens, phy- the nitrated tyrosine and scavenge perox-
tosterols, phytates, lectins, oligosaccharides ynitrites. Moreover anthocyanins express a
and polyunsaturated fatty acids (PUFA) potent antioxidant activity and protective
[30]. These groups consist of many related effect against hepatic ischemia-reperfusion
compounds, each with slightly different injury in vivo.
properties. It is important to stress that the
protection against cancer and cardiovascu- Catechins are unique flavonoids found
lar disease is undoubtedly the result of the in large quantities in green tea. In black tea
cumulative action of many natural sub- the level of catechins is about 30% that of
stances present in the diet. Since each plant green tea. Green tea extracts are described as
contains different bioactive components, the protective against experimentally induced
eating of various foods seems to be impor- cancer in animals. They act as strong
tant but needs further evidence. Taking this inhibitors of the in vitro nitrosation of sec-
into account, we may enjoy a lower risk of ondary amines and therefore lower tumor
occurrence of modern diseases. initiation [94]. High amounts of catechinsBioactive substances of plant origin 463
present in tea are also found in red wine and and other non-hormonal cancers, cardio-
chocolate, which may contribute signifi- vascular diseases and osteoporosis [5].
cantly to the daily intake of polyphenols Recently, Karamsetty et al. [46] found that
[100]. It is estimated that the daily intake soybean phytoestrogens genistein and
of polyphenols does not exceed 200 mg per daidzein act like estrogens in restoring nitric
day, which is relatively high compared to oxide-mediated relaxation in hypoxic rat
the intake of other antioxidant nutrients, pulmonary arteries and moreover, this effect
such as vitamins E, C or A. Polyphenolic is not mediated by the inhibition of tyrosine
compounds have beneficial health effects kinases.
because of their antioxidant properties and It is recommended to consume moder-
their inhibitory role in the various stages of ate amounts of phytoestrogens in their nat-
tumor development [38]. There are cohort ural form as plant foods. If their intake is
studies indicating a possible protective too high they could be potentially harmful to
action against coronary heart disease [49] human health although this is unlikely to
and strokes [45]. Polyphenols act through happen.
the scavenging of free radicals (reactive oxy-
gen species, ROS) and therefore are con-
sidered to be powerful antioxidants. 2.3. Phytosterols
Phytosterols are bioactive non-nutrient
2.2. Phytoestrogens substances structurally similar to choles-
terol. They exist in two forms: (1) unsatu-
Phytoestrogens have become one of the rated, common, present in many plants and
more topical areas of interest in clinical (2) saturated, called stanols, which are found
nutrition. They mimic human estrogens and only in small amounts in cereals, fruits and
therefore are considered as natural selective vegetables [71]. Northern European daily
estrogen receptor modulators (SERMs) [90]. consumption of phytosterols is in the range
There are two subclasses of polyphenols 100–400 mg and comes mainly from veg-
(isoflavonoids and lignans) isolated from etable oils, bread, fruits and vegetables. In
various plants [65]. The main consumable southern Europe the intake may be even
plant sources of phytoestrogens include higher as a result of high consumption of
isoflavonoids and lignans found mainly in vegetable oils and nuts. The health effects of
soybeans and flaxseed, respectively. Other phytosterols are the result of their structural
sources of phytoestrogens include sunflower similarity to cholesterol; therefore plant
and sesame seeds, various nuts, berries, gar- sterols compete with cholesterol absorption
lic and carrots [86]. Plant lignans are also from the intestinal tract. When typical
found in many cereals, grains, fruits and amounts of sterols (240–320 mg) are con-
vegetables [6]. Since Asians consume a lot sumed, only about 5% are absorbed from
of soybean products, their daily isoflavonoid the small intestine [53]. Thus, the dietary
intake is 25–100 mg. In western Europe intake of phytosterols causes an increased
isoflavonoid consumption is usually a few excretion of both dietary and biliary choles-
mg per day due to a much lower intake of terol in humans [35]. In addition to reducing
soybean products. Phytoestrogens may pre- the absorption of cholesterol, plant stanols
vent cancer in humans. In countries with inhibit the absorption of other plant sterols
high consumption of soybean products the [32]. In humans, this inhibition of intesti-
risk for hormone-related prostate and breast nal cholesterol absorption is accompanied
cancer is much lower than in populations by a compensatory increase in cholesterol
with a low consumption of soybeans [68]. synthesis, as reflected in the increase of
Phytoestrogens also protect against bowel serum cholesterol precursors, lathosterol464 A. Orzechowski et al.
and desmosterol. However, the net effect is phate forms is essential since a high degree
still a reduction in serum cholesterol. The of phosphorylation is necessary to bind min-
beneficial effects of vegetable oils are due to erals. In developing countries where the diet
the high amount of phytosterols which lower is almost wholly based on cereals and
serum cholesterol. Moreover, the interac- legumes, iron and zinc deficiency are fre-
tion between dietary fibre and phytosterols quently observed. Phytate-related mineral
could explain why diets rich in fibre may deficiencies are also reported in people from
reduce the risk of coronary heart disease. developed countries, such as pregnant
The use of a special margarine increases the women, infants and adolescents. There are
dietary intake of phytosterols to 1–3 g per several methods of decreasing the inhibitory
day which is a therapeutic amount. In 1995, effect of phytic acid on mineral absorption
the Finns introduced plant stanol esters (germination, fermentation, soaking, autol-
(PSE) in margarine, as dietary adjuncts to ysis and malting). Unfortunately heat pro-
lower cholesterol by more than 10% [15]. cessing at home during cooking or during
food manufacturing does not affect phy-
tates. Therefore, the selection of starter cul-
2.4. Phytates tures to improve phytate degradation is very
important. In some cases, commercial phy-
This group of bioactive substances is also tase can be added to remove phytate, espe-
called substances with antinutritional prop- cially from infant foods.
erties although this term is also appropriate
for flavonoids. In recent years, dietary phytate has
received increased attention due to its role in
Phytates are present in seeds which are an cancer prevention and/or therapy and its
important source of plant phosphorus stored hypocholesterolemic effect [54]. In turn, by
there in the form of phytic acid (myo-inos- binding an excess of free iron in the small
itol hexaphosphate acid, InsP6) [61]. The intestine, phytates may prevent the formation
antinutritional effects of phytic acid are pri- of free radicals by the Fenton reaction in
marily related to the strong chelating asso- the colon and consequently decrease iron
ciated with its six reactive phosphate groups. absorption for all who need less iron.
Its ability to complex with proteins and par-
ticularly with minerals has been a subject
of investigation from chemical and nutri- 2.5. Lectins
tional viewpoints [99]. High contents of
phytates are observed in cereal grains, In the past, the main scientific interest
legumes and nuts whereas in vegetables their was focused on the toxicity of lectins, for
concentrations are low. The hydrolysis of example ricin. Nowadays, these bioactive
phytates into inositol and phosphates or compounds are recognized as natural com-
phosphoric acid occurs as a result of phy- ponents of the human diet. It has been shown
tase action [79] or nonenzymatic cleavage, that dietary lectins, which bind avidly and
i.e. food processing [2]. Enzymes capable are endocytosed by cells of the brush border
of hydrolysing phytates are widely dis- epithelium, are powerful growth factors for
tributed in micro-organisms, plants and ani- the gut [83], induce changes in its digestive/
mals. Phytases, naturally present not only absorptive functions, modify the state of
in plant foods, but also in yeasts or other glycosylation of luminal receptors, alter the
microorganisms implemented in food pro- expression of genes coding for digestive
cessing, act in a stepwise manner to catalyse enzymes, transport and structural proteins
the hydrolysis of phytic acid. To reduce or and interfere with both the bacterial ecol-
eliminate the chelating ability of phytate, ogy and the immune response of the gut to
dephosphorylation of hexa- and penta-phos- food antigens. Furthermore, they stimulateBioactive substances of plant origin 465
pancreatic growth and have profound 2.7. Polyunsaturated Fatty Acids
effects on the immune system [81]. Plasma (PUFA)
cells involved in a multiplicity of immune
functions express high and variable levels Polyunsaturated fatty acids consist of two
of endogenous membrane lectins, most parent compounds: linoleic acid, a fatty acid
of which are used in cell-to-cell communi- of the w-6 family with 18 carbon atoms and
cation. two double bonds (18:2n6) and a-linolenic
acid, a fatty acid of the w-3 family with
18 carbon atoms and 3 double bonds
2.6. Oligosaccharides (18:3n3). These fatty acids have different
metabolic effects. Linoleic acid (LA) can
be elongated to arachidonic acid (AA), a
Oligosaccharides represent a structurally fatty acid with 20 carbon atoms and 4 dou-
diverse class of macromolecules of a rela- ble bonds (20:4n6) with two intermediary
tively widespread occurrence in nature. They metabolites termed g-linolenic acid (18:3n6,
are mainly present as glucans with differ- GLA) and dihomo-g-linolenic acid (20:3n6,
ent types of glycosidic linkages, while oth- DHLA) while a-linolenic acid can be elon-
ers mostly bind to protein residues as gated to either eicosapentaenoic acid (EPA),
oligosaccharide-protein complexes [25]. a fatty acid with 20 carbon atoms and 5 dou-
The most promising biopharmacological ble bonds (20:5n3) or docosahexaenoic acid
activities of these biopolymers are their (DHA), a fatty acid with 22 carbon atoms
immunomodulation and anti-cancer effects. and 6 double bonds (22:6n3). The fatty acids
Oligosaccharides and oligosaccharide-pro- with 20 carbon atoms, AA and EPA play an
tein complexes are considered as multicy- important role in prostaglandin metabolism
tokine inducers that are able to induce the and may influence the thrombotic process.
gene expression of various immunomodu- Cohort studies [39] indicate that the intake
latory cytokines and cytokine receptors. of a-linolenic acid is inversely related to
Numerous anti-tumor polysaccharides have coronary heart disease. Whether this effect
been discovered from mushrooms, fungi, is independent of other unsaturated fatty
yeasts, algae, lichens and plants and at pre- acids e.g. linoleic acid, is difficult to estab-
lish because different unsaturated fatty acids
sent are intensively studied [75]. Fructo-
are present in the same foods e.g. soybean
oligosaccharides (FOS) are short-chain poly-
oil. However, the hypothesis of a protective
mers of fructose which are produced effect of a-linolenic acid in relation to
commercially by hydrolysis of inulin or by coronary heart disease is supported by the
enzymatic synthesis from sucrose or lac- results of the Lyon trial. In this intervention
tose. They are not hydrolyzed in the human study, a Mediterranean diet enriched with
small intestine but degraded in the colon by a-linolenic acid was strongly protective in
the resident microflora. They are mainly relation to coronary heart disease [23, 84].
known for their ability to increase the However, more data is needed before defi-
endogenous growth of intestinal lactobacilli nite statements can be made about the pos-
and bifidobacteria in humans and animals sible protective effect of a-linolenic acid.
which is recognized as beneficial to health.
[8]. In vivo studies in rats have shown that
FOS increase the proportion of butyrate 2.8. Other mechanisms of action
which in turn stimulates water and sodium
absorption and modulates intestinal motility. A number of human intervention studies
FOS also increase Ca, Mg and Fe absorption concerning antioxidant and/or anti-genotoxic
and enhance bone calcium stores in rats [74]. effects of various polyphenols have shown466 A. Orzechowski et al. no convincing results [37, 50, 101]. Also ously anticipated, most likely by the regu- extensive studies with orally administered lation of gene expression. This in turn can high rates of plant extracts rich in phenolics affect cellular metabolism with profound have failed to demonstrate antioxidant effects on detoxification mechanisms and effects, except for a transient improvement in cell proliferation, differentiation, survival the amount of trapped free radicals [49, 107]. and death. According to estimated daily intake of flavonoids, the range of 100–200 mg.day–1 On the contrary, deleterious effects of is a very low level when compared with the polyphenolic compounds have also been levels used in the aforementioned studies. observed, and are associated with the ability Recent work has shown that the bioavail- to bind and precipitate macromolecules ability of potential antioxidants is too low to including protein and carbohydrates and have any substantial direct effect on reac- reduce the digestibility of food. The colour- tive oxygen species (Fig. 1). Moreover, the ing pigments in plants called flavonoids are vast number of phenolics present in food- the best known and best characterized of stuffs are glycosides and the free radical these groups. Flavonoids have been con- scavenging activity decreases with the pres- sidered antinutrients because they have been ence of a sugar moiety, so glycosides are shown to inhibit the activity of a wide range not antioxidants, although their corre- of enzymes including digestive enzymes sponding aglycons are. However, it is well such as hydrolases, but also isomerases, recognized that many polyphenols that do oxygenases, oxidoreductases, polymerases, not show antioxidant effects show anti- phosphatases, protein kinases and amino inflammatory, anti- or pro-estrogenic, anti- acid oxidases. Failure to scavenge free rad- mutagenic and anti-carcinogenic effects. icals in vitro does not necessarily mean that Therefore, it is postulated that dietary com- some flavonoids will not trigger biological pounds, even in very low concentrations, effects in vivo. Flavonoids might interfere may have a far greater impact than previ- with various transduction signal cascades Figure 1. Relationship between bioavailibility of potential antioxidants and cell functions.
Bioactive substances of plant origin 467
by affecting the eicosainoid synthesis via (XME) of phase I (CYP1A1, CYP1A2), and
cyclooxygenase/lipoxygenase pathways phase II (NADP(P)H-menadione oxidore-
[56], or protein tyrosine kinases [40, 85]. ductase, aldehyde dehydrogenase, UDP-
Some of them may also form complexes glucuronosyl-transferase, glutathione S-trans-
with metal cations, thereby interfering with ferase) xenobiotic elimination. There are
the absorption of minerals such as iron or specific transcription factors, which in turn
copper [14]. The ability to bind minerals specifically bind to XRE. Once activated
may be beneficial in some cases, since cop- by the assembly with aromatic hydrocar-
per and iron are the initiators of hydroxyl bons or halogenated derivatives such as
radical formation by the Fenton reaction dioxin (TCDD), the cytosolic protein called
[96]. Except in extreme cases, undernour- the aryl hydrocarbon receptor (AhR) translo-
ishment in western societies may actually cates to the nucleus where it heterodimerizes
lead to beneficial effects such as the pre- with the aryl hydrocarbon nuclear translo-
vention of obesity and genomic stability. cator forming a transcription factor that
binds to the XREs present in the 5’-pro-
moter [33]. Dietary flavonoids are ligands of
3. IMPACT ON GENOMICS the AhR and affect cyp1a1 expression, with
quercetin being a very potent activator
Polyphenols including flavonoids are to whereas kaempferol and green tea polyphe-
be considered as xenobiotics and as such nols (GTP) – catechins; especially (-)-epi-
may profoundly affect the activation and gallocatechin gallate (EGCG) inhibit cyp1a1
excretion of exogenous carcinogens. Cer- transcription induced by TCDD [19, 104].
tain polyphenols may directly or indirectly Alternatively, flavonoids are reported to act
induce phase II enzymes such as glutathione through the transcriptional regulation of
transferases (GSTs), NAD(P)H:quinone genes by directly affecting the antioxi-
reductases, epoxide hydrolases, and UDP- dant/oxidant response element (ARE/ORE)
glucuronosyltransferases that will enhance in the promoter regions of some of the genes
the excretion of oxidising species [29, 108]. (gsta1, cyp1a1, cyp1a2) of the XME [108].
Concomitantly, flavonoids significantly It should be noted that ARE/ORE is the elec-
decrease the activity of antioxidant enzymes trophile response element, so flavonoids
glutathione reductase (GR), catalase (CAT) may act directly on ARE/ORE as phenolic
and glutathione peroxidase (GPx) in the red radicals or indirectly by the effects on oxida-
blood cells of rats [11]. They are also reported tive stress. Flavonoids have been observed
to influence the expression and the activity to repress intrinsic antioxidant systems as
of cytochrome P450 (CYP) [19, 104]. a feedback mechanism exerted on antioxi-
Antioxidant activities have shown little or dant enzymes eventually pointing to the
no relationship to the above-mentioned importance of intracellular prooxidant-
antimutagenic/anticarcinogenic activities of antioxidant homeostasis.
flavonoids [34]. There are promoter regions of several
How do flavonoids induce such numer- genes (including XME) that posses another
ous and multidirectional modifications in response element that is activated by gluco-
the intracellular biochemical apparatus? It corticoid and glucocorticoid-like structures.
seems likely that the effects of some of them This, termed the glucocorticoid response ele-
may indirectly occur through the action on ment (GRE) is induced either by the gluco-
response elements in the regulatory regions corticoid receptor-ligand transcription factor
of the genes. The xenobiotic response ele- or by the glucocorticoid receptor-indepen-
ment (XRE) is localized in the promoter dent mechanism [60]. There is also the pos-
regions of several genes encoding proteins sibility that transcription factors formed by
such as xenobiotic metabolizing enzymes the glucocorticoid receptor-glucocorticoid468 A. Orzechowski et al.
interaction influence XRE the regulation of transduction. This may occur either by direct
gene expression. Flavonol quercetin has inhibition of the kinases itself or via the
been reported to selectively inhibit GRE- redox sensitivity of the kinase protein. At
dependent gene regulation [58]. present, little is known about the molecu-
The activation of xenobiotic response lar mechanisms of specific genes coding
elements by dietary agents has been known for proteins responsible for the observed
for some time, but the effects driven by the beneficial health effects of flavonoids. The
antioxidant response elements and through candidates to play the key role in the regu-
nuclear transcription factors such as AP-1 lation of cell life and death at the transcrip-
and nuclear factor kappa B (NF-kB) families tional level includes NF-kB and AP-1 tran-
are only now being recognized. scription factors. Conflicting data describe
the effects of catechins and teaflavins on
3.1. Modulation of signal transduction the activation of extracellular signal-regu-
cascades lated kinase (ERK2) and c-Jun N-terminal
kinase (JNK1) and the expression of c-jun
One important mechanism of regulation and c-fos mRNA as well as the activity
appears to be the inhibition by dietary agents of the activator protein 1 (AP-1) (Fig. 2).
of one or more of the kinase families of There is also contradicting evidence for
enzymes involved in the respective signal the induction of AP-1 and NF-kB by the
Figure 2. Suggested metabolic pathway of nutritive and non-nutritive dietary agents. NF-kB – nuclear
factor kappa B; AP-1 – activating protein-1, PPARs – peroxisome proliferator-activated receptors;
SREBPs – sterol regulatory element – binding proteins; ARE/ORE – antioxidant response ele-
ment/oxidant response element.Bioactive substances of plant origin 469 commercially used phenolic antioxidants mechanisms leading to the enhanced expres- butylated hydroxyanisol (BHA) and t-butyl- sion of genes responsible for cell resistance hydroquinone (tBHQ). They either activate to stress and apoptosis. The chemical struc- NF-kB (measured by the electrophoretic ture of flavonols is characterized by the pres- mobility shift assay) with the formation of ence of the 2-phenylbenzen-g-pyron ring. H2O2 [82], or phenoxyl radicals and/or their The ultimate difference between quercetin derivatives [51] or inhibit NF-kB DNA and kaempferol is confined to the presence binding [10]. Phenolics trigger c-Jun N-ter- of an additional hydroxyl (OH) residue in minal kinase (JNK1) and/or extracellular the 3’ position of the B ring [1, 95]. Thus, signal regulated protein kinase (ERK2) in one who compares the effect of quercetin a dose-dependent fashion [108]. In contrast or kaempferol on colorectal cancer cells to Yu et al. [108] who observed activation, might easily distinguish the role of the Chung et al. [18] found the inhibition of hydroxyl group present or absent in the par- ERK2, JNK1, and AP-1 activity. Since ticular flavonol. Anticarcinogenic proper- JNKs are strongly and preferentially acti- ties of flavonols resulted in part from the vated by stress stimuli, this signaling path- inhibition of NF-kB activity [78]. NF-kB way as one of the stress responses and is is a ubiquitous regulator of transcription in functionally involved in cellular survival almost every cell and it modulates the activ- and/or apoptosis [47]. It is probable that the ity of genes that are characterized by the effect of quercetin is also dose-dependent presence of the NF-kB consensus sequence on the regulation of MAPKs and leads to in the regulatory (enhancer/promotor) regions the induction/repression of gene expression of DNA [9]. Activation of NF-kB has been and cell survival or cell death. At certain lev- reported to suppress cell death, while the els quercetin might be an indirect NF-kB blockade leads to the amplification of the inducer by targeting several kinases (i.e. cytotoxic effects of TNF-a and promotes MAP kinases), which activate NF-kB. apoptosis [113]. When stimulated, NF-kB Upstream activators include NIK, MEKK1, promotes transcription, whereas the inactive MEKK2, MEKK3, TAK1, protein form resides within the cytoplasm, blocked kinase Cz, and S6 kinase [55, 69, 72, 88, by the IkB subunit (with the exception of 112]. Similarly, contradicting results were lymphocytes – B cells, where NF-kB is con- obtained from studies with quercetin and stitutively expressed in the nucleus) [26, other phenolics on the activity of NF-kB, 64]. According to the differences in the the key regulator of cellular antioxidant structure, at least five isoforms of NF-kB defence systems. Sato et al. [87] or Ishikawa have been identified but the most abundant et al. [43] reported the suppression of NF-kB are subunits p50 and p65 that form homo- or activation by quercetin in human synovial heterodimers which can bind to DNA [64]. cells, or glomerular cells, respectively, but On the contrary, TNF-a is a proinflamma- the cells were studied in serum free medium, tory cytokine, which is known to induce cell with additional one day fasting as the pre- death. TNF-a acts on the cell by the acti- treatment period to induce cell quiescence. vation of the membrane receptors TNF-R1 We reported transient activation of this tran- or TNF-R2. Association with the receptors scription factor by quercetin in conditions leads to conformational changes (oligomer- favoring cell proliferation [77]. It therefore ization into trimers) and the receptors are appears, that quercetin-induced NF-kB acti- able to recruit a signaling complex called vation is characterized by cell specificity. the DISC (death-initiated signaling com- Actually, phenolic antioxidants at high doses plex) composed of the TRADD (TNF-R1- also activate ICE/Ced-3 caspases [51, 52]. associated death domain) and FADD (Fas- An NF-kB RelA/p65 subunit acts as a signal associated death domain). Simultaneously from cytosol, which initiates transcription or alternatively, conformational changes in
470 A. Orzechowski et al.
the receptors can recruit a signaling com- in mind, however, that flavonoids are known
plex composed of TRADD and TRAF2 as the most powerful inhibitors of tyrosine
(TNF-associated factor 2) and/or RIP (recep- kinases. Whether flavonols are potent
tor interacting protein) for survival [91]. inhibitors/activators of STAT-1 and effect
After the association, TRAF2 and RIP could signal transduction form TNF-a to NF-kB
activate kinase NIK (NF-kB inducing with simultaneous activation of genes sup-
kinase) that stimulates NF-kB indirectly by porting cell viability, is a matter of debate
the activation of IkBa or -b kinases (IKKa, and needs experimental verification which is
IKKb). IKKb kinase i.e. phosphorylates the currently in progress in our laboratory.
IkBa inhibitory subunit in positions 32 and The developing resistance of tumor cells
36 of serine residues. After phosphoryla- to chemotherapy is a challenge to contem-
tion IkBa can be ubiquitinated and prote- porary medicine. A number of drug resis-
olytically degraded by the proteasome. Thus, tance mechanisms are not known as well as
NF-kB is not sequestered any more and the origin of this phenomenon. Apparently,
translocates into the nucleus [10, 26, 47, 59, apoptosis is a hallmark of an efficient cyto-
91]. NF-kB activation improves cell sur- toxic effect of chemotherapy or radiation
vival whereas inhibition enhances cytopathic therapy. Apoptosis is also widely accepted
and apoptotic effects of TNF-a indicating a as a mechanism leading to cell elimination
considerable role of functional NF-kB in induced by TNF-a. Therefore, TNF-a either/
cell viability. The protective effect of NF-kB or chemotherapy as well as radiation therapy
is in turn dependent on mRNA and proteins might be considered as important activators
that regulate the activity of antiapoptotic of NF-kB. It has been demonstrated that
genes. Obviously, NF-kB directly activates inhibition of NF-kB supports the therapies
Bcl-2/A1 (a homologue of Bcl-2) the protein based on the action of TNF-a [7, 102]. A
that plays an important role in the blockade marked role of NF-kB has been observed
of apoptosis associated with the activity of in developing resistance to chemotherapy
the mitochondria [113]. Additionally, the in the following cases: Hodgkin lymphoma,
activation of TNF-R1 by TNF-a is associ- juvenile myelomonocytic leukemia, prostate
ated with the increased activity of PI-3K cancer, virus-mediated leukemic T cells and
and PKB, the most powerful antiapoptotic tumor cells transformed with Ras oncogene.
kinases. On the contrary, the inhibition of Tumor cells are also characterized by a
NF-kB was shown to occur as a conse- higher nuclear representation of NF-kB,
quence of proteasome inhibitors, corticos- moreover the genes regulated by NF-kB are
teroids, and factors that are known to block often constitutively upregulated in neoplas-
mas [59, 70, 93]. NF-kB is thus linked to
NIK and IKK [36], as well as under the
tumor growth, because it inhibits apopto-
influence of STAT-1, a tyrosine kinase that
sis. Several experimental data support
appears to be a component of the signaling the evidence of a profound role played by
complex of TNF-R1 and TRADD. Appar- NF-kB in TNF-a-mediated apoptosis. Over-
ently, STAT-1 is recruited by TNF-R1 and expression of IkB renders tumor cells sig-
enables the formation of the DISC complex; nificantly less susceptible to TNF-a-induced
furthermore it reveals apoptotic domains of cell death [28]. The reaction was observed in
death-mediating proteins with the concomi- tumor cell lines such as Jurkat T cells,
tant inhibition of the assembly of the sur- human urine bladder line T24 and breast
vival complex, which releases NF-kB [103]. cancer MCF7. On the contrary, flavonoids
Substantial interest to study the physiologi- are cytopathic to tumor cells. The puzzling
cal role of the STAT-1 resulted from its dual issue of the developing resistance of tumor
role as the non-receptor tyrosine kinase and cells to cytopathic actions of flavonols in the
transcription factor (the STAT acronym presence of TNF-a-stimulated NF-kB activ-
stands for that meaning). One should bear ity remains unexplained and ambiguous [77].Bioactive substances of plant origin 471
Another possible mechanism of cell tox- balance between the protein products of
icity of flavonoids seems to be quite similar genes controlling cell life and death. The
to that reported by Serrano et al. [89] for key roles whether an individual cell dies or
other phenolic compounds such as gallic remains alive may be the modulation of
acid and its esters, which inhibit protein antioxidant defences [12]. Quercetin has
tyrosine kinases (PTKs). Similar findings been suggested to be beneficial for health,
were obtained by Kawada et al. [48] on the however, studies have shown that many
basis of studies with quercetin and resvera- antioxidants can also exhibit, a prooxidant
trol in cultured rat stellate and Kupfer cells. behavior [16, 24]. Plant polyphenols includ-
In their studies, the action of quercetin agly- ing quercetin aglycon may interfere with
con was associated with suppressed inositol the cellular redox state by the inhibition of
phosphate metabolism, tyrosine phospho- glutathione reductase [110] and the efflux
rylation, reduced level of cell cycle protein of glutathione S-conjugates [111]. The final
cyclin D1 and mitogen-activated (MAP) effect of plant phenolics on the viability of
kinase activation in PDGF/BB stimulated cells is therefore variable. At low concen-
stellate cells. trations quercetin and derivatives seem to
In certain cases quercetin aglycon could exert a stimulatory action on cell viability
promote tumorigenesis and tumor growth and survival, whereas at high doses (100 mM
[62] possibly by oxidative DNA damage in and higher) they are apoptogenic and cyto-
the presence of Cu2+ [106]. We suggest that toxic [3, 4, 51, 52, 85]. From a dietary point
the anticarcinogenic activity of quercetin of view, it remains to be established what
aglycon is dose dependent and is influenced doses could be considered as beneficial for
by the presence of cytotoxic agents as well health.
as serum survival factors (cytokines, oxy-
gen free radicals – OFR) [63, 86]. Pheno-
lics stay in the first line of antioxidant 3.2. PUFA as ligands
defence, donating electrons to OFR with a of transcription factors
resultant formation of phenoxyl radicals
[16]. Prooxidant phenoxyl radicals co-oxi- The development of obesity and associ-
dise NADH and GSH, which in turn are no ated insulin resistance involves a multitude
longer able to inhibit NF-kB activation [17]. of gene products, including proteins
It appears that apoptosis may be initiated involved in lipid synthesis and oxidation,
by phenolics. According to recent advances thermogenesis and cell differentiation [20].
in the interpretation of events that occur dur- The dietary w-6 and w-3 polyunsaturated
ing programmed cell death, the generation fatty acids (PUFA) suppress lipogenesis in
and spreading of ROS within the cell are the liver while they simultaneously induce
consequences of the increased permeabil- the transcription of genes encoding proteins
ity of the mitochondrial membrane [80, of lipid oxidation and thermogenesis [21].
109]. Lepley and Pelling [57] during a novel Furthermore, the lipoprotein metabolic path-
cell culture study with apigenin (a quercetin way is altered by peroxisome proliferator-
derivative), obtained evidence that flavonoid activated receptors (PPARs). The PPARs
antioxidants may enhance apoptosis in cer- are a member of the steroid hormone recep-
tain tumor cell lines. Hydrogen peroxide tor superfamily. Three types of PPARs have
(H 2O 2), similarly to quercetin has been been described: PPARa, PPARb/d (Nuc1),
reported to stimulate the activity of the mito- and PPARg. PPARa and PPARb are ubiq-
gen-activated protein kinases (MAPKs) uitously expressed in body tissues that pre-
ERK and JNK, and the expression of the dominantly catabolize fatty acids (i.e. heart,
proto-oncogenes c-fos and c-jun [97]. Cell liver, muscle, brown adipose tissue) whereas
elimination or survival is then a matter of PPARg is selectively expressed in adipose472 A. Orzechowski et al.
tissues (recently found in other tissues corroborated in studies performed by Mohan
including skeletal muscle) and seems to be et al. [67], who observed that oral supple-
associated with the differentiation of mentation with oils rich in w-3 and w-6
adipocytes. PPARa is activated by PUFA PUFA could protect animals against alloxan-
such as eicosapentaenoic acid (w-3; EPA) induced diabetes mellitus. It is thought that
or linoleic acid (w-6, LA) and heterodimer- PUFA exert the aforementioned effect by
izes with the 9-cis-retinoic acid receptor enhancing the antioxidant status and sup-
(RXRa). After ligand binding (EPA), it func- pressing the production of cytokines (TNF-
tions as a transcription factor in the regula- a in particular). Apparently, PUFA play a
tion of adipogenesis and insulin-mediated role as intrinsic ligands in activating the
glucose transport. There is a positive cor- PPARg – transcription factor, which up to
relation between the expression of Cu, Zn- date has been known to be activated merely
dependent superoxide dismutase (SOD-1) by thiazolidinediones (antidiabetic drugs).
and PPARa [42]. Moreover, the same group
observed that an increased liver PPARa
mRNA level confers a reduction of the 4. PERSPECTIVES
plasma TBARS levels indicating the
causative role of reactive oxygen species in In recent years research has been revo-
the pathology of insulin resistance [41]. lutionized by the implementation of rapidly
PUFA are not only strong ligands to PPARa, developing technologies. Examples are the
but also strong activators of PPARg and construction of DNA/RNA arrays, the devel-
PPARb [13]. Ligand binding enhanced the opment of proteomics, the widespread avail-
interaction of PPAR with its DNA-binding ability of probes for important signal
domains [44] called the PPAR response ele- molecules, the insertion of reporter genes
ment (PRE). Functional PRE that reside in downstream of regulatory sequences and
the 5’-flanking region have been found to the use of gene knock-out models. All of
exist in several genes including those these are having a major impact on the study
involved in the oxidation of fatty acids and of disease and disease development at the
thermogenesis (uncoupling proteins UCP-1 genome level. The same technologies are
and UCP-3), thus additionally supporting providing a unique opportunity for estab-
the evidence for its anti-diabetic and anti- lishing the role of diet and dietary agents in
obesity function [27, 92]. Repartitioning of protecting humans against diseases and dis-
metabolic fuels away from storage and orders. The effects of food-derived com-
towards oxidation reflects the fact that pounds on the regulation of a broad spec-
PUFA co-ordinately suppress the transcrip- trum of metabolic activities can thus be
tion of lipogenic genes, while simultane- investigated, often simultaneously.
ously inducing the transcription of genes
encoding proteins of lipid oxidation (b-oxi- ACKNOWLEDGEMENTS
dation of fatty acids) and thermogenesis [20,
22]. This effect of PUFA is in turn medi- This work was supported by a grant No 3
ated by the transcriptional and translational P06T 054 22 from the State Committee for Sci-
suppression of another group of transcription entific Research in Poland.
factors termed sterol regulatory element-
binding proteins (SREBPs) [73, 105]. Thus,
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