Polyphenols: What Are They and Why We Need Them

Ariane Anderson

Introduction2
Polyphenol Compounds
Chemical Structure...3
Synthesis..................5
Dietary Sources........6
Bioavailability..........8
Metabolism..............9
Health Promoting Properties of Polyphenolic Compounds
Antioxidant Capacity........11
In Vitro Antioxidant Capacity.....12
In Vivo Antioxidant Capacity..13
Non-Antioxidant Properties.13
Cell Signaling..13
DNA Repair.16
Conclusion........................17
Literature Cited.18

Introduction
Optimal health is desired by most and as miracle diets and super-foods flood the market
we forget the recommended balanced diet rich in fruits and vegetables. Health promoting foods
such as plant-foods are associated to a decrease in chronic disease risk factors. Studies suggest
that phytonutrients (polyphenols) are the bioactive ingredients responsible.
Polyphenols make up a large class of chemical compounds synthesized by certain plants
(vegetables, fruits, teas, etc.) that bear health components. Polyphenols biologically benefit us
physically and chemically, as they are antioxidants, anti-inflammatory, anti-carcinogenic, and
protect us from oxidative stress and a number of diseases.
Polyphenols are built upon several different groups. A group that makes up a large
portion are flavonoids. Flavonoids are also divided into several groups, and polyphenols and
flavonoids are often used interchangeably. Flavonoids are a classification of polyphenols.
However, polyphenols are not always flavonoids. There have been over 4,000 flavonoids
identified (Miranda & Buhler, 2000).
Recognized dietary antioxidants are vitamin C, vitamin E, selenium and carotenoids.
However, in recent studies polyphenols have been discovered to act as antioxidants. Polyphenols
are made up of chemical structures that demonstrate favorable interactions with free radicals and
other reactive oxygen species. Polyphenol intake depends on the consumption of fruits,
vegetables, grains, wine and teas. The polyphenol intake is considerably higher than vitamins.
Average daily intake of polyphenols can range from 50-800 mg, whereas average daily intake of
vitamin C is 70 mg, vitamin E is 7-10 mg, and carotenoids 2-3 mg.
The antioxidant capacity of polyphenols depend on the molecular structure, mainly the
position of the hydroxyl group as well as other features in the chemical structure. The position of
the hydroxyl group is important for antioxidant capacity due to their willingness to donate a
hydrogen to free radicals. This activity gives the free radical scavenging quality to phenolic
compounds.
Flavonoids are becoming well known for the health benefits related to consumption.
Flavonoids have antioxidant activity as well as other activities attributed to flavonoid intake such
as anti-allergic, anti-cancer, anti-inflammatory and anti-viral. For example, quercetin is a
flavonoid known for the ability to relieve hay fever, eczema, sinusitis and asthma. Studies have
demonstrated that heart disease is inversely related to flavonoid intake due to its ability to
prevent oxidation of low-density lipoprotein and thus reducing the risk of atherosclerosis. This
also means that flavonoids lower levels of cholesterol and triglycerides in the blood due to its
ability to prevent LDL oxidation. Isoflavones also have the ability to reduce levels of cholesterol
in the blood and can also prevent osteoporosis and reduce menopause symptoms.
The chemical interaction that polyphenols have on cell components is currently being
studied. Polyphenols affect the interactions between transcription factors and the DNA.
Polyphenols are known to react with free radicals via oxidant chain breaking reactions.
Polyphenols are also known to have different reactions on the mechanisms of action with
receptors and channels on proteins in cells.

Chemical Structure

Figure 1. The chemical structures of flavonoids. Table in courtesy of (Vauzour, Vafeiadou, &
Spencer, 2012).

Flavanoids are derived from the C6-C3-C6 backbone in which the two C6 units (Ring A
and B shown in Figure 1) are of phenolic nature. The chromane ring (Ring C) has vaiation due o
the hydroxylation pattern and allows further division of subgroups in flavonoids. The majority of
flavonoids have their Ring B attached to the C2 positions on Ring C. However, some flavonoids
whose Ring B is connected at the C3 and C4 position of Ring C are considered isoflavones. Most
of these compounds exist as glycosides in plants and antioxidant capacity depends on the
structural difference and glycosylation patterns.
Anthocyanidins are the principal component of the red, blue and purple pigments in most
flowers, fruits, vegetables and grains. They exist in the glycosidic form. More than 500
anthrocyanins are known depending on the hydroxylation, methoxylatopn patterns on Ring B.
The color of anthrocyanins is pH-dependent, red in acidic and blue in basic conditions (Tsao R. ,
2010).

Figure 2. Chemical structures of polyphenols. Table in courtesy of (Manach, Scalbert, Morand,

Rmsy, & Jimenez, Polyphenols: food sources and bioavailability, 2004).
Pheonlic acids are non-flavanoid compounds known as polyphenols that can be benzoic
acids and cinnamic acids. They are derived from a C1-C6 and C3-C6 backbone shown in Figure
1. Fruits and vegetables contain free phenolic acids while grain seeds or hulls contain phenolic
acids in the bound form.
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Synthesis
Phenolic acids are considered to be metabolites of the shikimate pathway. The shikimate
pathway is a seven step metabolic route used by plants for the biosynthesis of aromatic amino
acids. This pathway is not found in animals, which is why essential amino acids must be
obtained from diet. Biosynthesis of complex polyphenols, flavonoids, is linked to metabolism
through plastid and mitochondrial derived intermediates, requiring the export to the cytoplasm
where they are incorporated and stored (Tsao R. , 2010). The aromatic Ring B and Ring C are
considered to originate from phenylalanine, a product of the shikimate pathway and an
essential amino acid. Ring A originates from three units of malonyl-CoA, added through
sequential decarboxylation condensation reactions that initiate flavonoid biosynthesis (Tsao &
McCallum, 2009). Phenolic compounds are classified according to the nature and complexity
of the carbon structure, degree of skeletal modification and the link between the base usit and
other molecules such as carbohydrates, lipids, proteins or links to other polyphenols (Macheix,
Fleuriet, & Jay-Allemand, 1990).
Simple phenols (C6) are compounds with one monophenol-like catechin or several
phenolic groups. Phenolic acids (C6-C1 or C6-C3) are benzoic or hydroxybenzoic acids such
as gallic acid and cinnamic acids. Flavonoids (C6-C3-C^) are present in plants, are watersoluble and contribute to the plants pigment. They are the most abundant phenolic compounds
in nature. Ligins (C6-C3)n are complex phenolic polymers. Tannins (C6-C3-C6)n are found in
several different types and forms and are a group of condensed flavan-3-ols.
The main precursor of polyphenols is the amino acid L-phenylalanine. Environmental
factors can have a major effect on polyphenol content and depending on environmental
conditions, key biosynthetic enzyme phenylalanine ammonia lyase (PAL), induces production
of phenolic compounds at different times in relation to demand for plant protection
(Abountiolas, 2016). The PAL enzyme catalyzes the first step in the biosynthesis of
phenylpropanoids, which synthesize further into a variety of phenolic compounds. Conversion
of phenylalanine or tyrtosine to cinnamic acid is the first step of the phenylpropanoid pathway
which involves an ammonia elimination reaction also catalyzed by PAL (Alvarez-Parrilla &
Gonzalez-Aguilar, 2009). The pheylpropanoids are then channeled into the flavonoid pathway
via the chalcone synthase enzyme. Enzymes chalcone isomerase, flavone 3-beta-hydroxylase,
dihydroflavonol 4-reductase and anthrocyanidin synthase metabolise further in order to
synthesize anthocyanidin pigments that give the fruit its color (Winkel-Shirley, 2001).

Figure 3: Simplified pathway of phenolic compound synthesis (from: Douce, 2005)

Dietary Sources
Flavonoids are found in most plants. Fruits, vegetables, grains and beverages such
as teas and red wine are the main sources of polyphenols. Quercetin is a polyphenol found in all
plant products while other polyphenols are specific to particular foods. Flavanones are found in
citrus fruit, isoflavones are found in soya and etc.. Some foods contain multiple forms of
polyphenols, like apples, which contain flavanol monomers or oligomers, chlorogenic acis and
other hydroxycinnamic acids, phloretin, quercetin glycosides, and anthocyanins. The main
sources of dietary polyphenols are fruit and beverages, and to a lesser extent vegetables. The
total intake varies from studies due to large uncertainties and lack of comprehensive data.
Polyphenols also aid in the color of fruits and vegetables, and thus culinary preparation
can have an effect on polyphenol content since the outer parts have a higher concentration.
Temperature can also effect polyphenols depending on the chemical structure, onions and
tomatoes lose between 75-80% of their quercetin content after being boiled for 15 minutes and
65% after cooked in a microwave oven, 30% after frying (Crozier, Lean, McDonal, & Black,
1997). When jams and jellies are made the fruit is exposed to high temperatures during
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processing. Valuable components of the fruits are damaged such as anthocyanin due to
polymerization and other chemical reactions. Polyphenol oxidase contributes to color loss during
the process. However, antioxidant capacity showed to retain at more than 60% in raspberry jam
despite the losses of phenols and anthocyanin (Zhao, 2007). During wine-making processes, the
maceration accounts for the polyphenol content of red wines being 10 times as high than white
wine. When flavonoids are removed, causing discoloration, the polyphenol content is lowered.

Figure 4: Polyphenols from food sources and their properties. Table courtesy of (Vauzour, Vafeiadou, &
Spencer, 2012)

Bioavailability
In order to get the most from the health benefits of polyphenols it is essential to
understand the bioavailability. Polyphenols most common in the human diet are not necessarily
the most active within the body. The bioavailability of polyphenols is in relation to intrinsic
activity and how they are absorbed by the villi in the lower intestine. The structure of the
compounds also determines whether they are highly metabolized or rapidly eliminated. In
addition, the metabolites found in the blood stream that bring nutrients to organs differ from their
native structure in terms of bioavailability.

Figure 5: Overview of bioavailability of polyphenols (from: Bohn, 2014)

External factors

Environmental factors (sun exposure, degree of ripeness);

food availability

Food processing related factors

Thermal treatments; homogenization; liophylization;

cooking and methods of culinary preparation; storage

Food related factors

Food matrix; presence of positive or negative effectors

of absorption (fat, fiber)

Interaction with other compounds

Bonds with proteins (albumin) or with polyphenols with

similar mechanism of absorption

Polyphenols related factors

Chemical structure; concentration in food; amount introduced

Intestinal factors (enzyme activity; intestinal transit time;

colonic microflora).
Host related factors
Systemic factors (gender and age; disorders and/or pathologies;
genetics; physiological condition)
Table 1: Factors affecting the bioavailability of dietary polyphenols in humans.
Testing the bioavailability of polyphenols in vivo involves the intake of one portion of
food containing a tested polyphenol. The blood concentration reflects the ability of the organism
to take up the polyphenol. In this case, tissue uptake and bioactivity studies have minor
implications. However, studies show that even low amounts of polyphenols can be absorbed
repeatedly which significantly increases the concentrations in the blood plasma and cellular level
(Scalbert & Williamson, 2003). Due to the restraints on testing, bioavailability and bioactivity of
a single phenolic compound are difficult to obtain.
External factors affect the polyphenol content in plants, which can subsequently affect the
bioavailability in humans. These factors are based on environmental and fruit ripeness factors.
The ripeness of the fruit can also affect the polyphenol content. When fruit ripens the phenolic
acid content lowers. Food processing such as thermal treatment also affects the content and how
polyphenol compounds are absorbed. Cooking fruits and vegetables lowers the amount of
nutrients taken up by the gut in humans. Different cooking methods result in different phenolic
content for most vegetables. Storage is also proportional to the content of polyphenols. The
longer the product, such as fruit juice, is stored, the lower the content.
In recent years, studies have indicated that the effect of food matrix on bioavilibility.
Proteins, carbohydrates, and fats can affect polyphenol absorption. Sugar showed to lower
bioavailability of resveratrol glycosides in grape juice (Meng, Maliakal, Lu, Lee, & Yang, 2004),
while fat content enhanced absorption of flavonoids (Lesser, Cermark, & Wolffram, 2004).

Metabolism
Most polyphenols exist in the form of glycosides, polymers or esters that are not able to
be absorbed in their native form. In order for the nutrients to be absorbed they are hydrolyzed by
enzymes in the intestines. Microflora in the colon can also absorb nutrients from polyphenols
however the efficiency of absorption is reduced due to flora breaking down the aglycones. The

metabolism of polyphenols occurs in the small intestine where agylcones, the compound
remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom, are absorbed.
When aglcones are degraded, various simple aromatic acids are released.
During the course of absorption, polyphenols are conjugated in the small intestine before
the liver. The human colon harbors a highly complex microbial ecosystem that is acquired at
birth. Figure 3 illustrations the complex interactions between the guts microflora and the human
host. The colon receives dietary polyphenols and metabolites are excreted back into the intestine
via the enterohepatic cycle (Duynhovena, et al., 2011). Entrohepatic recycling allows a longer
presence of polyphenols within the body. The metabolism process includes methylation, sulfation
and glucuronidation, a common metabolic detoxification process that restricts their potential
toxic effects and facilitates bilary and urinary elimination (Manach, Scalbert, Morand, Remesy,
& Jimenez, Polyphenols: food sources and bioavailability, 2004). Conjugated mechanisms are
highly efficient, after consumption aglycones are either absent or in low concentrations in the
blood. Polyphenols circulating in the blood are conjugated derivatives bound to albumin.

Figure 6: The metabolic fate of dietary polyphenols in humans. In the colon, microbial bioconversion
pathway can be depicted. Microbial bioconversion products undergo further metabolism in the liver in
order to be absorbed and excreted. From: (Duynhoven, 2011)

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Health Promoting Properties of Polyphenolic Compounds

Antioxidant Capacity
Antioxidant capacity in foods is generally measured according to chemical reactions
involved, hydrogen or electron transfer reactions. To measure a hydrogen transfer reaction,
hydrogen atom transfer (HAT) assays apply the antioxidant and substrate; they compete for
thermally generated peroxyl radicals via decomposition of azo compounds (Abountiolas, 2016).
In electron transfer-based assays, the capacity is measured of an antioxidant and its ability to
reduce an oxidant, resulting in a color change read with a spectrophotometer. These assays
measure the electron transfer reaction between the added oxidant and antioxidants in order to
measure antioxidant capacity.

Figure 7. A schematic representation of free radicals on the signal transduction pathway. (From:
McCord, 2000)
In addition to evolutionary responses to combat the byproducts of oxidative metabolism,
antioxidants can limit oxidative damage before they inflict damage on the DNA and cell
membrane. The ability to synthesize or accumulate antioxidants is vital for our health and there
are hundreds of kinds of antioxidant molecules, especially in plants. High intake of fruits,
vegetables and whole grains have been linked to lower risk of many chronic disease due to their
richness in polyphenols. Many diseases are related to oxidative stress from reactive oxygen and
nitrogen species and phytochemicals, specifically polyphenols, are the main contributor of the
total antioxidant activities of fruits rather than vitamin C (Wang, Cao, & Prior, 1996).
Polyphenols are strong antioxidants that can neutralize free radicals by donating an electron or
hydrogen atom. The complex system and hydroxylation patterns such as the 3-hydroxy group in
flavonols are important contributors in antioxidant capacity.

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In Vitro Antioxidant Capacity

Extensive structure-activity studies have demonstrated that flavanols and phenolic
phytochemicals have scavenging effects on free radicals in vitro. Free radicals are molecules
with an unpaired electron in the outer orbit, making it unstable and very reactive. Oxygen and
nitrogen free radicals can be converted to non-radical reactive species or removed through
enzymatic and non-enzymatic reactions (Fang, Yang, & Wu, 2002). Researchers are focusing
their efforts in chemotherapeutics due to the recurrence of drug-resistant tumors. Diets rich in
grains, fruits and vegetables are known to reduce cancer risks making flavonoids anti-cancer
agents.
Free radicals play an essential role in biological evolution due to their beneficial effects
on organisms. Oxygen radicals exert critical reactions such as signal transduction, gene
transcription and regulation of guanylate cyclase activity in cells (Fang, Yang, & Wu, 2002). A
free radical and important signaling molecule is NO. Levels of NO is essential for relaxation and
proliferation of vascular muscle, No made by neurons serves as a neurotransmitter, and NO
generated by active macrophages mediate an immune response. However, oxidants, free radicals
and other reactive species cause the oxidation of biomolecules (protein, amino acids, lipids, and
DNA), leading to cell proliferation and death (McCord J. M., 2000). Thus, it is important to note
that free radicals serve as signaling and regulatory molecules at physiologic levels and
proliferating and noxious oxidants at pathologic levels.
The removal of free radicals can be exacted by dietary phytochemical antioxidants such as
phenolic and polyphenolic compounds (Decker, 1995). In this study, tea polyphenols were used
in vitro to enhance the resistance of oxidative stress in red blood cells, scavenge superoxide and
hydroxyl radicals, and inhibit modification of low-density lipoprotein (LDL) (Fang, You, &
Chen, 1998). The results indicated that the supplementation of tea polyphenols in vivo decreased
S180 sarcoma weight in mice and increased the survival time, or life span.
In another study on tea polyphenol, in vitro, the tea was found to significantly inhibit
S180 cell growth in mice with induced liver cancer. It was also found that the inhibition rate
increased with increasing content of tea polyphenol (Cui, et al., 2012). The results showed that
tea polyphenol had inhibitory effects in tumor weight on the S180 model mice. The tea
polyphenol significantly reduced activity of liver enzymes in the blood of hepatocarcinoma mice
due to its ability to reduce free-radical-induced oxidative damage. It was also noted that tea
polyphenols maintained the integrity of the plasma membrane, not allowing leakage of enzymes
(Cui, et al., 2012). This may be due to the tea polyphenols ability to trap reactive oxygen specie
(ROS).
Cranberry extract was shown to inhibit proliferation of tumor cell lines in vitro in a
limited number of studies (Ferguson, J., Chambers, & Koropatnick, 2004). The cranberry extract
delayed the growth and inhibited metastasis of human breast tumor cells (MDA-MB-435) when
provided as a diet supplement to tumor-bearing mice (Guthrie, 2000). Ocean Spray cranberries
were used to make an extract and the phytochemicals were shown to inhibit proliferation and
enhance apoptosis in experimental cancer models. The antiproliferative activity was associated
with a fraction that eluted in acidified methanol (Fr6) and contained phenolics and flavonoids
(Ferguson, J., Chambers, & Koropatnick, 2004). A flavonoid-rich fraction (Fr6) inhibited
proliferation by stopping the cell cycle progression and leading to apoptosis.

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In Vivo Antioxidant Capacity

The study in which cranberry extract was used to find the mechanism that caused
antiproliferation effects that flavonoids have on tumor cell lines also resulted with in vivo
findings. In order to determine the mechanism responsible for the antiproliferative effects of the
cranberry extract, the human breast cancer tumor cell (MDA-MB-435) line was chosen as a
model to display antiproliferative activity in vivo (Guthrie, 2000). In this study it was possible
that Fr6 (a flavonoid-rich fraction) was preventing cells from proliferating without killing the
cells so it was possible that Fr6 arrested cells in a specific phase of the cell cycle. However,
arresting a cell in the cell cycle could lead to apoptosis, growth inhibition of Fr6 could also be
due to a nonspecific toxic effect on cells. The study indicated that treatment with Fr6 resulted in
accumulation of cells in both G1 and G2/M. This suggests that there may be different effects at
different stages of the cell cycle when treated with Fr6. The findings indicated that in vivo, a
tumor treated with Fr6 would regress rather than sit dormant and then resume growth after
treatment was stopped.

Non-Antioxidant Properties
Oxidative stress plays a significant role in biological processes and evolution.
Polyphenols have been verified to have significant antioxidant qualities but studies suggest that
there is more to polyphenols than its ability to donate a hydrogen atom to reactive oxygen
species. Studies indicate that cellular interactions could play a major role in accompanying
phenolic antioxidant capacity. Evidence denotes that the metabolites of polyphenols exert
antioxidant activity in biological fluids. Sulphated and glucuronidated forms of flavonoids have
lower capacity for donating hydrogen ions. Furthermore, it is likely that flavonoids undergo
intracellular metabolism when subjected to thiols (Manach & Donovan, 2004).

Cell Signaling
So far, flavonoids have been linked to reduce health factors such as cardiovascular
disease, cancer, inflammation, digestive problems, diabetes and neurological complications.
In the plasma membrane, polyphenols shield from external aggressors by changing
physicochemical characteristics and interacting with channels, receptors and enzymes.
In the cytosol (antioxidant, cell signaling (transcription factors), regulation of enzymes, receptors
Polyphenols induce cytochrome P450 in the endoplasmic reticulum.
Intracellular signaling pathways play essential roles to protect cells against extracellular
attacks. The mitogen activates proteins kinases (MAPK) are involved in directing cellular
responses to stimuli such as mitogens, osmotic stress, heat shock and proinflammatory cytokines.
They also regulate cell functions including proliferation, gene expression, diffrentioation,
mitosis, cell survival, and apoptosis (Pearson, et al., 2001). Activation and phosphorylation of

13

MAPKs leads to amplification of the signal and mediate a broad range of biological processes
including proliferation, cell division, apoptosis, inflammation, and growth or cell cycle arrest,
depending on the stimulus. Flavonoids mediate the inhibition of oxidative stress-induced
apoptosis by preventing the activation of JNK. This may be possible by having an effect on one
of the upstream MAPK-activating proteins that transduces signals to JNK. Oxidative stress has a
diverse effect on the signaling pathway in cells, specifically in the MAPK pathway (Torres &
Forman, 2003). However, flavonoids meditate the inhibition of this activation although it is not
clear if this is due to antioxidant capacity or due to inhibitory actions at signaling molecules.

Figure 8: A simplified overview of the MAPK pathway in mammals.

Flavonoids inhibit oxidative stress-induced apoptosis by preventing
activation of JNK preventing apoptosis in cells. (from: Mitogen-activated
protein kinase, 20016)
Research has also been conducted on the beneficial effects of epicatechin, a flavone that
shows evidence that the cytoprotective nature of polyphenols is based on their interactions in cell
signaling pathways (Williams, Spencer, & Rice-Evans, 2004). The research papers reviewed on
epicatechin agreed that phenolic activity had beneficial effects on active oxygen radicals but
could not find the mechanism behind the neutralization. Antioxidant capacity is a recognize
mechanism but some studies suggest that signaling pathways may be an important component as
well.
The formation of reactive oxygen species is a normal by-product of cellular reactions.
Polyphenols and other related flavonoids are being studied for their effects on combating free
radicals. Since free radicals are a very reactive species it is important to understand the effects on
cell membrane integrity when polyphenols and free radicals interact. In order to understand the
effects of polyphenols on cell membrane integrity, a study was read on the effects of silver

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nanoparticles, using tea polyphenols, have on cell function. The design of this study was to find
counteracting effects of ROS. Epicatechin, a flavonoid that aids against risk of stroke, heart
failure, cancer and diabetes, and is also an antioxidant that protects the skin from UV damage
and tumor formation (Moulton, Braydich-Stolle, Nadagouda, Kunzelman , Hussain , & Varma ,
2010). In this study it was used as a tea extract, coating nanoparticles that are known to induce
formation of ROS, in order to find the effects that flavonoids have on cell structure. In cells that
had no internalized nanoparticles, no evidence of cytotoxicity was observed. Instead, a general
increase in mitochondrial function was observed which was inversely related to the concentration
of epicatechin (Moulton, Braydich-Stolle, Nadagouda, Kunzelman , Hussain , & Varma , 2010).
The protective and prolific reactions to the nanoparticles is likely the result of antioxidants
present on the surface of the nanoparticle since it was coated, or capped, using epicatechin. Data
from the study on the mitochondrial function (MTS) and lactate dehydrogenase (LDH; a stable
cytosolic enzyme released upon cell lysis) illustrated that cell viability was positively affected
due to the antioxidants protecting the cells.
Nanoparticles synthesized using tea extract were internalized by the cells with an inverse
relationship to concentration, the higher the concentration of the extract the greater the cellular
interaction and internalization (Moulton, Braydich-Stolle, Nadagouda, Kunzelman , Hussain , &
Varma , 2010). No cellular morphology was apparent despite the cells being internalized and no
apparent cytotoxic effect was found from the presence of nanoparticles. The tea extract that
remains on the surface of the nanoparticles, due to synthesis, unregulated free radicles, protecting
the cells from ROS damage. Tea has also been known to trap reactive oxygen species, reducing
their ability to damage proteins and thus protecting cell membrane integrity.
One of epicatechins metabolites, 3-O-methyl epicatechin has been shown to elicit
cytoprotective effects agains oxidative stress. The cytoprotective action of this compound was
also found to inhibit caspase-3 activation and activation of pro-apoptic MAPK proteins
(Schroeter, Spencer, Rice-Evans, & Williams, 2010). Due to the amounts of studies confirming
that the antioxidant actions of flavonoids protect against oxidative stress, this study pre-treated
with flavonoids and found that it did not strongly reduce overall intracellular oxidative stress by
exposure to oxidized low-density lipoprotein (oxLDL) and did not alter oxLDL uptake. This
suggests that the protection from cell death by oxidative stress is not just from flavonoids
hydrogen-donating properties but that flavonoids act selectively within the MAPK signaling
cascade (Kong, Rong, Chen, Mandlekar, & Primiano, 2000). Oxidative stress stimulates
phosphorylation and activation of ERK1/2, which is involved in pro-survival signaling (Figure
4). Studies indicate that inhibition of MEK, an upstream activator of ERK1/2 could block cell
death. However, the results indicated that neuroprotective effects of flavonoids were not linked
to the inhibitory action within the ERK1/s cascade. Results indicate that flavonoids may exert
protective actions through an attenuation of a pro-apoptic signaling cascade downstream of JNK
(Schroeter, Spencer, Rice-Evans, & Williams, 2010).

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DNA Repair
In the nucleus, polyphenols interact with DNA and the regulation of enzymes. Tea
polyphenols scavenge active oxygen radicals and inhibit DNA biosynthesis of tumor cells. They
also block the inhibition effect of carcinogens in intercellular communication and induce
apoptosis
The polyphenol epigallocatechin-3-gallate (EGCG) can inhibit DNA methyltransferase (DNMT)
activity and reactivate methylation-silenced genes in cancer cells (Fang, et al., 2003). DNA
methylation is a key component in gene regulation but the cause of methylation in tumor cells
remains unknown. The expression of DNMT levels have been closely studied at the RNA level
and have reported overexpression for DNMT1. Overexpression of DNMT1 in tissue culture cells
gradually induces CpG island hypermethylation and results in cellular transformation
(Robertson, 2001). Hypermethylation of CpG islands in the promoter region are an important
mechanism to silence expression of many important genes in cancer (Fang, et al., 2003).
Inhibition of DNMT would block the hypermethylation of the newly synthesized DNA strand,
resulting in re-expression of silenced genes. DNMT inhibitors have shown to inhibit cancer cell
growth, induce cancer cell apoptosis, and reduce tumor volume in mice but the toxic side effects
are concerning. In this study EGCG was found to exert inhibitory effects on DNMT1 by
blocking cytosine from entering its active site and preventing methylation. Thus demonstrating
that EGCG inhibits DNMT activity without any toxic side effects.

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Conclusion
In the result of reading numerous studies on polyphenols, all conclusions point to
phenolic compounds having a positive effect on cancer, diseases and overall health. With respect
to in vivo studies, the scavenging effects and cell signaling properties of metabolites had reduced
risk factors associated with the study. The antiproliferative activity in vivo suggested that cell
signaling attributes to cell cycle arrest when flavonoid extracts were used. Both conclusions
suggest there may be more important roles of polyphenols than just antioxidant capacity,
although both factors have favorable outcomes.
The polyphenol EGCG was found to inhibit DNMT activity, inhibiting cancer cell growth
and inducing cancer cell apoptosis. This result is much more favorable than current DNMT
inhibitors that come with toxic side effects. The only concerning factor is the in vivo study by
Guthrie that suggested that flavonoid-rich fractions only made the tumor sit dormant while
treated and once the treatment of Fr6 stopped, the tumor resumed growth. However, Guthries
research was based on an extract and after reading many of studies it is clear that different
polyphenols and different metabolites have different functions and effects in organisms.
This also brings me to another important conclusion that the interactions on cell
signaling pathways from polyphenol metabolites have been studied on specific diseases and cell
types. The certain outcome of how polyphenols affect cancer and diseases is unclear although
studies suggest that they are helpful. It is my opinion that humans who have healthy lifestyles
and eat diets rich in polyphenols will be ahead of the game in preventing chronic diseases and
cancers. For those who have cancer and diseases due to poor nutrition may reduce risk factors
that could depreciate their health by switching to a diet rich in polyphenols. If further studies
indicate that polyphenol extracts can indeed cause apoptosis of cancer cells in humans the
outlook would be positive. However, reversing years of damage from oxidative stress is unlikely.
Living a healthy lifestyle and having optimum health is vital to the survival of
organisms. Nutrient poor diets that infiltrate most households in America today are killing our
kind. Thankfully science has shed some light on the implications that nutrient poor diets have on
our health but many are already addicted to foods high in fat and sugar content. I believe that
polyphenol extracts and supplements may provide relief and essential nutrients to many but it
does not solve the issue. Studies on polyphenols should be made more mainstream so that
others can understand that diets rich in polyphenols will significantly reduce health risk factors
as opposed to having unhealthy eating habits and being aware that polyphenols are possibly
being used to kill cancer cells or that polyphenol extracts can supplement their diet.

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