Flavonoids
- Flavonoids are a large family of polyphenolic compounds synthesized
by plants. (More Information)
- Scientists are interested in the potential health benefits of
flavonoids associated with fruit and vegetable-rich diets. (More Information)
- Many of the biological effects of flavonoids appear to be related
to their ability to modulate cell-signaling pathways, rather than
their antioxidant activity. (More Information)
- Although higher intakes of flavonoid-rich foods are associated
with reductions in cardiovascular disease risk, it is not yet
known whether flavonoids themselves are cardioprotective. (More Information)
- Despite promising results in animal studies, it is not clear
whether high flavonoid intakes can help prevent cancer in humans.
(More Information)
- It is not yet clear how flavonoid
consumption affects neurodegenerative disease risk in humans.
(More Information)
- Higher intakes of flavonoid-rich foods have been associated
with reduced risk of chronic disease in some studies, but it is
not known whether isolated flavonoid supplements or extracts will
confer the same benefits as flavonoid-rich foods.
Flavonoids are a large family of compounds synthesized by
plants that have a common chemical structure
(1).
The basic structure of a flavonoid is shown in
figure
1. Flavonoids may be further divided into subclasses (see
table
1). Over the past decade, scientists have become increasingly interested
in the potential for various dietary flavonoids to explain some of the
health benefits associated with fruit- and vegetable-rich diets. This article
reviews the scientific evidence for the hypothesis that dietary flavonoids
promote health and prevent disease in humans. For more detailed information
on the health effects of isoflavones, a subclass of flavonoids with estrogenic
activity, see the separate article on
Soy
Isoflavones. For more information on the health benefits of foods
that are rich in flavonoids, see the separate articles on
Fruits
and Vegetables,
Legumes,
and
Tea.
Table 1: Common Dietary Flavonoids
(Select the highlighted text to see chemical structures.)
|
Flavonoid Subclass
|
Dietary Flavonoids |
Some Common Food Sources |
Anthocyanidins
|
Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin,
Petunidin
|
Red, blue, and purple berries; red and purple grapes;
red wine |
Flavanols
|
Monomers (Catechins):
Catechin,
Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin
gallate
Dimers and Polymers:
Theaflavins,
Thearubigins, Proanthocyanidins |
Catechins: Teas (particularly
green and white), chocolate, grapes, berries, apples
Theaflavins, Thearubigins: Teas (particularly black
and oolong)
Proanthocyanidins: Chocolate, apples, berries,
red grapes, red wine |
Flavanones
|
Hesperetin, Naringenin, Eriodictyol
|
Citrus fruits and juices, e.g., oranges, grapefruits,
lemons |
Flavonols
|
Quercetin, Kaempferol, Myricetin, Isorhamnetin
|
Widely distributed: yellow onions, scallions, kale,
broccoli, apples, berries, teas |
Flavones
|
Apigenin, Luteolin
|
Parsley, thyme, celery, hot peppers, |
Isoflavones
|
Daidzein, Genistein, Glycitein
|
Soybeans, soy foods, legumes |
Metabolism and Bioavailability
Flavonoids connected to one or more sugar molecules are known as flavonoid
glycosides, while those that are not connected to a sugar molecule are called
aglycones. With the exception of flavanols (catechins and proanthocyanidins),
flavonoids occur in plants and most foods as glycosides
(2).
Even after cooking, most flavonoid glycosides reach the small intestine
intact. Only flavonoid aglycones and flavonoid glucosides (bound to glucose)
are absorbed in the small intestine, where they are rapidly metabolized
to form methylated, glucuronidated, or sulfated
metabolites
(3). Bacteria that normally colonize
the
colon also play an important
role in flavonoid metabolism and absorption. Flavonoids or flavonoids
metabolites that reach the colon may be further metabolized by bacterial
enzymes,
and then absorbed. A person's ability to produce specific flavonoid
metabolites may vary and depends on the milieu of the colonic microflora
(4, 5). In general,
the
bioavailability
of
flavonoids is relatively low due to limited absorption and rapid
elimination.
Bioavailability differs for the various flavonoids: isoflavones
are the most bioavailable group of flavonoids, while flavanols
(proanthocyanidins and tea catechins) and anthocyanins are very poorly
absorbed
(6). Since flavonoids are rapidly and extensively metabolized, the
biological activities of flavonoid metabolites are not always the same
as those of the parent compound [reviewed in
(7)].
When evaluating the data from flavonoid research in cultured cells, it
is important to consider whether the flavonoid concentrations and metabolites
used are physiologically relevant
(8).
In humans, peak
plasma concentrations
of soy isoflavones and citrus flavanones have not been found to exceed
10 micromoles/liter after oral consumption. Peak plasma concentrations
measured after the consumption of anthocyanins, flavanols and flavonols
(including those from tea) are generally less than 1 micromole/liter
(3).
Direct Antioxidant Activity
Flavonoids are effective scavengers of free radicals in the test tube
(
in vitro)
(9,
10). However, even with very high flavonoid intakes,
plasma
and intracellular flavonoid concentrations in humans are likely to be
100-1,000 times lower than concentrations of other
antioxidants,
such as ascorbate (
vitamin
C), uric acid, or glutathione. Moreover, most circulating flavonoids are actually
flavonoid
metabolites, some
of which have lower antioxidant activity than the parent flavonoid. For
these reasons, the relative contribution of dietary flavonoids to plasma
and tissue antioxidant function
in
vivo is likely to be very small or negligible
(7,
11, 12).
Metal Chelation
Metal ions, such as iron and copper, can
catalyze
the production of
free radicals.
The ability of flavonoids to chelate (bind) metal ions appears to contribute
to their antioxidant activity
in
vitro (13, 14). In living organisms,
most iron and copper are bound to proteins, limiting their participation
in reactions that produce free radicals. Although the metal-chelating
activities of flavonoids may be beneficial in pathological conditions
of iron or copper excess, it is not known whether flavonoids or their metabolites function
as effective metal chelators
in
vivo (11).
Effects on Cell-Signaling Pathways
Cells are capable of responding to a variety of different stresses or
signals by increasing or decreasing the availability of specific proteins.
The complex cascades of events that lead to changes in the expression
of specific genes are known as
cell-signaling pathways or signal transduction pathways. These pathways
regulate numerous cell processes, including growth,
proliferation,
and death (
apoptosis). Although
it was initially hypothesized that the biological effects of flavonoids
would be related to their
antioxidant
activity, available evidence from cell culture experiments suggests that
many of the biological effects of flavonoids are related to their ability
to modulate cell-signaling pathways
(7).
Intracellular concentrations of flavonoids required to affect cell-signaling
pathways are considerably lower than those required to affect cellular
antioxidant capacity. Flavonoid
metabolites
may retain their ability to interact with cell-signaling proteins
even if their antioxidant activity is diminished
(15,
16). Effective signal transduction requires proteins known as kinases
that
catalyze the
phosphorylation
of target proteins at specific sites. Cascades involving specific phosphorylations
or dephosphorylations of signal transduction proteins ultimately affect
the activity of
transcription
factors—proteins that bind to specific response elements on
DNA
and promote or inhibit the
transcription
of various
genes. The results of
numerous studies in cell culture suggest that flavonoids may affect chronic
disease by selectively inhibiting kinases
(7,
17). Cell growth and proliferation
are also regulated by growth factors that initiate cell-signaling cascades
by binding to specific receptors in cell membranes. Flavonoids may alter
growth factor signaling by inhibiting receptor phosphorylation or blocking
receptor binding by growth factors
(18).
Modulation of cell-signaling pathways by flavonoids could help prevent
cancer by:
Stimulating phase II detoxification enzyme activity
(19, 20): Phase II detoxification
enzymes
catalyze reactions
that promote the
excretion
of potentially toxic or
carcinogenic
chemicals.
Preserving normal cell cycle regulation (21,
22): Once a cell divides, it passes through a sequence of stages collectively
known as the cell cycle before it divides again. Following
DNA
damage, the cell cycle can be transiently arrested at damage checkpoints,
which allows for DNA repair or activation of pathways leading to cell death
(
apoptosis) if the damage
is irreparable
(23). Defective
cell cycle regulation may result in the propagation of
mutations
that contribute to the development of cancer.
Inhibiting proliferation and inducing apoptosis (24-26): Unlike normal cells, cancer cells proliferate rapidly and lose
the ability to respond to cell death signals that initiate apoptosis.
Inhibiting tumor invasion and angiogenesis (27,
28): Cancerous cells invade normal tissue aided by
enzymes
called matrix-metalloproteinases. To fuel their rapid growth, invasive tumors must develop new
blood vessels by a process known as angiogenesis.
Decreasing inflammation (29-31):
Inflammation can result
in locally increased production of
free
radicals by inflammatory enzymes, as well as the release of inflammatory
mediators that promote cell proliferation and angiogenesis and inhibit
apoptosis
(32).
Modulation of cell-signaling pathways by flavonoids could help prevent
cardiovascular disease by:
Decreasing inflammation (29-31):
Atherosclerosis is now
recognized as an inflammatory disease, and several measures of
inflammation
are associated with increased risk of
myocardial
infarction (heart attack)
(33).
Decreasing vascular cell adhesion molecule expression
(34, 35): One of the earliest events
in the development of atherosclerosis is the recruitment of inflammatory
white blood cells from the blood to the arterial wall. This event is dependent
on the expression of adhesion molecules by the
vascular
endothelial cells that line the inner walls of blood vessels
(36).
Increasing endothelial nitric oxide synthase (eNOS) activity
(37): eNOS is the enzyme that catalyzes
the formation of nitric oxide by vascular endothelial cells. Nitric oxide
is needed to maintain arterial relaxation (
vasodilation).
Impaired nitric oxide-dependent vasodilation is associated with increased
risk of
cardiovascular
disease (38).
Decreasing platelet aggregation (39,
40):
Platelet aggregation
is one of the first steps in the formation of a blood clot that can occlude
a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively.
Inhibiting platelet aggregation is considered an important strategy in
the primary and secondary prevention of cardiovascular disease
(41).
Cardiovascular Disease
Epidemiological Evidence
Several
prospective
cohort studies conducted in the U.S. and Europe have examined the
relationship between some measure of dietary flavonoid intake and
coronary
heart disease (CHD) risk
(42-49).
Some studies have found that higher flavonoid intakes to be associated
with significant reductions in CHD risk
(42-46,
50),
while others have reported no significant relationship
(47-49,
51).
In general, the foods that contributed most to total flavonoid intake
in these cohorts were black tea, apples, and onions. One study in the Netherlands
also found cocoa to be a significant source of dietary flavonoids. Of
seven prospective cohort studies that examined relationships between
dietary flavonoid intake and the risk of stroke, only two studies found
that higher flavonoid intakes were associated with significant reductions
in the risk of stroke
(45,
52),
while five found no relationship
(46,
49, 50,
53, 54). Although data from prospective
cohort studies suggest that higher intakes of flavonoid-rich foods
may help protect against CHD, it cannot be determined whether such protection
is conferred by flavonoids, other nutrients and phytochemicals in flavonoid-rich
foods, or the whole foods themselves
(55).
Vascular Endothelial Function
Vascular endothelial
cells play an important role in maintaining cardiovascular health by producing
nitric oxide, a compound that promotes arterial relaxation (
vasodilation)
(56).
Arterial vasodilation resulting
from endothelial production of nitric oxide is termed
endothelium-dependent
vasodilation. Several clinical trials have examined the effect
of flavonoid-rich foods and beverages on endothelium-dependent
vasodilation. Two controlled
clinical trials found that daily consumption of 4-5 cups
(900-1,250
ml) of black tea for four weeks significantly improved
endothelium-dependent
vasodilation in patients with coronary artery disease
(57)
and in patients with mildly elevated serum
cholesterol levels
(58)
compared with the equivalent amount of caffeine alone or hot water. Other
small clinical trials found similar improvements in endothelium-dependent
vasodilation in response to daily consumption of about 3 cups (640 ml)
of purple grape juice
(59) or a
high-flavonoid dark chocolate bar for two weeks
(60).
More recently, a 6-week cocoa intervention trial in 32 postmenopausal
women with high cholesterol levels found significant improvements in
endothelial function with daily cocoa supplementation
(61). Improvements in endothelial function were also noted in conventionally medicated
type 2 diabetics following flavanol-rich cocoa supplementation for 30 days
(62). The flavanol epicatechin appears to be one of the compounds in flavanol-rich cocoa responsible for its vasodilatory effects
(63).
Interestingly, a recent randomized controlled trial in 44 older adults
found that low doses of flavonoid-rich dark chocolate (6.3 grams/day for
18 weeks; equivalent to 30 calories) increased levels of plasma
S-nitrosoglutathione, an indicator of nitric oxide production, compared
to flavonoid-devoid white chocolate
(64).
Endothelial nitric oxide production also inhibits the adhesion and aggregation
of
platelets, one of the first
steps in blood clot formation
(56).
A number of clinical trials have examined the potential for high flavonoid
intakes to decrease various measures of platelet aggregation outside of
the body (ex vivo); such trials have reported mixed results. In general, increasing flavonoid
intakes by increasing fruit and/or vegetable intake did not significantly
affect ex vivo platelet aggregation
(41,
65, 66),
nor did increasing black tea consumption
(67,
68). However, several small clinical trials in healthy adults have
reported significant decreases in ex vivo measures of platelet aggregation
after consumption of grape juice (~500 ml/day) for 7-14 days
(69-71).
Similar inhibition of platelet aggregation has been reported
following acute or short-term consumption of dark chocolate
(72) and following acute consumption of a flavonoid-rich cocoa beverage
(73, 74). In addition, a
placebo-controlled
trial in 32 healthy adults found that 4-week supplementation with
flavanols and procyanidins from cocoa inhibited platelet aggregation and
function
(75). The
results of some controlled clinical trials suggest that relatively high
intakes of some flavonoid-rich foods and beverages, including black tea,
purple grape juice, and cocoa, may improve vascular endothelial
function, but it is not known whether these short-term improvements will
result in long-term reductions in cardiovascular disease risk.
Cancer
Although various flavonoids have been found to inhibit the development
of chemically-induced cancers in animal models of lung
(76),
oral
(77), esophageal
(78),
stomach
(79), colon
(80),
skin
(81), prostate
(82, 83),
and mammary (breast) cancer
(84),
epidemiological studies
do not provide convincing evidence that high intakes of dietary flavonoids
are associated with substantial reductions in human cancer risk. Most
prospective cohort
studies that have assessed dietary flavonoid intake using food frequency
questionnaires have not found flavonoid intake to be inversely associated
with cancer risk
(85). Two prospective
cohort studies in Europe found no relationship between the risk of various
cancers and dietary intakes of flavones and flavonols
(86,
87), catechins
(88), or tea
(89). In a cohort of postmenopausal
women in the U.S., catechin intake from tea, but not fruits and vegetables,
was inversely associated with the risk of rectal cancer, but not other
cancers
(90). Two prospective cohort
studies in Finland, where average flavonoid intakes are relatively low,
found that men with the highest dietary intakes of flavonols and flavones
had a significantly lower risk of developing lung cancer than those with
the lowest intakes
(44, 45).
When
individual dietary flavonoids were analyzed, dietary quercetin
intake,
mainly from apples, was inversely associated with the risk of
lung cancer; myricetin intake was inversely associated with the risk of
prostate
cancer
(45). Tea is an important
source of flavonoids (flavanols and flavonols) in some populations, but
most prospective cohort studies have not found tea consumption to be inversely
associated with cancer risk [reviewed in
(91)].
The results of
case-control
studies, which are more likely to be influenced by recall bias, are
mixed. While some studies have observed lower flavonoid intakes in people
diagnosed with lung
(92), stomach
(93, 94), and breast
(95)
cancer, many others have found no significant differences in flavonoid intake
between cancer cases and controls
(96,
97). There is limited evidence that low intakes of flavonoids from
food are associated with increased risk of certain cancers, but it is
not clear whether these findings are related to insufficient intakes of
flavonoids or other nutrients and phytochemicals found in flavonoid-rich foods.
For more information on flavonoid-rich foods and cancer, see separate
articles on
Fruits and Vegetables,
Legumes, and
Tea.
Clinical trials will be necessary to determine if specific flavonoids
are beneficial in the prevention or treatment of cancer; a few clinical
trials are currently under way (see
http://www.cancer.gov/clinicaltrials).
Neurodegenerative Disease
Inflammation,
oxidative
stress, and transition metal accumulation appear to play a role in
the pathology of several
neurodegenerative
diseases, including
Parkinson's
disease and
Alzheimer’s
disease (98). Because flavonoids have anti-inflammatory, antioxidant, and
metal-chelating properties, scientists are interested in the neuroprotective
potential of flavonoid-rich diets or individual flavonoids. At present,
the extent to which various dietary flavonoids and flavonoid
metabolites
cross the blood brain barrier in humans is not known
(99, 100).
Although flavonoid-rich diets and flavonoid administration have been found
to prevent
cognitive impairment
associated with aging and inflammation in some animal studies
(101-104),
prospective cohort
studies have not found consistent inverse associations between flavonoid
intake and the risk of
dementia
or neurodegenerative disease in humans
(105-109).
In a cohort of Japanese-American men followed for 25-30 years, flavonoid
intake from tea during midlife was not associated with the risk of Alzheimer’s
or other types of dementia in late life
(105).
Surprisingly, higher intakes of isoflavone-rich tofu during midlife were
associated with cognitive impairment and brain atrophy in late life (see
Soy Isoflavones)
(106).
A prospective study of Dutch adults found that total dietary flavonoid
intake was not associated with the risk of developing Parkinson's disease
(107) or Alzheimer’s disease
(108),
except in current smokers whose risk of Alzheimer’s disease decreased
by 50% for every 12 mg increase in daily flavonoid intake. In contrast,
a study of elderly French men and women found that those with the lowest
flavonoid intakes had a risk of developing dementia over the next five years
that was 50% higher than those with the highest intakes
(109).
More recently, a study in 1,640 elderly men and women found
that those with higher dietary flavonoid intake (>13.6 mg/day) had
better cognitive performance at baseline and experienced significantly
less age-related cognitive decline over a 10-year period than those with
a lower flavonoid intake (0-10.4 mg/day)
(110). Additionally, a
randomized,
double-blind,
placebo-controlled
clinical trial in 202 postmenopausal women reported that daily
supplementation with 25.6 g of soy protein (containing 99 mg of
isoflavones) for one year did not improve cognitive function
(111). However, a randomized, double-blind, placebo-controlled,
cross-over trial
in 77 postmenopausal women found that 6-month supplementation with 60
mg/day of isoflavones improved some measures of cognitive performance
(112). Although scientists are interested in the potential of flavonoids to protect
the aging brain, it is not yet clear how flavonoid consumption affects
neurodegenerative disease risk in humans.
Food Sources
Dietary sources of flavonoids include tea, red wine, fruits, vegetables,
and legumes. Individual flavonoid intakes may vary considerably depending
on whether tea, red wine, soy products, or fruits and vegetables are commonly
consumed [reviewed in
(3)]. Although
individual flavonoid intakes may vary, total flavonoid intakes in Western
populations appear to average about 150-200 mg/day
(3,
113). Information on the flavonoid
content of some flavonoid-rich foods is presented in
table
2 and
table 3. These values should be considered approximate since a number of
factors may affect the flavonoid content of foods, including agricultural
practices, environmental factors, ripening, processing, storing, and cooking.
For more information about the flavonoid content of foods, see the USDA
databases for the
flavonoid and
proanthocyanidin
content of selected foods. For information on the isoflavone content of
soy foods, see the separate article on
Soy
Isoflavones or the USDA database for the
isoflavone
content of selected foods.
Table 2. Anthocyanin, Flavanol, and Proanthocyanidin Content
of Selected Foods
Table 3. Flavone, Flavonol, and Flavanone Content
of Selected Foods
Supplements
Anthocyanins
Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry
extracts that are rich in anthocyanins are available as dietary supplements
without a prescription in the U.S. The anthocyanin content of these products
may vary considerably. Standardized extracts that list the amount of anthocyanins
per dose are available.
Flavanols
Numerous tea extracts are available in the U.S. as dietary supplements
and may be labeled as tea catechins or tea polyphenols. Green tea extracts
are the most commonly marketed, but black and oolong tea extracts are
also available. Green tea extracts generally have higher levels of catechins
(flavanol monomers), while black tea extracts are richer in theaflavins
and thearubigins (flavanol polymers found in tea). Oolong tea extracts
fall somewhere in between green and black tea extracts with respect to
their flavanol content. Some tea extracts contain caffeine, while others
are decaffeinated. Flavanol and caffeine content vary considerably among
different products, so it is important to check the label or consult the
manufacturer to determine the amounts of flavanols and caffeine that would
be consumed daily with each supplement. (For more information on tea flavanols,
see the Micronutrient Information Center article on
Tea and Dr. Higdon's newsletter article,
"Tea and Chronic Disease Prevention.")
Flavanones
Citrus bioflavonoid supplements may contain glycosides of hesperetin
(hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin
is also available in hesperidin-complex supplements
(114).
Flavones
The peels of citrus fruits are rich in polymethoxylated flavones:
tangeretin, nobiletin, and sinensetin
(3).
Although dietary intakes of these naturally occurring flavones are generally
low, they are often present in citrus bioflavonoid supplements.
Flavonols
The flavonol aglycone, quercetin, and its glycoside rutin are available
as dietary supplements without a prescription in the U.S. Other names
for rutin include rutinoside, quercetin-3-rutinoside, and sophorin
(114).
Citrus bioflavonoid supplements may also contain quercetin or rutin.
Adverse Effects
No adverse effects have been associated with high dietary intakes of
flavonoids from plant-based foods. This lack of adverse effects may be
explained by the relatively low bioavailability and rapid metabolism and
elimination of most flavonoids.
Quercetin
Some men taking quercetin supplements (1,000 mg/day for one month) reported
nausea, headache, or tingling of the extremities
(115).
Some cancer patients given intravenous quercetin in a phase I clinical
trial reported nausea, vomiting, sweating, flushing, and dyspnea (difficulty
breathing)
(116). Intravenous administration
of quercetin at doses of 945 mg/m
2 or more was associated with
renal (kidney) toxicity in that trial.
Tea Extracts
There have been several reports of hepatotoxicity (liver
toxicity) following consumption of supplements containing tea (Camellia
sinensis) extracts
(117, 118). In clinical trials of caffeinated green tea extracts, cancer patients
who took 6 g/day in 3-6 divided doses have reported mild to moderate gastrointestinal
side effects, including nausea, vomiting, abdominal pain, and diarrhea
(119, 120). Central nervous system
symptoms, including agitation, restlessness, insomnia, tremors, dizziness,
and confusion, have also been reported. In one case, confusion was severe
enough to require hospitalization
(119). These side effects were likely
related to the caffeine in the green tea extract
(120).
In a 4-week clinical trial that assessed the safety of decaffeinated
green tea extracts (800 mg/day of EGCG) in healthy individuals, a few
of the participants reported mild nausea, stomach upset, dizziness, or
muscle pain
(121).
Pregnancy and Lactation
The safety of flavonoid supplements in pregnancy and lactation has not
been established
(114).
Drug Interactions
Inhibition of CYP 3A4 by Grapefruit Juice and Flavonoids
As little as 200 ml (7 fluid ounces) of grapefruit juice has been found
to irreversibly inhibit the intestinal drug metabolizing
enzyme,
cytochrome P450 (CYP) 3A4
(122).
Although the most potent inhibitors of CYP3A4 in grapefruit are thought
to be furanocoumarins, particularly dihydroxybergamottin, the flavonoids
naringenin and quercetin have also been found to inhibit CYP3A4
in
vitro. Inhibition of intestinal CYP3A4 can increase the bioavailability
and the risk of toxicity of a number of drugs, including but not limited
to HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin),
calcium channel antagonists (felodipine, nicardipine, nisoldipine, nitrendipine,
and verapamil), anti-arrhythmic agents (amiodarone), HIV protease inhibitors
(saquinavir), immunosuppressants (cyclosporine), antihistamines (terfenadine),
gastrointestinal stimulants (cisapride), benzodiazepines (diazepam, midazolam,
and triazolam), anticonvulsants (carbamazepine), anxiolytics (buspirone)
serotonin specific reuptake inhibitors (sertraline), and drugs used to
treat erectile dysfunction (sildenafil)
(123).
Grapefruit juice may reduce the therapeutic effect of the
angiotensin
II receptor antagonist, losartan. Because of the potential for
adverse
drug interactions, some clinicians recommend that people taking
medications
that undergo extensive presystemic metabolism by CYP3A4 avoid
consuming grapefruit juice altogether to avoid potential toxicities
(122).
Inhibition of P-glycoprotein by Grapefruit Juice and Flavonoids
P-glycoprotein is an efflux transporter that decreases the absorption
of a number of drugs. There is some evidence that the consumption of grapefruit
juice inhibits the activity of P-glycoprotein
(122).
Quercetin, naringenin, and the green tea flavanol, epigallocatechin gallate
(EGCG), have been found to inhibit the efflux activity of P-glycoprotein
in cultured cells
(124). Thus,
very high or supplemental intakes of these flavonoids could potentially
increase flavonoid bioavailability, potentially increasing the toxicity of drugs that are
substrates of P-glycoprotein. Drugs known to be substrates of P-glycoprotein
include digoxin, antihypertensive agents, antiarrhythmic agents, chemotherapeutic
(anticancer) agents, antifungal agents, HIV protease inhibitors, immunosuppressive
agents, H2 receptor antagonists, some antibiotics, and others [reviewed
in
(125)].
Anticoagulant and Antiplatelet Drugs
High intakes of flavonoids from purple grape juice (500 ml/day) and dark
chocolate (235 mg/day of flavanols) have been found to inhibit
platelet
aggregation in ex vivo assays
(69-71,
75). Theoretically, high intakes
of flavonoids (e.g., from supplements) could increase the risk of bleeding
when taken with anticoagulant drugs, such as warfarin (Coumadin), and
antiplatelet drugs, such as clopidogrel (Plavix), dipyridamole (Persantine),
non-steroidal anti-inflamatory drugs (NSAIDs), aspirin, and others.
Nutrient Interactions
Nonheme Iron
Flavonoids can bind nonheme iron, inhibiting its intestinal absorption.
Nonheme iron is the principal form of iron in plant foods, dairy products,
and iron supplements. The consumption of one cup of tea or cocoa with
a meal has been found to decrease the absorption of nonheme iron in that
meal by about 70%
(126, 127).
To maximize iron absorption from a meal or iron supplements, flavonoid-rich
beverages or flavonoid supplements should not be taken at the same time.
Vitamin C
Studies in cell culture indicate that a number of flavonoids inhibit
the transport of vitamin C into cells, and supplementation of rats with
quercetin and vitamin C decreased the intestinal absorption of vitamin C
(128). More research
is needed to determine the significance of these findings in humans.
