Q J Med 2001; 94:277±282

Commentary
QJM
Tea flavonoids and cardiovascular health
R.A. RIEMERSMA, C.A. RICE-EVANS 1 , R.M. TYRRELL 2 , M.N. CLIFFORD 3
and M.E.J. LEAN 4
From the Cardiovascular Research Unit, University of Edinburgh, 1Wolfson Centre for
Age-Related Diseases, King's College London, 2Department of Pharmacy and Pharmacology,
University of Bath, 3Food Safety Research Group, University of Surrey, and 4Department of
Human Nutrition, University of Glasgow, UK

Summary
Tea is rich in antioxidant polyphenols (catechins,
flavonols, theaflavins and thearubigins). Epidemio-
logical evidence relating regular consumption of
tea or related polyphenols to CHD is equivocal.
Catechins are absorbed from tea, but low plasma
concentrations are attained. The bioavailability of
theaflavins and thearubigins is unknown. Tea does
not reduce blood pressure or plasma lipids in well-
controlled human trials. Tea polyphenols inhibit
LDL lipid peroxidation in vitro, but the effect
ex vivo is small. The plasma antioxidant potential
increases after drinking green but not black tea.
Tea consumption tended to reduce the develop-
ment of aortic atherosclerosis in rabbits. Tea poly-
phenols exert marked effects on cells, and inhibit
neutrophil migration and inflammatory responses,
sometimes at low concentrations. These diverging
results suggest potential beneficial effects, but
emphasize the need for good human trials of
tea using early markers of CHD before firm
conclusions can be drawn.

Introduction
Consumption of fruit and vegetables is associated
with lower coronary heart disease (CHD) mortality
rates.1 The reason for this association is not clear.
Fruit and vegetables are rich in fibre, potassium,
antioxidant vitamins and polyphenolic substances
and may displace other nutrients, such as saturated
fatty acids, that could lead to CHD. These diets
tend to be low in saturated fatty acids and rich in
mono- and/or polyunsaturated fatty acids, which
may also be protective.
Early epidemiological observations did not relate
tea drinking to reduced CHD mortality. However
the risk of myocardial infarction was reduced
by 40% in one study but not in two others
(Figure 1).2± 4 It is difficult to explain discrepancies
between general surveys, due to lack of detail about
exposure to tea, e.g. quantity, strength and variety.
Tea is an unusual `food'. It is not classified as
`fruit and vegetable' and contains few conventional
nutrients, but a high amount of flavonoids (e.g.
flavanols including catechins, flavonols, theaflavin,
thearubigin).5 Recently, several large-scale epi-
demiological studies have re-examined the relation
between consumption of tea and CHD by includ-
ing estimates of flavonol consumption.6±10 Some,
but not all, support the view that tea or flavonoids
reduce the risk of CHD (Figure 1). The design of
these prospective studies was highly variable in
other respects, particularly in the average tea
consumption. In the Finnish study examining the

Address correspondence to Professor R.A. Riemersma, Cardiovascular Research Unit, University of Edinburgh,
George Square, Edinburgh EH8 9XF. e-mail: rudolph.riemersma@ed.ac.uk
ß Association of Physicians 2001
278 R.A. Riemersma et al.

Figure 1. Relative risk of myocardial infarction and CHD mortality by tea consumption. The relative risk of myocardial
infarction (a) and of CHD mortality (b) in humans with the highest vs. the lowest consumption of tea has been examined in
several studies. The relative risk (number above the bar), adjusted for classical risk and dietary factors and the 95%CIs (bar)
of each study wReferencex is given. The relative risk in the category with the lowest consumption was set at 1.0. Flavonoid
intake was also measured in five recent studies and the relative risk of CHD mortality by flavonoid consumption is presented
for comparison (b). Dashes represent studies where the relative risk could not be calculated.

relation between flavonoid intake and CHD, tea
consumption was so low that it was not recorded.6
Less than 10% of the US population drank tea
as their preferred beverage.7,10 On the other hand
very few Welsh or Dutch men did not drink tea
at all, and tea was the most important source of
dietary flavonols.8,9
Dietary and lifestyle factors are usually related.
It is possible that those who do or do not drink tea,
or who consume large amounts of flavonoids
regularly, differ in some other way that affects
CHD risk, such as cigarette smoking. In the UK, tea
consumption and CHD are both high in manual
workers, perhaps due to the strong association
between socio-economic factors and CHD.4'9 The
association between increased CHD mortality and
tea remained after adjusting for socio-economic
factors.9 Residual confounding is a possibility,
 Tea flavonoids and cardiovascular health 279

because tea consumption in the US study is
associated both with factors that increase (age,
hypertension) and decrease (non-smoking, dietary
fibre) the risk of CHD.7 These opposing influences
might tend to cancel each other. It is difficult to
ensure full adjustment.
In this article we examine critically the various
aspects of food-derived polyphenols originating
from tea which might be related to cardiovascular
protective properties in (cell) systems in vitro, in
animal models and in humans.
Tea flavonoids
Flavonoids are widespread in plants and in food of
plant origin. Most flavonoids occur naturally with a
sugar molecule attached, although the catechins of
tea do not share this feature. Flavonoids are classi-
fied into six categories according to the oxidation
level of the central heterocyclic ring (Figure 2).
Analysis of the diet is simplified by converting
the glycosides to 25±30 aglycones, but only a few
are relevant to tea. A typical cup of tea (200 ml)
contains 24±40 mg catechins, 8±15 mg flavonols
plus flavones, ;85 mg thearubigins and 7±15 mg
theaflavins, which together amount to 166±193 mg
per cup (D.A. Balentine, personal communication).
The yellow, brown and red pigments (theaflavins,
thearubigins) are `derived polyphenols' generated
during processing of tea. These heterogeneous,
large polymers are difficult to analyse. Dietary
intake of phenols and polyphenols ranges from
100 to 2000 mg per capita per day.11 Black tea is
therefore one important source of dietary phenols.
Tea polyphenols, catechins and flavonols
scavenge reactive oxygen species12,14 and chelate
transition metal ions in a structure-dependent
manner.12,15 These flavonoids are antioxidants by
virtue of the number and arrangement of their
phenolic hydroxyl groups.14 Flavonoids found in
tea scavenge NO and peroxynitrite (produced
from superoxide radical and NO).16,17 Tyrosine is
particularly vulnerable to nitration by peroxynitrite,
and increased levels of 3-nitrotyrosine have been
reported in atherosclerotic lesions.18 It is not known
whether tea polyphenols prevent the accumulation
of nitrotyrosine in atherosclerotic lesions.

Figure 2. Tea polyphenols. Tea contains polyphenolic flavonoids. In green tea, catechins (catechin, epicatechin,
epigallocatechin, epicatechin gallate, epigallocatechin gallate) represent 80±90% and flavonols (kaempferol, quercetin and
myricetin glycosides) -10% of total flavonoids.5 These polyphenols form complex condensation products (theaflavins,
thearubigins) during the production of black tea. The catechin content of black tea is only 20±30%, whilst the theaflavins
and thearubigins represent ;10 and 50±60% of total flavonoids. The structure proposed for thearubigins is hypothetical.
The reducing properties of tea polyphenols depend on the dihydroxybenzyl ring and their ability to delocalize free
electrons. Adjacent keto- and hydroxy-groups are important for ion-chelation.12,15
280 R.A. Riemersma et al.
Bioavailability of flavonoids
Knowledge of the absorption and metabolism
of flavonoids is crucial to the understanding of
whether these compounds or their metabolites have
the potential to exert the biological activity in vivo
that the in vitro studies suggest. Almost 50%
of orally administered radiolabelled catechin was
excreted in the form of urinary metabolites.19,20
This indicates that catechins and/or their gut flora
metabolites are well-absorbed. Plasma concentra-
tions of catechins peak at 1.5±2.6 h in almost all
subjects. The increase in plasma total catechin
concentrations is greater after ingestion of a single
large dose of green tea than one of black tea
solids (equivalent to 3±6 cups), ranging from 0.63
to 1.8 mmol/l and from 0.2 to 0.34 mmol/l, respec-
tively.21±24 Plasma levels returned to baseline at
24 h. Less than 10% of epigallocatechin and
epicatechin was excreted 3±6 h after ingestion of
1.2 g tea solids by healthy volunteers. Interestingly,
catechin gallates were not detected in their urine.25
Absorbed flavonoids are extensively modified
and converted to glucuronides and sulphates pre-
dominantly in the liver and some are methylated
by catechol-O-methyl transferase.26 There are no
published data concerning the absorption of
theaflavins and thearubugins. Thearubigin is likely
to be extensively metabolized by the colonic micro-
flora, and some of its antioxidant effects in vivo
may be related to a range of phenolic acids (e.g.
3,4-dihydroxyphenylacetic acid, etc.). Some of
these low-molecular-weight molecules are readily
absorbed and may retain the antioxidant proper-
ties of their parent compound.27 The absorption,
metabolism and excretion of flavonoids from tea
has been reviewed in more detail elsewhere.26,28
LDL oxidation in vitro and ex vivo
There is substantial evidence that `oxidized' LDL
is central to early events leading to atherosclerosis.
Minimally oxidized LDL induces the expression
of monocyte chemoattractant protein 1, monocyte
adhesion molecules and metalloproteinase 1, and
thereby promotes monocyte infiltration and forma-
tion of foam cells in the coronary arterial wall.29
Flavonoids from green and black tea (and red
wine), when added directly to isolated LDL, pro-
tect against lipid peroxidation induced by free
radicals, copper ions and cells.13,22,30,31 Studies
with purified tea catechins confirm these observa-
tions.22 The resistance of isolated LDL (0.17 mg
protein/ml) to oxidation induced by CuSO4
in vitro was already demonstrable at 50 mg/l in
one study.32 A higher concentration is necessary
when LDL particles are preincubated with tea
flavonoids, re-isolated and then subjected to
copper-mediated lipid peroxidation (050 mg/l or
;80±160 mmol/l).22,31
In contrast to the protective effects of flavo-
noids against LDL oxidation in vitro, ingestion of
green or black tea fails to inhibit LDL oxidation
ex vivo.22,31±33 These results were explained by
the fact that the concentrations of the tea catechins
had risen insufficiently to delay the onset of lipid
peroxidation following the ingestion of tea.31,33
The possibility that these water-soluble compounds
(including flavonoid glucuronides) were lost
during LDL isolation from plasma was recently
explored.34,35 Lipoprotein fatty acid oxidation
of dilute, whole serum (presumably reflecting
predominantly LDL particles) was therefore used.
Four cups of black (but not green) tea increased
resistance slightly, and onset of the rapid phase
of lipid peroxidation was delayed by 7"4%
(p = 0.05).34 These results were not confirmed
in another study.35 It is doubtful whether such
a marginal effect could influence LDL oxidation
in vivo.31 The possibility that tea might affect
the development of atherosclerosis by other cellular
mechanisms has apparently not been addressed.
Effects in vivo
The effects of tea (6 cups/day for 4 weeks) on serum
cholesterol and blood pressure have been exam-
ined. Neither black nor green tea affected serum
cholesterol31,32,36 or blood pressure in controlled
trials.36,37Observational studies had previously
suggested that five or more cups tea/day reduced
serum cholesterol and blood pressure slightly.38
This may be due to the confounding association
between tea consumption and lifestyle factors (e.g.
an inverse association with coffee consumption,
which may increase serum cholesterol).38,39
One study reported that one cup of green or
black tea increased the plasma antioxidant potential
(ability to scavenge free radicals) by 40±50%, with
addition of milk preventing this rise.40 Other tea
studies showed little or no increase in the plasma
antioxidant potential after drinking one cup equal
to the strength of 4 to 6 cups with or without
milk.23,24,33,34 Regular tea consumption also does
not increase plasma antioxidant potential.31,33 The
designs of all these studies were optimized to
observe an effect. Often the influence of dietary
flavonoids from other sources was reduced, and
large amounts of tea (up to 10 cups/day) were
drunk for up to 4 weeks. A small transient increase
in plasma antioxidant potential was reported for
green tea.31,34
 Tea flavonoids and cardiovascular health
Effects in cellular systems
Several, but not all, polyphenols inhibit cell growth
and proliferation, particularly of transformed cells,
and promote programmed cell death (apoptosis).
Tea polyphenols enhance cellular antioxidant
enzyme activity or antioxidant defence. However,
the relevance of some of these cancer-related
studies is not certain, in view of the high polyphenol
concentrations used (40±400 mmol/l) (reviewed in
reference 41).
Epigallocatechin gallate, at a physiologically
relevant concentration (0.6 mmol/l), inhibited neutro-
phil migration through cultured human endothelial
cell monolayers.42
Furthermore, polyphenolic compounds of green
tea may prevent endothelial cell-mediated LDL
lipid peroxidation and thereby inhibit expression of
haem oxygenase gene.43 These observations could
be important, since haem oxygenase has been
linked with the transformation of monocytes to
resident macrophages.44
NFkB plays a central role in the inflammatory
response by stimulating the expression of TNFa
and NO synthase. Epigallocatechin gallate
(2.5±10 mmol/l) inhibited lipopolysaccharide and
interferon-c-induced nitrite production by mouse
peritoneal macrophages by more than 50%.45
Some of these effects could be relevant to
endothelial dysfunction and the development of
atherosclerosis, but considerable further work is
needed to elucidate the cellular mechanism(s)
of any protective cardiovascular effect of tea
polyphenols.
Atherosclerosis
Green and black tea flavonoids provided in
drinking water (3 g/l for 21 weeks) reduced the
tendency of LDL to oxidize ex vivo, but failed to
reduce the development of aortic atherosclerotic
lesions in cholesterol-fed female rabbits.46 Despite
the fact that a large number of animals were
examined (20/group), the study lacked statistical
power to confirm an apparent 30% reduction in
the atherosclerotic lesion after green tea (p = 0.11).
The cholesterol-fed atherosclerotic rabbit may not
be the best model to study the role of antioxidants
in preventing atherosclerosis,46 as the predominant
lipoprotein of the rabbit b -VLDL is avidly taken up
by macrophages, with no requirement for oxidative
modification.47
The effect of tea consumption on the develop-
ment or regression of atherosclerotic lesions in
humans has not been directly examined.
281
Conclusion
These diverging experimental and epidemiological
results emphasize the need for specially designed
well-controlled studies of tea or tea flavonoids
using early markers of CHD, such as endothelial
dysfunction or atherosclerotic progression as an
endpoint. Doubts about any protective effect of tea
will remain until such trials have been conducted.
Acknowledgements
The authors are members of the Brooke Bond Tea
Scientific Advisory Board.
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