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2;
School of Pharmaceutical Sciences, University of Shizuoka, 52–1, Yada, Shizuoka, 422-8526, Japan;
*
Shizuoka Sangyo University, 4–1-1, Surugadai, Fujieda, Shizuoka, 426-8668, Japan;
Central Pharmaceutical Research Institute, Japan Tobacco Incorporated 23, Nukogi, Hatano, Kanagawa, 257-0024, Japan;
**
National Institute of Nutrition and Health, 1–23-1, Toyama, Shinjuku-ku, Tokyo, Japan;
Food Research Laboratories, Mitsui Nohrin Company Limited, 223–1, Miyahara, Fujieda, 426-0133, Japan; and
University of Shizuoka, Graduate School of Health Sciences, 52–1, Yada, Shizuoka, 422 8526, Japan
2To whom correspondence should be addressed. tomitat{at}sea.u-shizuoka-ken.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • apoprotein E–deficient mice • atherosclerosis • catechins • antioxidants • aortic lipids
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Witztum and Steinberg 1991
). An epidemiologic study
indicated that European populations with higher plasma concentrations
of natural antioxidants, ascorbic acid and 
-tocopherol have a lower
incidence of coronary heart disease (Gey et al. 1987
).
Several epidemiologic investigations indicated that flavonoid intake is
inversely associated with the mortality of coronary heart disease
(Hertog et al. 1993
and 1997
, Knekt et al. 1996
, Rimm et al. 1996
). In addition, the
Oppland County Study (Stensvold et al. 1992
), Scottish
Heart Health Study (Brown et al. 1993
) and a study by
Sesso et al. (1999)
all indicated an inverse correlation
between black tea consumption and the risk of coronary heart disease.
There have been no epidemiologic investigations, however, of green tea
and coronary heart disease.
Green tea leaves (Camellia sinensis) contain
antioxidative tea catechins consisting of various flavan 3-ols as
follows: (+)-catechin
(C),3
(–)-epicatechin (EC), (–epicatechin gallate (ECg),
(–)-epigallocatechin (EGC) and (–)-epigallocatechin gallate (EGCg).
Among them, EGCg with a hydroxy group at R1 and a galloyl group at R2
is the principal component (Fig. 1
). In contrast, black tea contains mainly thearubigins and theaflavins,
complex condensation products of tea catechins. Tea catechins have a
variety of pharmacologic effects, i.e., antioxidative (Lin et al. 1996
, Yoshino et al. 1994
), antimutagenic
(Jain et al. 1989
), anticarcinogenic (Katiyar et al. 1993
, Wang et al. 1995
, Yang et al. 1997
), anticancer promoting (Nakamura et al. 1997
), anti-inflammatory (Sano et al. 1999
),
antimicrobial (Yoshino et al. 1996
) and hypolipidemic
effects (Yoshino et al. 1994
). Recently, Cao and Cao (1999)
reported that EGCg inhibits angiogenesis.
|
and 1995
). We also
reported that daily consumption of tea catechins [equivalent to 740 mL
(7–8 cups) of tea] for 1 wk significantly prolonged the lag time of
LDL oxidation in humans (Miura et al. 2000
). The present
study investigated whether daily consumption of catechins prevents the
development of atherosclerosis using atherosclerosis-susceptible
C57BL/6J, apoprotein E-deficient [apoE (-)] mice, which were
generated by Zhang et al. (1992)
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasma cholesterol and triglycerides were analyzed enzymatically with Sterozyme 545 and Determiner LTG assay kits (Kyowa Medics, Tokyo, Japan), respectively. (+)-Catechin, EC, ECg, EGC, EGCg and the tea extract (Polyphenon E), which contains 79 g/100 g tea catechins, were supplied by Mitsui Nohrin (Fujieda, Japan).
Stability of tea catechins and analysis by HPLC.
Tea extract was dissolved in a 30 g/L sucrose solution (0.8 g/L), and
placed in a drinking bottle for mice. The solution was either supplied
to the mice or kept for 24 h at 25 ± 1°C. After that, 2 mL
of the solution was extracted with 5 mL of ethyl acetate and the
solvent of the upper layer was completely removed under a stream of
N2 gas. Tea catechins in the residue were dissolved in
eluent A [acetonitrile/phosphate buffer (25 mmol/L, pH 2.4) 5:95] and
analyzed using reversed-phase HPLC (Hollman et al. 1999
) [Intelligent pump L-6200, Chromatointegrator D-2500,
UV-VIS detector L 4200 set at 278 nm, column oven L-5020 set at
30°C, Hitachi (Tokyo, Japan); column ODS 4.6 x 150 mm, GL
Sciences (Tokyo, Japan)]. The flow rate was 1.0 mL/min. The solvents
used for separation were mixtures of eluent A and eluent B
[acetonitrile/phosphate buffer (25mmol/L, pH 2.4) 25:75]. The
gradient was as follows: 0–5 min, 15% B; 5–20 min, linear gradient
15–80% B; 20–23 min, 80% B; and 23–25 min, 15% B.
Animals and treatments.
Studies were performed using atherosclerosis-susceptible C57BL/6J,
apoE-deficient [apoE (-) mice (n = 17) and
wild-type apoE (+) mice (n = 16)], which were
purchased from Jackson Laboratories (Bar Harbor, ME) and bred in our
laboratory. The Committee of the University of Shizuoka approved the
protocol for experimental animals. Male apoE (-) mice, 10 wk old, were
divided into two groups (tea and control) and fed an atherogenic diet
(Zhang et al. 1992
) containing 1.25 g/100 g cholesterol,
0.5 g/100 g sodium cholate, 12.5 g/100 g cocoa butter in CRF-1
(Oriental Yeast, Tokyo, Japan) for 14 wk (Table 1
). When the atherogenic diet was given to apoE-deficient mice
starting at ages younger than 10 wk, growth was significantly impaired
(data are not shown). Thus, the experiment was started when the mice
were 10 wk of age. When mice were killed 10 and 12 wk after the start
of the atherogenic diet, fatty plaques in the aorta were not evident.
Therefore, in this study, animals were killed at 14 wk.
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Fast protein liquid chromatography (FPLC) of lipoproteins.
Plasma lipoproteins were analyzed using an FPLC system (Pharmacia, Uppsala, Sweden). Filtered plasma (5 µL) was applied to a Superose 6 column (1 x 30 cm), eluted at a 0.5 mL/min flow rate with 10 mmol/L Tris-HCl buffer (pH7.4) containing 150 mmol/L NaCl, 0.1 g/L Na2EDTA and 0.2 g/L NaN3, and fractionated into 1-mL fractions. Total cholesterol in each fraction was measured enzymatically using Sterozyme 545.
Plasma lipid peroxides.
To assess the in vivo oxidative state of lipoproteins, plasma lipid
peroxides were measured through formation of thiobarbituric acid
reactive substances (TBARS). The effects of various tea catechins on
Cu2+-mediated LDL oxidation were examined previously
(Miura et al. 1994
). Lipid hydroperoxides measured by a
reaction with diphenyl-1-pyrenylphosphine using linoleic acid
13-hydroperoxide (Asaka et al. 1987
) as a standard
produced a result comparable to that measured by TBARS formation.
Therefore, TBARS formation was examined in the present experiment.
Measurement of TBARS was performed according to Yagi (1976)
with slight modification. Fluorescent TBARS were
extracted with butanol and the intensity was measured at 515 nm
(excitation) and 535 nm (emission) using a Hitachi spectrofluorometer
(F3010, Hitachi, Tokyo). TBARS were expressed as malondialdehyde (MDA;
nmol) formed from 1,1,3,3- tetraethoxypropane, which was used as a
reference compound.
Analysis of atherosclerotic area in the aorta.
Each aorta from the arch to the femoral bifurcation was cleaned free of connective tissue and fat, and weighed after being lightly dried on filter paper. The aorta was cut longitudinally with scissors and pinned to a silicon plate to be photographed. The surface area of the aorta covered by lesions and the entire surface area were analyzed using NIH image software; the extent of atherosclerosis was expressed as a percentage of the entire surface area. Fatty streak lesion in aortic sinus was stained with Masson trichrome.
Analysis of aortic lipids.
Immediately after measurement of the atherosclerotic area, each aorta
was cut into small pieces with scissors, and homogenized in 5 mL
CHCl3/methanol (2:1) mixture (Chiba et al. 1997
). After soaking for 15 h at 4°C, the diced aorta
was removed; the solvent was mixed vigorously with 2 mL of 5 g/L NaCl
and centrifuged for 10 min at 1000 x g. The upper
layer was again extracted with 2 mL CHCl3 and the combined
CHCl3 layers were dried under N2 gas. The
residue was sonicated with 150 µL isopropanol and
emulsified by heating for 20 min with 1 mL of 2% Triton X-100 at
70°C. Aliquots of the extract were assayed for total cholesterol and
triglycerides using Sterozyme 545 and Determiner LTG, respectively.
Statistical analysis.
Data are expressed as mean ± SD. Data were analyzed using Student’s t test, Welch’s t test or two-way ANOVA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The green tea extract (Polyphenon E) contained EGCg (58.4 g/100 g) as
the principal component (Table 2
). Because tea catechins and EGCg, in particular, are easily oxidized,
their stability during the feeding period was examined (Table 3
). The catechins kept in brown drinking bottles remained 
90% intact
after 24 h. When the solution was offered to the mice through the
bottles, however, EGCg, EGC and ECg were reduced to 33, 37 and 67%,
respectively. The air bubbles that entered into the solution each time
the mice drank appeared to have oxidized the catechins.
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It was confirmed by a preliminary experiment that the concentration of
tea catechins present in the drinking water does not impair growth of
apoE (+) mice. Sucrose was used to mask the bitter taste of the tea
extract. The tea group consumed 4 mL water/d; thus, mice ingested
3.2 mg of the tea extract per day. The calculated amounts of catechins
remaining in drinking bottles after 12 h were EGCg, 66.2%; EGC,
68.4%; EC, 95.0%; and ECg, 83.6% (Table 3)
. Provided that mice
consumed fluid containing catechins at this concentration on average
throughout the day, and taking into account the composition in the tea
extract (Table 2)
, the amount of the tea extract ingested would be
1.7 mg/(d · mouse).
Body weights at the end of the 14-wk experiment were significantly
higher in the tea group than in the control group although they were
pair-fed (Table 4
). Figure 2
shows the lipoprotein profile of the apoE (+)-mice (A) and apoE (-)-
mice (B). In contrast to the apoE (+)-mice (Fig. 2A
), only
VLDL were detected in apoE (-)-mice (Fig. 2B
), and the
levels of VLDL cholesterol increased with time of cholesterol feeding.
Tea ingestion did not affect plasma total cholesterol concentration
through the experimental period (not significant, two-way ANOVA)
(Fig. 3
) or plasma triglyceride concentrations (Table 4)
.
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At the start of the experiment, the plasma TBARS concentrations were 6–8 µmol MDA/L without any difference between the two groups. By wk 8, the level had increased and was significantly lower in the tea group than in the control group [20.0 ± 4.90 (n = 7) vs. 30.3 ± 4.14 (n = 7) µmol MDA/L, P < 0.001].
Antiatherogenic effects of the tea extract.
The atheromatous area, aortic weights, and aortic lipids in the tea and
control groups are shown in Table 5
. In the control group, 36% of the entire aortic area was covered with
fatty plaque, whereas only 27% of the aortic area was covered in the
tea group. Tea ingestion significantly attenuated the atherosclerotic
area by 23% (P < 0.01). The atherosclerotic lesion
area of the arch was similar in extent in both groups. In addition,
there was no difference between the two groups in the degree of the
lesion in aortic sinus stained with Masson trichrome at this advanced
stage.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 1995
) and ex vivo
(Miura et al. 2000
). Thus, we tested the antiatherogenic
effects of green tea extract in apoE-deficient mice in this study.
Apoprotein E is involved in the clearance of chylomicrons and VLDL.
Lack of apoE, therefore, causes accumulation of cholesterol-rich
remnants in plasma, whose prolonged circulation is atherogenic.
Zhang et al. (1992)
generated apoE-deficient mice by
gene targeting. These mice develop atherosclerosis spontaneously and
cholesterol loading accelerates atherosclerosis.
A previous in vitro experiment indicated that the components of tea
catechins possess varying inhibitory effects on
Cu2+-mediated oxidation of LDL in the following
order: EGCg > ECg > EC > C > EGC. The effect of
t-BHT was 25% that of EGCg and 50% that of EGC
(Miura et al. 1994
). EGCg and ECg also inhibited
platelet aggregation 4 to 5 times more than aspirin (data not shown).
To test ex vivo antioxidative effects of tea catechins in
humans, we used tea extract whose components were analyzed
precisely, rather than the pure component, because tea extract is
commercially available in health food stores, and it is illegal to
administer the pure components of tea catechin to humans. This study
used a tea extract containing 58% of the most effective component,
EGCg. Although the same amounts of food and fluid as consumed by the
tea group were pair-fed to the control group, the body weights in
the tea group were greater than those in control group. The reason
remains unclear. Tea ingestion may relieve physiologic damage due to
loading of the atherogenic diet because the diet greatly impaired
growth in mice at ages younger than 10 wk.
Green tea is the most popular beverage in Japan and the principal
component, EGCg, exerts a much stronger antioxidative effect than
teaflavin and tealubidin, the major components of black tea on the
basis of weight (Wiseman et al. 1997
). Considering the
catechin degradation in the drinking water supplied, mice ingested a
daily average of 1.7 mg tea catechin/mouse when they consumed 4 mL
of the solution containing 0.8 g tea extract/L.
A standard way of preparing Japanese green tea is to soak 10 g of
green tea leaves in 430 mL hot water (90°C) for 1 min. The resulting
tea beverage contains 280 mg tea catechins. Japanese people daily
ingest 413 mg tea catechins on average because they ordinarily drink 7
to 8 cups (740 mL) of green tea per day. On the basis of body weight
(average Japanese, 60 kg and mice, 25 g), the intake of 1.7 mg tea
catechin extract by mice per day corresponds to a human ingesting
approximately eightfold the ordinary intake.
Daily ingestion of tea catechins for 14 wk prevented the accumulation of aortic cholesterol and triglycerides and atheroma formation in the aorta in apoE-deficient mice fed an atherogenic diet, without affecting plasma lipid concentration in comparison with the control group. This suggests that tea catechins rendered plasma lipoproteins of apoE-deficient mice less atherogenic.
A variety of plasma lipid-lowering agents exert antiatherogenic
effects, but only a few agents have such effects without lowering
plasma lipids. Among them are probucol, which possesses a strong
antioxidative property (Kita et al. 1987
), a lipoprotein
lipase-enhancing agent, 4-diethoxyphosphonylmethyl
N-(4-bromo-2-cyanophenyl) benzamide (NO-1886; Chiba et al. 1997
), an antioxidant, N,
N'-diphenyl 1,4-phenylene diamine (Tangirala et al. 1995
) and dietary antioxidants (vitamin E, ß-carotene and
vitamin C, Crawford et al. 1998
).
Hayek et al. (1997)
fed red wine or its polyphenols,
quercetin and catechin, to apoE-deficient mice fed a regular diet
for 6 wk. They observed reduced susceptibility to LDL oxidation and an
attenuation of the development of atherosclerotic lesions in the aortic
arch in mice fed red wine or quercetin and, to a lesser extent, in mice
fed catechins. It is difficult to compare their catechin results with
the present study because the quality of the catechin they used was not
described.
The mechanisms underlying the antiatherogenic effects of tea catechins
are not clearly understood. Recent evidence from various lines of
investigation, however, provides plausible explanations. Reactive
oxygen species are involved in atherogenesis through the induction of
endothelial leukocyte adhesion molecule-1 expression (Witztum and Steinberg 1991
) and monocyte chemotactic protein-1
(Butcher 1991
) on the endothelium. In addition, a
cytotoxic peroxynitrite generated by the reaction between superoxide
and nitric oxide modifies lipoproteins (Leeuwenburgh et al. 1997
) and reduces the activities of superoxide dismutase
(MacMillan-Crow et al. 1996
) and gultathione peroxidase
(Asahi et al. 1997
), both of which are antioxidative
enzymes.
Several lines of investigation demonstrated that catechins have potent
scavenging effects on superoxide and hydroxyl radicals (Kashima 1999
, Kondo et al. 1999
, Nanjo et al. 1999
). In addition, tea catechins inhibit
peroxynitrite-mediated tyrosine nitration of apoB-100 of LDL
(Haenen et al. 1997
, Pannala et al. 1997
). EGCg, the major component of green tea catechins,
reduced inducible nitric oxide synthase mRNA expression in
lipopolysaccharide- and interferon-activated mouse peritoneal cells
by competitively inhibiting the binding of arginine and
tetrahydrobiopterin (Chan et al. 1997
). Lin and Lin (1997)
reported that EGCg blocks the induction of nitric
oxide synthase by down-regulating lipopolysaccharide-induced
activity of the transcription factor, nuclear factor-
B, which is a
pleiotropic mediator for induction of genes, including genes relevant
to atherogenesis (Collins 1993
) and inflammatory
responses (Schreck et al. 1991
).
In conclusion, the present study, together with previous findings, suggests that chronic ingestion of green tea extract prevents the development of atherosclerosis without changing the plasma lipid levels, probably through the potent antioxidative activity.
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FOOTNOTES |
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3 Abbreviations used: apo, apoprotein; C,
(+)-catechin; EC, (–)-epicatechin; ECg, (–)-epicatechingallate; EGC,
(–)-epigallocatechin; EGCg, (–)-epigallocatechin-gallate; FPLC, fast
protein liquid chromatography; MDA, malondialdehyde; TBARS,
thiobarbituric acid reactive substances.
Manuscript received July 17, 2000. Initial review completed August 14, 2000. Revision accepted September 19, 2000.
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