tea catechins reduce serum cholesterol levels in mild and
TRANSCRIPT
Original Article j. Clin. Biochem. Nut., 33, 101-111, 2003
Tea Catechins Reduce Serum Cholesterol Levels in Mild and Borderline Hypercholesterolemia Patients
Osami Kajimoto,1* Yoshitaka Kajimoto,2,3 Mitsuharu Yabune,3 Ayumu Nozawa,4 Kozo Nagata,4 and Takami Kakuda4
1 Center for Health Care, Osaka University of Foreign Studies, 8-1-1 Aomadani-higashi, Mino, Osaka 562-8558, Japan
2Department of Internal Medicine and Therapeutics [A8], Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
3Department of Clinical Trial and Research, Soiken Inc., Senri-Life-Science Building, 1-4-2 Shin-Senri-Higashi, Toyonaka, Osaka 560-0082, Japan
4Central Research Institute, ITO EN, Ltd., 21 Mekami, Sagara-cho, Haibara, Shizuoka 421-0516, Japan
Received 19 May, 2003; Accepted 6 August, 2003
Summary Blood cholesterol-lowering effect and safety of tea catechins were examined in a
placebo-controlled double-blind study in which a beverage containing tea catechins (a 250 ml beverage containing 197.4 mg of catechins) was given twice a day at breakfast and dinner for 12 weeks. The subjects used were adult males and females with mild and borderline hypercholesterolemia with the range of serum total cholesterol levels 180-259 mg/dl (male/ female, 38/22; age, 48±9 years; total cholesterol, 222±20 mg/dl), who were not taking drugs that may affect lipid metabolism. The study was initiated with a 2-week pre-observa-tion period followed by a 12-week intake period and a 2-week post-observation period. The results revealed that the serum total cholesterol levels in the test beverage group (initial intake level) was significantly decreased at 8 weeks (228±23 mg/dl to 220±21 mg/dl,
p< 0.01) and the decrease was maintained until 12 weeks (222±20 mg/dl, p< 0.05). Such significant decreases in serum cholesterol levels were not observed in the placebo group at any time points. In terms of the safety, no abnormal findings were noted in blood tests, physical measurements and interviews by physicians. Thus these results demonstrated the benefits and safety of tea catechins in individuals with mild or borderline hypercholes-terolemia.
Key Words: catechin, tea, cholesterol, hyperlipidemia
Introduction
There has been a sharp increase in the number of
patients with hyperlipidemia in the wake of western-ization of the Japanese diet. The results of the National Nutrition Survey of 1999 [1] revealed that 4.6% of males and 7.4% of females are hyperlipidem-
is with a serum cholesterol level of >260 mg/dl. Also, as many as 22.3% of Japanese males and 25.4% of females had a cholesterol level ranging between 220 and 259 mg/dl and were categorized as having either borderline or mild hyperlipidemia. Hyperlipi-demia is a well-known risk factor for arteriosclerosis
[2, 3], and coronary artery disease, both of which are increasing sharply in the Japanese population [4]. Suppression of serum cholesterol levels by drug interventions was shown to be effective for the pre-vention of these diseases. Currently, various anti-hyperlipidemic agents are available worldwide but
* To whom correspondence should be addressed. Tel: + 81-727-30-5152 Fax: + 81-727-30-5153 E-mail: [email protected]
101
102 0. Kajimoto et al.
there are concerns for adverse reactions concomitant with long-term drug administration [5]. The funda-mental requirement for improving serum cholesterol level is to improve daily lifestyle through preventing shortage of exercise and an unbalanced diet.
However, restricting the intake of foods contain-ing large amounts of cholesterol is not easily achieved insofar as there are many high-cholesterol foods, the taste of which is pleasing to large numbers of people. Therefore, there is a strong need for the development of foods that can efficiently reduce the serum cholesterol level in the context of daily life. Accordingly, attention has recently been drawn to tea
polyphenols, the principal ingredient of green tea, as a serum cholesterol regulator. According to previous reports, tea catechins, which are a typical tea poly-
phenol, were shown to have the antioxidative [6], the anticancer [7], the blood sugar elevation inhibition [8], and antihypertensive effects [9]. Moreover, it was recently suggested that tea catechins may have serum cholesterol-lowering effects. An initial trial revealing potential cholesterol-lowering efficacy of tea catechins came from a report by Nozawa et al [10], in which they showed that an 8-week intake of a tea catechin-containing beverage significantly low-ered the serum cholesterol levels in borderline or mild hypercholesterolemic males. To further evaluate the benefits of tea catechins in borderline or mild hypercholesterolemia, we here investigated the effect of longer-term (12 weeks) intake of a catechin-con-taining beverage in both male and female subjects with borderline or mild hypercholesterolemia.
Materials and Methods
Subjects The subjects, who were paid volunteers leading a healthy daily life, were recruited by Soiken Inc. and were under a regular periodical (every three months or more frequent) progress check. According to 2 or more tests that were carried out within 3 months, 63 adults (male/female: 40/23) aged between 20 and 60 with borderline and mild hypercholesterolemia (range of 180-259 mg/dl) were sampled. Individuals who were being administered drugs administration by physicians, or taking drugs or health-foods that may affect lipid metabolism were not enrolled in this study. Also, those who were deemed unsuitable as subjects by the investigator were excluded.
Among the 63 candidates who were originally recruited, 3 (male/female: 2/1) were eliminated from
the study, as their total cholesterol levels did not ful-fil the criteria at 2 weeks before the initial intake, and the final number of subjects selected at the com-mencement of the study was thus 60 (male/female ratio: 38/22). The allocation controller (Dr. Hiroshi Hirata, a former Assistant Professor of the Third Department of Internal Medicine, Okayama Univer-sity Medical School), who was not directly involved in the study, divided these 60 subjects into 2 equal
groups by matching, prior to the observation period, their age, body weight, BMI, blood pressure, and levels of triglycerides, total cholesterol, HDL choles-terol and RLP cholesterol. The background of the subjects is given in Table 1. There were no differences between the 2 groups in age, body weight, BMI, blood cell components, blood chemistry tests, and blood pressure, etc. Also, in the male/female stratifi-cation, no differences were found between the test and the placebo beverage group with respect to age or total cholesterol level.
The study was conducted with the approval of the Ethical Committee of the Soiken Inc. (Chairman: Attorney Masaharu Inoue) and in compliance with the objective of the Helsinki Declaration (adopted in 1964, revised in 1975, 1983, 1989, 1996, and 2000). The physician fully briefed the subjects on the details of the research, such as methods, etc., and obtained their written consent.
Sample compounds Beverage containing 197.4 mg of tea catechins
(328.9 mg as tea polyphenols) per bottle (250 ml), which was supplied by ITO EN, Ltd. (manufactured by ITO EN, Ltd., product name THEA-FLAN 905), was used in this study. In addition to the tea catechins, the test beverage was supplemented with cyclodextrin, vitamin C, and green tea liquid extract not containing tea catechins. The placebo beverage contained the same ingredients as the test beverage except for tea catechins. Table 2 gives the catechins composition per bottle of the test beverage. Prior to the study, the allocation controller verified that there were hardly any differences between the test and the placebo beverage in their properties and sensory aspect.
Intake method and schedule The study was a comparative study of parallel
groups of 2 kinds of beverage using the double-blind method. Figure 1 gives the study schedule. Each individual in both the test and placebo beverage
J. Glin. Biochem. Nutr.
Serum Cholesterol-Lowering Effect of Tea Catechins 103
groups took 1 bottle (250 ml) of the beverage twice a day at breakfast and dinner for 12 weeks after the 2-week pre-observation period. The subjects were in-structed not to change their daily life and to avoid non-routine excessive drinking and eating. The study was started on September 7, 2002, for all the sub-jects.
Measurement process Blood tests. A total of 6 blood tests were carried
out at 2 weeks before the initial intake, on initial intake, at 1, 2, and 3 months after the initial intake
Table 1. Background factors of study subjects.
Values: mean±SD. No significant differences were found between the groups (t-test).
Table 2. Tea catechin composition per bottle of test bev-
erage.
Vol. 33, No. 3, 2003
104 0. Kajimoto et al.
and on the completion of the post-observation (1 month after the final intake). The items tested were blood cell components (RBCs, WBCs, hematocrit, hemoglobin, platelets, MCV, MCH, MCHC), total cholesterol, triglycerides, RLP cholesterol, HDL cholesterol, LDL cholesterol, 3 lipoprotein, apolipo-
protein AT, apolipoprotein B, apolipoprotein CIII, apolipoprotein E, free fatty acid, GOT, GPT, y-GTP, LDH, ALP, uric acid, BUN, creatinine, total protein, A/G ratio, albumin, total bilirubin, fasting blood sugar (BS), Na, K, Ca, Mg, Cl, and HbA1c. The LDL cholesterol was calculated by using the equation of Friedewald et al. [11], i. e., LDL cholesterol=total cholesterol- HDL cholesterol- tri-glycerides/5. For the tests, blood samples were taken at Soiken Clinic by 11: 30 a.m, in the fasting state and the measurements were outsourced to a clinical test company (Sakai Bio-Clinical Laboratory, Inc.). Blood samples were taken in the sitting position after a minimum of 5 min in the resting state to avoid extrinsic influences on serum protein compo-nents and serum lipid levels.
Blood pressure, body weight and BMI. Blood pres-sure and body weight were measured a total of 6 times, at 2 weeks before the initial intake, on initial intake, at 1, 2, and 3 months after the initial intake, and on the completion of the post-observation. The blood pressure measurements were done by the same nurse for the same subjects in a sitting position with clothes on but with shoes off after a minimum of 5 min in the resting state. Body weight was mea-sured undressed down to underwear by using a Ta-
vita TBF-614. Height was measured only at 2 weeks before the initial intake, and BMI was calculated from the obtained height and body weight.
Medical examinations and interviews. Medical examinations and interviews by a physician were conducted a total of 6 times, at 2 weeks before the initial intake, on initial intake, at 1, 2, and 3 months after the initial intake and on the completion of the post-observation, and any subjective symptoms such as general malaise, loss of appetite, nausea, vomiting and headache, etc., and the onset of any adverse events were investigated.
Calorie intake from food and drink, alcohol consump-tion and amount of exercise. The subjects were instructed to avoid excessive drinking and eating during the study period and were required to make daily entries in a diary as to their alcohol consump-tion and food intake. For the calorie intake from food and drink during the study period the intake of nutritional ingredients was calculated by the super-vising dietician for a 3-day period prior to each test. Alcohol intake was recorded each day of the study period. For the amount of exercise, a pedometer was supplied, and the amount of exercise taken over a 3-day period prior to each a test was measured.
Method of statistical processing. The values given in the tables show means±SD. Two-way ANOVA was used for the intergroup comparison of the lipid test values during the intake period. The paired t-test was used for evaluation of the variations within the test beverage and placebo beverage groups, respec-tively, during the intake period, and a non-paired t-
Fig. 1. Study schedule. A, Physiological tests, medical examination, and interview; A, Blood tests, physiological tests, medical examination and interview; * , Recording of daily alcohol consumption during the study period and of
food and amount of exercise for 3 days prior to each test date.
J. Glin. Biochem. Nutr.
Serum Cholesterol-Lowering Effect of Tea Catechins 105
test for the comparison between the test and placebo beverage groups. The SPSS Ver.10 from SPSS Inc. was used for the statistical software, and the signifi-cant level for both tests was set at 5% or less.
Results
Blood test values Serum lipids. Table 3 shows the serum lipid test
values during the study period. The 2-way ANOVA test revealed a difference in
the pattern of variation between the test beverage
group and the placebo beverage group (p<0.05). In the test beverage group, the total cholesterol level was significantly decreased at 2 and 3 months after the initial intake as compared with the level at initial intake (p <0.01 and p<.05, respectively). This clearly contrasts with the level of total cholesterol at 3 months in the placebo beverage group, which showed a significant increase rather than a decrease.
LDL cholesterol levels also differed between the 2 groups according to the results of the 2-way ANO-VA test (p<0.01). In contrast to the placebo bever-age group in which a significant elevation of LDL level was found (p<0.05) at 3 months, the test bev-erage group showed a significant reduction in LDL cholesterol at 2 and 3 months after the initial intake (p <0.01 for both). The total and LDL cholesterol lowering effect of the test beverage appeared to peak at 2 months, and no further decrease was observed between 2 and 3 months.
There were no significant differences in serum HDL levels between the 2 test groups. Although the test beverage group revealed an elevated HDL level at 2 months (p <0.001), this increase may not be rel-evant to the effect of tea catechins because the place-bo group also saw similar elevations at 2 and 3 months (p <0.05, p <0.001, respectively).
In agreement with the result for the LDL choles-terol level, the apolipoprotein B level was significant-ly different between the 2 test groups according to the 2-way ANOVA test (p<0.001). Also, a signifi-cant reduction in the values of the AT (arteriosclero-sis index) was found in the test beverage group at 2 and 3 months after the initial intake (p<0.001,
p<0.05 respectively). There were no marked varia-tions found in other serum lipid components.
Next, we evaluated the effect of gender on the results of the principal serum lipid values (Table 4). In males, the 2-way ANOVA test revealed the dif-ference in the pattern of variation between the test
beverage group and the placebo beverage group
(p <0.05, p<0.01). A significant reduction was observed in total cholesterol (p<O.Ol,p<O.O5) and in LDL cholesterol levels (p <0.05) in males at 2 and 3 months, respectively, after the initial intake. In females, on the other hand, there was no difference in pattern of variation for total cholesterol between the test beverage and placebo groups. Also, no sig-nificant reductions in total cholesterol levels were observed at any time points. However, even in females, there was a significant reduction in the LDL cholesterol levels at 2 and 3 months in the test beverage group (p<O.O5 for both) but not in the pla-cebo group. Also, the AT showed a significant reduc-tion at 2 months in the males (p<0.01) and at 2 and 3 months in the females (p <0.05 and p <0.01, respectively). Other blood biochemical test values. The items test-ed were listed in Materials and Methods (Blood test). Statistically significant variations were observed in albumin, A/G ratio, Ca, uric acid, Na, Cl, K, and HbA1~ levels during the intake period for both groups. In addition to these, a significant eleva-tion in ALP level (from 209 ± 62 IU/liter pre-intake to 220±71IU/liter post-intake) and a significant reduction in total bilirubin level (from 0.9±0.3 mg/ dl to 0.8±0.4 mgidl) were found in the test beverage
group, and significant reductions in total protein and BUN levels were observed in the placebo beverage
group. However, all of those variations stayed within the normal ranges, and no cases revealed abnormal variations in any of the blood biochemical data obtained. Blood cell components. During the intake period, an elevation in the hemoglobin, hematocrit, MCV, MCH, MCHC, and platelets was found in both groups, and an elevation of RBCs in the placebo beverage group (data not shown). However, all were minor variations within the normal ranges.
Physiological findings Table 5 gives the changes in blood pressure, body
weight and BMI. In both groups, a minor but signif-icant increase in the body weight and in BMI was found. Also, in the placebo beverage group, the sys-tolic blood pressure rose significantly at 3 months, and the diastolic blood pressure, at 2 and 3 months, after the initial intake.
Val. 33, No. 3, 2003
Tab
le
3.
Cha
nges
in
te
st
valu
es
of
seru
m
lipid
co
mpo
nent
s.
V
alue
s: m
ean±
SD.
Sign
ific
ant
diff
eren
ce f
rom
in
itial
int
ake:
*<
035
** <
O.O
l **
* <
0.00
1 Pa
ired
t-t
est
. Si
gnif
ican
t di
ffer
ence
fro
m p
lace
bo b
ever
age:
+
<0.
1 #
<0
.05
(t-t
est )
. p
Tab
le
4.
Cha
nges
in
m
ale/
fem
ale
test
va
lues
of
se
rum
lip
id
com
pone
nts.
Val
ues:
mea
n±SD
. Si
gnif
ican
t dif
fere
nce
from
initi
al i
ntak
e: *
<0.
05,
** <
0.01
Pa
ired
t-t
est
. Sig
nifi
cant
dif
fere
nce
from
pla
cebo
bev
erag
e: +
<
0.1
# <
0.05
(t-
test
).
Tab
le
5.
Cha
nges
in
ph
ysio
logi
cal
find
ings
.
Val
ues:
mea
n±SD
. Si
gnif
ican
t dif
fere
nce
from
initi
al i
ntak
e: *
<
0.05
, **
<0.
01
Pair
ed t
-tes
t . S
igni
fica
nt d
iffe
renc
e fr
om p
lace
bo b
ever
age:
n.s
(t-
test
).
Tab
le
6.
Cha
nges
in
di
et,
alco
hol
cons
umpt
ion
and
amou
nt
of
exer
cise
.
Val
ues:
m
ean±
SD.
Sign
ific
ant
diff
eren
ce
from
in
itial
in
take
: *,
,<0J
5 J5
**
<
0.01
Pa
ired
t-
test
.
Sign
ific
ant
diff
eren
ce
from
pl
aceb
o be
vera
ge:
# <
0.05
t-
test
.
~
Serum Cholesterol-Lowering Effect of Tea Catechins 109
Medical examinations and interviews (changes in sub-jective symptoms)
According to the result of medical examinations and interviews that were performed before and after the observation period and during the intake period, no clinical symptoms such as gastrointestinal symp-toms, nausea, vomiting and headache or no other signs of possible side effects which were likely to be caused by the test beverage were found during the study period.
Calorie intake from food and drink, alcohol consump-tion, and amount of exercise
Table 6 gives the daily amounts of calorie intake from food and drink, alcohol consumption, and exer-cise assessed by the number of pedometer paces dur-ing the study period. In the test beverage group, pro-tein intake rose significantly at 3 months after the initial intake as compared with the value at the initial intake (p<0.05). Carbohydrate intake also rose sig-nificantly in the test beverage group at 1 month after the initial intake (p<0.05) and this increase was maintained to the completion of the post-observa-tion period (2 months, p <0.01; 3 months and there-after p<0.01), although it was also increased even in the placebo beverage group at 2 months after the ini-tial intake (p<0.05). Dietary fiber intake rose signif-icantly in both groups at 1 month and 2 months (test beverage group, 1 month, p <0.01; 2 months, p < 0.05; placebo beverage group, 1 month, p <0.05; 2 months, p<0.05). No significant variations in alco-hol consumption were found during the study period in either group, but the difference between the 2
groups reached statistical significance on completion of the post-observation period (p <0.05). Also, a sig-nificant difference was found in the amount of exer-cise between the 2 groups at 2 months after the ini-tial intake (p <0.05).
Discussion
Tea catechins are the bitter and astringent taste components of tea, which are otherwise known as tannins. Also, they are known as a type of polyphe-nols, which are widely present in fruits such as astringent persimmons and the astringent coat of
grapes. The leaves of tea contain several types of cat-echins as water-soluble ingredients, but only green tea (leaves) characteristically contains 4 of the so-called main catechins, (-)-epigallocatechin gallate
(EGCg), (-)-epicatechin (EC), (-)-epicatechin
gallate (ECg), and (-)-epigallocatechin (EGC), which are known for their antioxidative and other
potentially beneficial physiological activity [6,12]. In addition to those 4 types of main catechins, green tea also contains their respective isomers, (-)-gallocat-echin gallate (GCg), (-)-catechin (C), (-)-catechin
gallate (Cg) and (-)-gallocatechin (GC). The cholesterol-lowering effect of the catechins
has already been demonstrated in various animal studies [1.3,14], and the effect appeared to be exert-ed by catechins inhibiting the absorption of choles-terol in the intestinal tract [15-17]. Ingested cate-chins form an insoluble deposit with either dietary cholesterol, endogenously synthesized cholesterol that was excreted into the intestinal tract, or choles-terol in bile acid micelles, and thereby inhibit their absorption. The ester catechins in particular are reported to be more potent than other catechins in terms of their ability to eliminate cholesterol from bile acid micelle [15]. Because the test beverage used for this study contained 4 types of ester catechins
(EGCg, GCg, ECg, Cg), its cholesterol-lowering effect demonstrated in the present study may be attributable to the inhibition of the absorption of cholesterol in the intestinal tract. Further, tea cat-echins are known for their proliferative effect on enteric Lactobacilli [18, 19]. Lactobacilli utilizes dietary sugar and fiber and produces propionic acid
[20], which is known to inhibit the activity of HMG-CoA synthase in the liver and thereby sup-
press the synthesis of cholesterol [21]. Thus the pos-sible increase in the enteric Lactobacilli population may also in part mediate the cholesterol-lowering effect of tea catechins.
According to the results of the dietary analysis, the intake of dietary fiber in the test group was increased at 1 and 2 months (Table 6). Because the dietary fiber is a well known reducer of the blood cholesterol levels, it is likely that the increase in dietary fiber intake also contributed to the reduction in cholester-ol. However, the dietary fiber intake was also increased in the placebo beverage group, despite the fact that there were no reductions in the cholesterol levels in the placebo group. Therefore, we can specu-late that tea catechins exerted their cholesterol-low-ering effect independent of the increase in the dietary fiber intake.
Due to possible interference by the menstruation cycle, there has been a hesitation in using female samples in studies evaluating the effects of test drugs on lipid metabolism. Indeed, estrogens have been
Vol. 33, No. 3, 2003
110 0. Kajimoto et al.
found to be associated with hypolipidemic effects due to their enhancement of LDL receptor function, although the estrogen effect on the HMG CoA reductase activity seems to vary depending on exper-imental conditions [22, 23]. In the present study, nonetheless we used female samples as well as males and showed that the catechins-containing test bever-age could reduce serum LDL-cholesterol levels both in males and females. As far as we know, this is the first report that proved the LDL cholesterol-lower-ing effect of tea catechins in females. Also, there is a widely recognized clinical concern that the excess intake of tea beverage may cause anaemia by inhibit-ing the absorption of iron. This is especially impor-tant for females, because physiologically they tend to be anaemic. However, in the present study, we showed that the relatively long (12 weeks) intake of the test beverage did not cause any signs of anaemia even in the female subjects, suggesting that the tea catechin-containing beverage is beneficial and safe for female subjects with borderline or mild hyper-lipidemia. We previously performed a similar study using male subjects with mild or borderline hypercholes-terolemia, in which the tea catechin-containing bev-erage was given for 8 weeks [10]. In that study, both the total and LDL cholesterol levels kept gradually decreasing during the 8-week intake period, and therefore the study might have failed to evaluate the maximum and ultimate effect of tea-catechins. In the present study, we observed the effect of tea cat-echin-containing beverage for 12 weeks and found that the total cholesterol- and LDL cholesterol-low-ering effects of test beverage appeared to reach their maximum at 8 weeks.
According to the assessment by pedometer paces (Table 6), there was a large increase in exercise in the test beverage group at 2 months and this may have affected the lipid metabolism. However, it does not seem to be the main cause of the decrease in total or LDL cholesterol levels. Even when we minimized the effect of the variance in exercise by eliminating the subjects whose exercise amounts were dramati-cally changed at either time points during the test period as compared with that at initial intake (increased by >200% or decreased by >90%), thus making the difference in the exercise amount between the 2 groups disappear, the significant dif-ferences that had been observed in total or LDL cholesterol levels were not affected (data not shown).
In spite of the increase in exercise amount, there
was a slight increase in body weight and BMI in the test beverage group. The placebo group, in which exercise amount was not changed, also showed increased body weight and BMI. Because it was observed in both groups, it would not be relevant to the intake of tea catechins. Similar phenomena were also observed for total and LDL cholesterol levels: the total and LDL cholesterol levels became higher than the baseline levels (at initial intake) at 12 weeks in placebo group. Although the exact reason for this is not known, it may be relevant to the seasonal fac-tor. Also, we would like to note that there was a slight increase in blood pressure only in the placebo
group but not in the test beverage group, although it is unknown whether this is relevant to the difference in exercise or to the effect of tea catechins.
Other blood test values also revealed some signifi-cant variations during, before and after the intake
period. However, such variations always stayed with-in the normal ranges and were observed also in the
placebo beverage group, suggesting that they do not represent adverse effect of the test beverage but are simply normal physiological variations. Support for this view also comes from the fact that the variations could be seen even before initiation of the intake of the test beverage. Considering the absence of any abnormal findings that would be of clinical concern in haematology, hepatic and renal function, glucose and electrolyte metabolism, and blood pressure even during the relatively long period of the intake, we consider that a high level of safety of the tea cat-echins was proved in this study.
In conclusion, our present observations clearly demonstrated the atherogenic LDL cholesterol-low-ering effect of the tea catechin-containing beverage in both males and females. Because no adverse effects were observed during the 12-week intake
period, we believe, such a beverage to be highly safe and beneficial for borderline and mild hyperlipi-demia patients.
Acknowledgments
We thank all the persons who enrolled at Soiken Inc. for participation in this study.
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