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Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Setagaya, Tokyo, 156-8502 Japan and * School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, 422-8526 Japan
2To whom correspondence and reprint requests should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • isoflavone • flavonoid • Japanese • LDL cholesterol • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). More than 600 food factors in vegetables are
now considered to influence human health (Huang et al. 1994
). A large number of epidemiologic studies investigating
the relationship between diet and cancer were reviewed, and a
preventive effect of the consumption of vegetables and fruits on
various types of cancer has been confirmed (Steinmetz and Potter 1996
). This protective effect has been attributed in general to
the antioxidative capacities of vitamin C, E and carotenoids in food.
However, the importance of other potentially protective compounds, such
as flavonoids in vegetables and fruits, has been recognized
(Hertog et al. 1992a
and 1992b
). Epidemiologic studies
show that dietary flavonoid intake is inversely associated with
mortality from coronary heart disease
(CHD)3
(Hertog et al. 1993
, Knekt et al.1996
)
and incidence of stroke (Keli et al. 1996
). These
results were supported by in vitro studies, such as the inhibition of
LDL oxidation and platelet aggregation by flavonoids (De Whalley et al. 1990
, Tzeng et al. 1991
). Flavonoids are
strong antioxidants and scavengers of free radicals (Husain et al. 1987
).
The Japanese consume a wide range of isoflavone-rich soybean
products (Ministry of Health and Welfare 1998
). Such a
high intake of isoflavones is assumed to protect against cancer,
especially estrogen-related cancers, such as breast, endometrial,
ovarian, prostatic and colon cancer (Adlercreutz et al. 1995
, Watanabe and Koessel 1993
, Watanabe et al. 1997
). Isoflavones have shown antioxidant activity in
both in vivo and in vitro studies (Ruiz-Larrea et al. 1997
, Watanabe et al. 2000a
). Genistein, in
particular, can inhibit the oxidative modification of isolated LDL
(Hodgson et al. 1996
).
These phytochemicals may benefit human health if they are consumed
appropriately in the diet. Intake of isoflavone-rich soy hypocotyl
tea or isoflavone-rich tablets decreased phosphatidylcholine
hydroperoxide and phosphatidylethanolamine hydroperoxide in red blood
cells and lowered urinary excretion of 8-hydroxy-2'-deoxyguanosine in
humans (Watanabe et al. 2000a
), but hormonal levels were
also influenced as a result of this intervention trial (Watanabe et al. 2000b
). No guidelines exist for consumption of these
phytochemicals; thus it is not known what level of intake is
appropriate for the prevention of disease. The investigators studied an
appropriate dietary amount of flavonoids and isoflavones for the
prevention of disease. Accurate estimation of phytochemical intake is
important. We created food composition tables for four flavonols, one
flavone and two isoflavones to estimate intake. The validity of this
table was verified by comparing the correlated intakes with plasma and
urinary isoflavone levels (Arai et al. 2000
). The intake
of flavonols, flavones and isoflavones was calculated with the use of
this table, and the relationship between these phytochemicals and
various anthropometric and blood chemistry data were analyzed in a
cross-sectional study.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study was conducted in September 1997 and 1998 in the northern part
of Japan. An urban rural community (population 
50,000) in this area
has been our field for a population-based prospective study and
nutritional training since 1980. The subjects were 115 female
volunteers, who each agreed to participate to this study and gave
written informed consent. The study design was approved by the Ethical
Committee in Tokyo University of Agriculture. All subjects were
housewives who also worked in agriculture, such as the cultivation of
vegetables and rice. Fifteen subjects were employees of local
government and private industry. The physical activities of each
subject were classified according to guidelines of the Ministry of Health and Welfare (1994)
as follows: light,
n = 27; moderate, n = 68; and
semiheavy, n = 20. Ninety-one women (79%) were
postmenopausal. The prevalence of regular cigarette smoking and alcohol
consumption was 4 (3.5%) and 42 (36.5%) women, respectively.
Each person completed a 3-d dietary record and anthropometric
measurements were taken on d 4 of the study, including blood sampling
for biochemical analysis. Each subject recorded the amount and kind of
food and beverages consumed during the study period. These dietary
records were then checked by trained dieticians and coded for
calculating the level of energy and nutrients using the Standard Tables
of Food Composition (The Science and Technology Agency of Japan 1982
).
The anthropometric measurements were carried out for height, weight and blood pressure. Body mass index (BMI, kg/m2) was calculated from height and weight. The number of steps taken during the study period was measured by a walking meter (EM-200, Yamasa Watch, Tokyo, Japan). The subjects constantly wore a walking meter from rising in the morning to bedtime at night.
After an overnight fast, blood samples were collected with a vacuum
syringe containing heparin powder. The plasma was isolated by
centrifugation (2000 x g, 10 min, 4°C) and used
for biochemical analysis of total protein (TP), albumin, total
cholesterol (TC), triacylglycerol (TG), HDL cholesterol (HDL-C), uric
acid, creatinine, glutamic oxaloacetic transaminase (GOT), glutamic
pyruvic transaminase (GPT), 
-glutamyl transpeptidase (-GTP),
alkaline phosphatase, cholinesterase and total bilirubin. Biochemical
analysis was done with a clinical analyzer (Hitachi 7250, Hitachi,
Tokyo, Japan). Plasma LDL cholesterol concentration (LDL-C) was
calculated using the Friedewald formula (Friedewald et al. 1972
). The albumin/globulin ratio was calculated from the
concentration of TP and albumin. The RBC count, hemoglobin and white
blood cell count were analyzed from whole blood by an automatic
analyzer (SE-9000, SYSMEX, Hyogo, Japan).
Analysis of flavonols, flavone and isoflavones in food.
The amounts of four kinds of flavonols (myricetin, fisetin, quercetin and kaempferol) and one kind of flavone (luteolin) were determined in 15 vegetables, 8 fruits, 2 legumes, 1 potato and green tea. The amounts of two kinds of isoflavones (daidzein and genistein) were determined in soybeans, bean sprouts and traditional Japanese soybean products, such as tofu (soybean curd), natto (fermented soybean), miso (soybean paste) and shoyu (soy sauce). In most cases, at least three food samples were purchased at a local market and prepared for analysis on the same day. The whole foods were washed in water, chopped and homogenized. The samples were then freeze-dried and kept frozen at -80°C until analysis.
The analysis of flavonols and flavone was carried out by a modified
method of hydrolysis by Hertog et al. (1992b)
, and
extraction and HPLC condition by Terada and Miyabe (1993)
and Shimoi et al. (1997)
. In brief, a
0.25-g freeze-dried food sample was extracted with 25 mL of 50%
methanol containing 1.2 mol/L HCl and 1.6 g/L
tert-butylhydroquinone for 2 h at 90°C. The
extract was diluted to 100 mL with methanol. After centrifugation (1000
x g, 5 min, 4°C), a 2-mL aliquot was dried by
evaporation under nitrogen gas flow, dissolved in 20
µL of methanol and added to 1.5 mL of 0.01 mol/L
oxalic acid. Finally, it was applied to Sep-Pak C18 cartridges
(Waters, Milford, MA). These were washed with 1 mL of 0.01 mol/L oxalic
acid, 1 mL methanol/water/0.01 mol/L oxalic acid (25:73:2. v/v/v) and
10 mL water; the flavonoids were eluted with 5 mL methanol and the
methanol fraction was dried by evaporation under nitrogen gas flow. The
residue was dissolved in 100 µL methanol, of which 10
µL was used for HPLC analysis. Flavonoids were
measured by the JASCO HPLC system (JASCO, Tokyo, Japan) with a Capcell
Pak C18-UG120 column (150 x 4.6 mm i.d., 5-µm
particle size) (Shiseido, Tokyo, Japan) at 50°C. Flavonoid peaks were
detected at 372 nm. The flow rate was carried out at 0.7 mL/min and the
mobile phase was methanol/distilled water/0.5 mol/L oxalic acid
solution (40:60:2, v/v/v). The retention times of the flavonoids were
3.4 (myricetin), 3.9 (fisetin), 6.2 (quercetin), 7.5 (luteolin) and
11.0 min (kaempferol).
The isoflavones were analyzed using the hydrolysis and extraction
method of Mazur et al. (1996)
combined with the HPLC
method described by Gamache et al. (1997)
.
Freeze-dried samples (0.01 g) were put in glass tubes and 0.5 mL of
distilled water was added to each. After the samples stood for 10 min,
they were hydrolyzed overnight at 37°C with 0.5 mL of an enzyme
solution [0.5 mL Helix pomatia juice (Type HP-2S,
Sigma, St. Louis, MO) in 10 mL of 0.2 mol/L acetate buffer (pH 4.0)
containing 0.15 g ascorbic acid]. The hydrolyzed samples were
extracted twice with 5 mL diethyl ether, and the ether fraction was
dried by evaporation under nitrogen gas flow. The residue was dissolved
in 1 mL methanol, and 20 µL of that solution was
analyzed by HPLC with diode-array UV detection scanning from 250 to
400 nm (Beckman Coulter K.K., Tokyo, Japan). Isoflavone peaks were
detected at 254 nm. The HPLC column ODS-80Ts-Qa (150 x 4.6 mm
i.d., 5-µm particle size) (Tosoh, Tokyo, Japan) was
used with a guard column (TSKguardgel ODS-80Ts, 1.5 x 3.2 mm
i.d., 5 µm particle size) (Tosoh), and the temperature
kept at 25°C using a column oven. HPLC analysis was carried out by
linear gradient, from 1.5:0.5:8.0 [methanol, acetonitrile, 0.2 mol/L
acetate buffer (pH 4.0), v/v/v] to 6.0:3.0:1.0 for 45 min, and
returned to the initial condition for 5 min. The flow rate was 1.0
mL/min. The retention times of daidzein and genistein were 21.0 and
25.0 min, respectively.
All measurements were carried out in duplicate. Quantification of each flavonoid and isoflavone was done by measuring peak areas on the basis of calibration plots of the peak area of standards at various concentrations. HPLC standards were purchased from Sigma-Aldrich Japan K.K. (Osaka, Japan; quercetin and myricetin), Funakoshi (Tokyo, Japan; kaempherol), Wako Pure Chemicals (Osaka, Japan; luteolin and fisetin) and Indofine Chemical Company (Somerville, NJ; daidzein and genistein). All solvents and chemicals used were HPLC grade or analytical grade.
Statistical analysis.
Statistical analysis was conducted using the SPSS package (SPSS 1998
). Pearson’s correlation coefficients were calculated
between intake of antioxidant vitamins and phytochemicals and dietary
variables or various health indices, such as anthropometric and blood
biochemical analysis data. Two-sided P-values
< 0.05 were considered significant. Significant association was
further analyzed to exclude false judgement by multiple regression
analysis (residual model).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
2
. The number of pre- and postmenopausal women was 24 (20.9%) and 91
(79.1%), respectively. The length of the menstrual cycle of
premenopausal women, aged 43.3 ± 6.8 y, was 29 d (range
25–35 d). Postmenopausal women had significantly higher plasma TC
(5.64 ± 0.91 vs. 5.04 ± 0.79 mmol/L) and LDL-C (3.61
± 0.86 vs. 3.13 ± 0.76 mmol/L) as well as systolic blood
pressure (128 ± 14 vs. 116 ± 18 mm Hg), and plasma hepatic
function markers such as GOT (27 ± 10 vs. 21 ± 5
U/L), GPT (25 ± 14 vs. 18 ± 8 U/L)
and -GTP (0.41 ± 0.33 vs. 0.27 ± 0.15
µkat/L) compared with premenopausal women. Daily intake of
energy, protein, fat, carbohydrates and vitamins, antioxidative
activity and selected foods rich in phytochemicals are shown in
Table 3
. There was no significant difference in dietary intake of nutrients or
food groups between premenopausal and postmenopausal women. The average
intake of energy and nutrients exceeded the recommended dietary
allowance for Japanese (Fig. 1
).
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) was 16.7 ± 9.2 mg/d, ranging from 2.0 to 42.4 mg/d (Fig. 2
). The composition of the total flavonoid intake was 55.9% quercetin,
35.3% kaempferol, 4.6% fisetin, 2.5% myricetin and 1.7% luteolin.
Among the five flavonoids, the intake of quercetin and kaempherol was
greatest (Table 5
).
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.
Quercetin intake came mainly from onions (83.6%), whereas kaempferol
came from various vegetables and fruits. Vegetable and fruit intake,
used for the calculation of flavonoid intake, consisted of 78.0 and
70.4% of all vegetable and fruit consumption by weight, respectively,
in the dietary records.
Intake of total isoflavones (sum of daidzein and genistein) calculated
from the 3-d dietary records using the isoflavone composition table
(Table 6
) was 47.2 ± 23.6 mg/d, ranging from 12.0 to 118.9 mg/d (Fig. 2)
.
Isoflavone intake exceeded 100 mg/d in six subjects (5.2%). Genistein
made up most of the isoflavone intake (30.5 ± 15.6 mg/d), and
daidzein intake (16.6 ± 8.0 mg/d) was about half that of
genistein (Table 7
). Isoflavone intake was attributable to tofu (sum of various types,
37.0%, 49.4 g/d), natto (31.0%, 14.8 g/d) and miso (15.7%, 17.0
g/d), which accounted for 84.3% of pulse consumption by weight in the
dietary records (Table 7)
.
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After adjustment for age, BMI and total energy intake, flavonoid intake
was inversely associated with plasma TC (r = -0.236,
P < 0.05) and LDL-C (r = -0.220,
P < 0.05). Among the five flavonoids, quercetin intake
was inversely correlated with plasma TC (r = -0.261,
P < 0.01) and LDL-C (r = -0.263,
P < 0.01) (Fig. 3
). After further adjustment for age, BMI and total energy intake,
dietary variables (intake of fat, carotenoids, vitamin C, dietary fiber
and cholesterol), green tea consumption, number of steps taken,
systolic and diastolic blood pressure, cigarette use, alcohol use and
menopausal status, the association between quercetin intake and plasma
LDL-C was unaffected (r = -0.316, P
< 0.01). Plasma HDL-C and TG, however, did not correlate with
the intake of any flavonoids. Isoflavone, carotenoid, vitamin C and E
intakes were not significantly correlated with plasma lipid
concentrations. Other blood and biochemical data were not correlated
with the intake of any flavonoids, isoflavones or antioxidant vitamins.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Watanabe and Koessel 1993
). We estimated the intakes of flavonols, flavone and isoflavones in Japanese women and tried to determine any relationship that existed between these phytochemicals and various anthropometric and blood biomarkers in a cross-sectional study drawn from a population-based prospective study.
Our content table for flavonols, flavone and isoflavones agrees well
with previous reports. Hertog et al. (1992a)
reported
that the quercetin concentration in onions was 347 µg/g, and
Crozier et al. (1997)
reported it to be 342 µg/g. We
obtained a similar value (337 µg/g). Toda et al. (1997)
reported concentrations of isoflavones in 24 commercial
Japanese soybean foods. Their isoflavone values and ours (sum of
daidzein and genistein) are shown as follows: tofu (momen type), 422
vs. 435 µg/g; miso, 476 vs. 457 µg/g; and natto, 1081 vs. 974
µg/g.
The main methodological problem in obtaining accurate measurements of
the amount of flavonoids in foods was achieving complete hydrolysis of
all glycosides of flavonols, flavones and isoflavones without
substantial loss of flavonoid and isoflavone. In the case of
isoflavones, enzymatic hydrolysis of glucuronidase, sulfatase and other
unknown enzymes in Helix pomatia juice yielded a maximum
amount of isoflavones (Mazur et al. 1996
). In contrast,
flavonol and flavone hydrolysis presented some difficulty.
Harborne (1965)
reported that the time required for
complete hydrolysis depended on the binding site of sugar on the
flavonoid nucleus: C7>C4'>C3. Onions contain mainly C4' glycosides
and tea C3 rutinosides (rutin). Apples contain a variety of quercetin
glycosides, such as glactosides and rhamnosides (Harrmann 1976
). Hertog et al. (1992b)
reported that
flavonoid content after >2 h of hydrolysis was 10% higher than that
after only 2 h of hydrolysis. Because we did not optimize
conditions according to food type, flavonoid content in some foods
could have been underestimated.
The average intake of flavonoids was 16.7 ± 9.2 mg/d in this
study. This value agrees well with our previous study, in which the
average flavonoid intake was 16.2 ± 9.5 mg/d (Kimira et al. 1998
). Shimoi and Kinae (1997)
analyzed the
flavonoid concentration in seven different kinds of duplicate meals.
The range of flavonoid concentration was from 5 to 30 mg/meal. Thus
the intake of flavonoids in the Japanese diet is estimated to be from
10 to 90 mg/d. Hertog et al. (1995)
estimated that the
average intake of total flavonoids was 65 mg/d in two areas in the
western part of Japan. Tea was the major source of flavonoids in their
study, in which > 80% of flavonoid intake came from about seven
cups (700 mL) of green tea per day. In our study, the main sources of
flavonoid intake were vegetables, such as onions, tomatoes and
molokheya, followed by fruits and green tea. The average intake of
green tea was 206 mL/d (2 cups). The intake of catechin
[(-)-epigallocatechin gallate] from tea was estimated to be 40
mg/d.
Willet (1998)
reported that the number of days required
for the estimation of various nutrient intakes differed greatly.
Wakai et al. (1999)
calculated that the number of days
required for determining 95% of the observed values of daidzein and
genistein was 34, 76 and 305 d to obtain accurate intake estimates
within a range of 30, 20 and 10%, respectively. Our study considered
only five types of flavonoids out of 4000 that are known; but these
five are known to be important components because of their
antimutagenic (Kanazawa et al. 1997
) and antioxidative
properties (Catapano 1997
, Ho 1997
).
Regardless of the above-described limitations, the present study showed that plasma LDL-C correlated inversely with the intake of quercetin, even after adjusting for other antioxidant vitamins.
Igarashi and Ohmura (1995)
reported that rats fed a
cholesterol-enriched diet had lower TC when diets were supplemented
with isoramnetin, rhamnetin or quercetin, among which quercetin was the
most effective. The fecal excretion of cholesterol and bile acids from
rats fed quercetin was slightly higher than that of control rats.
Flavonoids have been reported to have an antioxidant effect due to
their ability to scavenge free radicals or to chelate metal ions
(Belguendouz et al. 1997
, Husain et al. 1987
). It has been suggested that the TC- and LDL-C–reducing
effects of flavonoids prevent CHD and other chronic diseases in concert
with the antioxidative effect of flavonoids.
Imai and Nakachi (1995)
also reported a significant
reduction of serum TC and TG in Japanese men who consumed >1000 mL (10
cups) of green tea per day. In our study, however, green tea
consumption was not related to plasma lipid concentration, and
adjusting for green tea consumption did not alter the inverse
correlation of flavonoid intake with plasma lipids. Cassidy et al. (1995)
reported that the administration of textured soy
protein significantly reduced plasma TC and LDL-C concentrations in
premenopausal women. Whether isoflavones have a
cholesterol-lowering effect is still unresolved (Bakhit et al. 1994
, Carroll 1991
, Hodgson et al. 1998
), Nelson et al. 1997, Potter et al. 1993
. In our intervention study using isoflavone tablets,
plasma cholesterol and TG concentrations were not affected
(Watanabe et al. 2000b
).
Intake of isoflavones exceeded that of other dietary
antioxidants, such as flavonoids (16 mg), carotenoids (3 mg) and
vitamin E (8 mg), reaching a level that was approximately one half that
of vitamin C (108 mg) (Fig. 2)
. Isoflavones in the Japanese diet may
contribute much to antioxidant effects in the body. Although the
isoflavones were not correlated with plasma LDL-C in our study,
these antioxidant properties would contribute to the prevention of LDL
oxidation and lower mortality from CHD (De Whalley et al. 1990
, Palinski et al. 1989
, Parthasarathy et al. 1992
, Witztum and Steinburg 1991
).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BMI, body mass index; CHD, coronary heart disease; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; -GTP, -glutamyl transpeptidase; HDL-C, high density lipoprotein cholesterol concentration; LDL-C, low density lipoprotein cholesterol concentration; TC, total cholesterol concentration; TG, triacylglycerol concentration; TP, total protein.
Manuscript received December 3, 1999. Initial review completed May 4, 2000. Revision accepted May 24, 2000.
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