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Research and Development Division, Kikkoman Corporation, Chiba, Japan;
*
Noda Institute for Scientific Research, Chiba, Japan; and
Kikkoman General Hospital, Chiba, Japan
1To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • isoflavone absorption • aglycone • genistein • daidzein • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Interest in soy ingredients has increased
recently all over the world. Epidemiologic studies have shown that the
consumption of soybeans decreases the risk of various diseases and
conditions, including breast cancer (Adlercreutz et al. 1991
, Lee et al. 1991
), prostate cancer
(Severson et al. 1989
), colon cancer (Watanabe and Koessel 1993
), osteoporosis (Knight and Eden 1996
), menopausal symptoms (Adlercreutz et al. 1992
) and coronary heart disease (Clarkson et al. 1995
). Isoflavones in soybean exist primarily as glucoside
forms: 6''-O-malonylglucosides and
6''-O-acetylglucosides (Izumi et al. 1997
,
Kudou et al. 1991b
, Naim et al. 1973
, Ohta et al. 1979
and 1980
, Walter 1941
) and rarely as aglycone forms. Isoflavone aglycones (IFA)
are contained in miso, natto and soy sauce, Japanese traditional
fermented soy foods (Wang and Murphy 1994
). The
representative isoflavone glucosides (IFG) in soybean are genistin and
daidzin, and their corresponding IFA are genistein and daidzein
(Fig. 1
). Soy isoflavones have been reported to have a variety of biological
activities, including estrogenic (Shutt and Cox 1972
),
antioxidative (Kapiotis et al. 1997
, Naim et al. 1976
), antiosteoporotic (Anderson and Garner 1997
, Ishida et al. 1998
) and anticarcinogenic
(Herman et al. 1995
). Genistein in particular inhibits
the proliferation of a variety of tumor cell lines in culture
(Barnes 1995
) and is thought to be the most effective
isoflavone in cancer treatment and prevention.
|
,
Hutchins et al. 1995
, Wang et al. 1994
,
Xu et al. 1995
). King and Bursill (1998)
investigated the concurrent patterns of plasma and urinary isoflavone
excretion after consumption of soy meals containing IFG.
Watanabe et al. (1998)
evaluated more detailed
pharmacokinetics of IFG in seven healthy Japanese men after consumption
of a single dose of baked soybean powder containing IFG, and reported
that more genistein than daidzein appeared in the blood circulation.
King et al. (1996)
, in studies with rats on the
pharmacokinetics of pure genistein or genistin that was contained in a
soy extract, found that the plasma concentration of genistein in
genistein-treated rats was more than two times higher than that in
soy extract (genistin)-treated rats 2 h after the intake of an
equal amount. It is generally thought that IFG are converted to the
corresponding IFA by gut microflora or gut glucosidases, and then IFA
are absorbed from the small intestine (Brown 1988
,
Day et al. 1998
). To date, however, no one has studied the difference between the absorption of IFA and IFG in humans. In this paper, we make the first report of this difference in absorption in eight healthy Japanese volunteers using the same molecular amounts of IFA and IFG.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Daidzein (>99%), genistein (>99%) and H-5 sulfatase were purchased from Sigma Chemical (St. Louis, MO). Daidzin (>99%) and genistin (>99%) were purchased from Nacalai Tesque (Kyoto, Japan). Other chemicals were of analytical or HPLC grade.
Subjects.
In low dose intake tests, the healthy volunteers were four men and four women between 31 and 58 y of age; body weight ranged from 51 to 85 kg and body height from 152 to 187 cm. In the high dose intake tests, the healthy volunteers were four men and four women between 38 and 57 y of age; body weight ranged from 54 to 80 kg and body height from 156 to 183 cm. In long-term intake tests, the subjects were eight men between 38 and 55 y of age with body weight of 58 to 82 kg and body height of 165 to 176 cm. The study design was approved by the ethics committee of the authors’ laboratory, and informed consent of the subjects was obtained in writing.
Diet and blood sample collection.
The studies consisted of four feeding days. In the single-intake tests, each study day was separated by a 2-mo washout period. In the low and high single-intake experiments, the participants were requested to avoid any soy foods, for example, miso (fermented soybean paste), natto (fermented soybean), tofu and soy protein products, from 3 d before the test until completion of the test. During the washout period, there were no diet restrictions.
IFA and IFG were provided in the form of tablets (Table 1
). We used SoyAct (Kikkoman Corporation, Noda, Japan) as IFA or a
soybean extract (prepared by the same company) as IFG. SoyAct is a
fermented soybean extract containing 30% IFA (genistein, 43.63%;
daidzein, 56.37%), saponin, sugar, protein and fat. The soybean
extract contains ~40% IFG (genistin, 54.55%; daidzin, 45.45%),
saponin, sugar, protein and fat. Concentration of isoflavones in those
extracts was measured according to the method of Kudou et al. (1991a)
. The subjects took these tablets after breakfast (0930
h). Blood samples were collected in heparinized vacuum syringes by
medical technologists before tablet intake (0900 h), and at 2 (1130 h),
4 (1330 h), 6 (1530 h) and 24 h (0930 h of the next day) after
intake. Medical doctors consulted with the subjects about any health
abnormalities during the tests.
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In both single- and continuous-intake tests, blood samples were centrifuged at 2000 x g for 10 min at 4°C and the plasma was separated and stored at -20°C before analysis.
Isolation and identification of isoflavones in plasma.
Plasma (50 µL) was added to 0.2 mol/L acetate buffer
(pH 5.0, 50 µL) with 500 U H-5 sulfatase
and incubated for 1 h at 37°C in a water shaking bath. Released
aglycones were extracted with 0.9 mL methanol/acetic acid (100:5, v/v)
with sonication and vortexing, and centrifuged at 5000 x g for 5 min at 4°C. The supernatant was diluted to
double its quantity with 100 mmol/L lithium acetate in water, and the
diluted samples were used for HPLC. Plasma concentration of isoflavones
was measured according to the method of Piskula et al. (1999)
. The HPLC was carried out on an HPLC column (TSKgel
ODS-80TS, 5 µm, 150 x 4.6 mm, TOSOH, Tokyo,
Japan). The composition of the mobile phase for HPLC analysis was
water/methanol/acetic acid (58:40:2, v/v/v) containing 50 mmol/L
lithium acetate, and effluent was monitored by an amperometric
electrochemical detector (ICA-3060, TOA, Tokyo, Japan) set at +950 mV.
Analysis of biochemical markers.
Biochemical markers of the subjects, i.e., plasma triglyceride,
glutamic-oxaloacetic transaminase, glutamic-pyruvic
transaminase, 
-glutamyltranspeptidase, creatinine, blood urea
nitrogen, total cholesterol, eosinocyte, erythrocyte and leukocyte,
were analyzed at SRL Tokyo Medical (Chiba, Japan).
Statistics.
Reported values represent means ± SD (n = 8). Statistical analysis was evaluated by paired t test to identify significantly different means; SigmaPlot for Windows Version 4.00 (SPSS, Chicago, IL) was used.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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With the consumption of IFA, plasma concentrations of genistein and
daidzein reached their highest values 2 h after intake (Fig. 2
). The concentration of genistein was higher (P < 0.01)
than that of daidzein at each time point despite the similar intake of
the two isoflavones (Fig. 2)
.
|
, and, again, the
concentration of genistein was higher (P < 0.01) at
each time point. In these single-intake tests, the plasma
concentration of either chemical after IFA intake was higher
(P < 0.05) than after IFG intake at 2, 4, 6 h.
All plasma biochemical markers measured were within the normal range
after IFA intake (data not shown). No subjects complained of any health
abnormalities. High dose, single administration.
When 1.7 mmol of IFA was consumed, plasma concentrations of genistein
and daidzein were highest 4 h after intake (Fig. 3
). Similar to after low IFA intake, the concentration of genistein was
higher (P < 0.01) than that of daidzein at each time
point despite the almost equal intakes.
|
. The concentration of genistein was
higher (P < 0.05) at each time point despite nearly
equal intakes. The concentrations after IFA intake were higher
(P < 0.05) than those after IFG at 2, 4 and 6 h
after ingestion (Fig. 3)
. The highest plasma concentration of either
compound after IFA intake was more than five times higher than that
after IFG (Fig. 3)
. Plasma total isoflavone concentration ratios after
IFA intake relative to after IFG intake were 3.2, 6.6 and 4.3 at 2, 4
and 6 h after intake, respectively. All plasma biochemical markers
were within the normal range after the intake of IFA. No subjects
complained of any health abnormalities (data not shown). Long-term administration.
The plasma concentration of genistein and daidzein during the
consumption of IFA was more than twice as high as those of IFG at 2
(P < 0.05) and 4 wk (P < 0.005) after
intake began (Fig. 4
). The concentration of genistein was higher (P < 0.05)
than that of daidzein at each time point during both IFA and IFG
consumption. All plasma biochemical markers were within normal ranges
after the intake of IFA. No subject complained of any health
abnormalities (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Naik et al. (1994)
reported that genistein inhibited the growth of MLL
prostate cancer cells and PC-3 cells in a dose-dependent manner.
Matsukawa et al. (1993)
reported that genistein
inhibited in a dose-dependent manner the growth of HGC-27 cells
derived from human gastric cancer.
Using rats, King et al. (1996)
studied the
pharmacokinetics of pure genistein or genistin that was contained in a
soy extract and found that the plasma concentration of genistein in
genistein-treated rats was significantly higher than that in soy
extract (genistin)-treated rats 2 h after intake. In our study,
similar results were obtained in humans. IFG are very poorly absorbed
from the gut compared with IFA, because of the higher hydrophilicity
and greater molecular weight of IFG (Brown 1988
). It has
been assumed that IFG have to be converted into IFA to be absorbed into
the human body. Friend and Chang (1984)
reported that
glucosidases of intestinal microflora in the lower bowel could liberate
the aglycones from the glucosides and promote their absorption.
Day et al. (1998)
reported that human gut tissues have a
ß-glucosidase capable of absorbing efficiently various
naturally occurring isoflavonoid glucosides. We think that our results
with humans support these reports in part. IFA was absorbed more
quickly and in greater amounts than IFG. It is presumed that IFA are
absorbed directly from the small intestine without being affected by
gut microflora or gut glucosidases. In low and high dose intake tests,
IFG administered required a longer time period to reach the highest
isoflavone concentration in plasma than did IFA (Figs. 2
, 3)
.
The time lags between the highest concentrations after IFA and IFG
intake likely are attributable to the absorption of IFA from the
stomach as found in the study with rats by Piskula et al. (1999)
. In plasma, the high dose took a longer time to reach
the highest isoflavone concentration than did the low dose. The
relative absorption ratio in the stomach may be higher with a low dose
than with a high dose.
IFA are absorbed more efficiently than IFG. The intake of
isoflavones in the high dose test was >15 times higher than that in
the low dose test. The highest plasma concentration of total
isoflavones in the high dose test was 21 times higher than that in the
low dose test after IFA intake, whereas plasma concentration after the
high dose test was only 12 times higher than after the low dose test
when IFG was administered (Figs. 2
, 3)
. These results suggest that IFG
have to be converted to IFA by intestinal glucosidases to be absorbed
into the human body, and that the conversion of IFG into IFA may be a
rate-determining step in human absorption. The highest isoflavone
concentrations in plasma after IFA intake were more than two times
greater than those after IFG intake in the low dose, single
administration, whereas at high administration, it was over five times
greater (Figs. 2
, 3)
.
In our study, as well as the studies by Watanabe et al. (1998)
and King and Bursill (1998)
, the plasma
concentration of genistein was higher than that of daidzein each time
(Figs. 2
, 3)
. Watanabe et al. (1998)
reported that
urinary daidzein excretion was much higher than that of genistein and
that the half-life of genistein (8.4 h) in plasma was longer than
that of daidzein (5.8 h) when subjects were fed baked soybean powder
containing IFG. Our results also showed that genistein is higher and is
elevated longer than daidzein in human plasma after IFA intake,
perhaps allowing for certain pharmacological effects. Whole soy likely
is superior to soy germ that is rich in daidzin and daidzein because of
the larger amount of genistin and genistein it contains.
Soy isoflavones reportedly have estrogenic (Shutt and Cox 1972
), antioxidative (Kapiotis et al. 1997
,
Naim et al. 1976
), antiosteoporotic (Anderson and Garner 1997
, Ishida et al. 1998
) and
anticarcinogenic (Herman et al. 1995
) activities. They
are expected to be effective against various conditions such as
menopausal symptoms, coronary heart disease, osteoporosis and cancers.
To obtain the desired effects, it is necessary to maintain a constant
plasma concentration for a long period. In our long-term intake
tests, the plasma concentrations of genistein and daidzein during the
ingestion of IFA were >100% higher than those during IFG intake at 2
and 4 wk after the start of intake (P < 0.05) (Fig. 4)
, suggesting that IFA are more effective than IFG in maintaining the
desired plasma concentrations. Moreover, we assume that the
long-term intake of IFA or IFG may be completely safe because the
subjects’ plasma biochemical markers remained within normal ranges and
no one complained of any unusual health problems.
In conclusion, the results of our single- and continuous-intake tests with IFA and IFG revealed the superior absorptivity of IFA in humans. Therefore, IFA are more useful than IFG in maintaining a high level of isoflavone concentration in plasma. Genistein is absorbed more efficiently than daidzein and a higher plasma concentration was maintained. We expect that our findings may be applicable to the treatment of certain diseases and conditions if the efficacious plasma concentrations of isoflavones are proved. Genistein-rich products such as fermented whole-soy foods and their extracts may be useful in preventing osteoporosis, menopausal symptoms, coronary heart disease and cancers.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received October 26, 1999. Initial review completed December 7, 1999. Revision accepted February 21, 2000.
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C. Manach, A. Scalbert, C. Morand, C. Remesy, and L. Jimenez Polyphenols: food sources and bioavailability Am. J. Clinical Nutrition, May 1, 2004; 79(5): 727 - 747. [Abstract] [Full Text] [PDF]
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 R. M. Harris, D. M. Wood, L. Bottomley, S. Blagg, K. Owen, P. J. Hughes, R. H. Waring, and C. J. Kirk Phytoestrogens Are Potent Inhibitors of Estrogen Sulfation: Implications for Breast Cancer Risk and Treatment J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1779 - 1787. [Abstract] [Full Text] [PDF]
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L. Zubik and M. Meydani Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1459 - 1465. [Abstract] [Full Text] [PDF]
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 G. D. Anderson, G. Rosito, M. A. Mohustsy, and G. W. Elmer Drug Interaction Potential of Soy Extract and Panax Ginseng J. Clin. Pharmacol., June 1, 2003; 43(6): 643 - 648. [Abstract] [Full Text] [PDF]
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K. D. R. Setchell, N. M. Brown, P. B. Desai, L. Zimmer-Nechimias, B. Wolfe, A. S. Jakate, V. Creutzinger, and J. E. Heubi Bioavailability, Disposition, and Dose-Response Effects of Soy Isoflavones When Consumed by Healthy Women at Physiologically Typical Dietary Intakes J. Nutr., April 1, 2003; 133(4): 1027 - 1035. [Abstract] [Full Text] [PDF]
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K. D. Setchell, M. S Faughnan, T. Avades, L. Zimmer-Nechemias, N. M Brown, B. E Wolfe, W. T Brashear, P. Desai, M. F Oldfield, N. P Botting, et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women Am. J. Clinical Nutrition, February 1, 2003; 77(2): 411 - 419. [Abstract] [Full Text] [PDF]
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 C.-J. Liu, J. W. Blount, C. L. Steele, and R. A. Dixon Bottlenecks for metabolic engineering of isoflavone glycoconjugates in Arabidopsis PNAS, October 29, 2002; 99(22): 14578 - 14583. [Abstract] [Full Text] [PDF]
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M. Richelle, S. Pridmore-Merten, S. Bodenstab, M. Enslen, and E. A. Offord Hydrolysis of Isoflavone Glycosides to Aglycones by {beta}-Glycosidase Does Not Alter Plasma and Urine Isoflavone Pharmacokinetics in Postmenopausal Women J. Nutr., September 1, 2002; 132(9): 2587 - 2592. [Abstract] [Full Text] [PDF]
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K. D. Setchell, N. M Brown, L. Zimmer-Nechemias, W. T Brashear, B. E Wolfe, A. S Kirschner, and J. E Heubi Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability Am. J. Clinical Nutrition, August 1, 2002; 76(2): 447 - 453. [Abstract] [Full Text] [PDF]
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N. Tsunoda, S. Pomeroy, and P. Nestel Absorption in Humans of Isoflavones from Soy and Red Clover Is Similar J. Nutr., August 1, 2002; 132(8): 2199 - 2201. [Abstract] [Full Text] [PDF]
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K. Murota, S. Shimizu, S. Miyamoto, T. Izumi, A. Obata, M. Kikuchi, and J. Terao Unique Uptake and Transport of Isoflavone Aglycones by Human Intestinal Caco-2 Cells: Comparison of Isoflavonoids and Flavonoids J. Nutr., July 1, 2002; 132(7): 1956 - 1961. [Abstract] [Full Text] [PDF]
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 G. A. Greendale, G. FitzGerald, M.-H. Huang, B. Sternfeld, E. Gold, T. Seeman, S. Sherman, and M. Sowers Dietary Soy Isoflavones and Bone Mineral Density: Results from the Study of Women's Health Across the Nation Am. J. Epidemiol., April 15, 2002; 155(8): 746 - 754. [Abstract] [Full Text] [PDF]
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M. Kano, F. Ishikawa, S. Matsubara, H. Kikuchi-Hayakawa, and Y. Shimakawa Soymilk Products Affect Ethanol Absorption and Metabolism in Rats during Acute and Chronic Ethanol Intake J. Nutr., February 1, 2002; 132(2): 238 - 244. [Abstract] [Full Text] [PDF]
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C. D. Allred, Y. H. Ju, K. F. Allred, J. Chang, and W. G. Helferich Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein Carcinogenesis, October 1, 2001; 22(10): 1667 - 1673. [Abstract] [Full Text] [PDF]
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S. Yamamoto, T. Sobue, S. Sasaki, M. Kobayashi, Y. Arai, M. Uehara, H. Adlercreutz, S. Watanabe, T. Takahashi, Y. Iitoi, et al. Validity and Reproducibility of a Self-Administered Food-Frequency Questionnaire to Assess Isoflavone Intake in a Japanese Population in Comparison with Dietary Records and Blood and Urine Isoflavones J. Nutr., October 1, 2001; 131(10): 2741 - 2747. [Abstract] [Full Text] [PDF]
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 K. D. R. Setchell Soy Isoflavones--Benefits and Risks from Nature's Selective Estrogen Receptor Modulators (SERMs) J. Am. Coll. Nutr., October 1, 2001; 20(90005): 354S - 362. [Abstract] [Full Text]
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W. Pan, K. Ikeda, M. Takebe, and Y. Yamori Genistein, Daidzein and Glycitein Inhibit Growth and DNA Synthesis of Aortic Smooth Muscle Cells from Stroke-Prone Spontaneously Hypertensive Rats J. Nutr., April 1, 2001; 131(4): |
