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Noda Institute for Scientific Research, 399 Noda-City, Chiba 278-0037, Japan
2Correspondence to permanent address: Institute of Animal Reproduction and Food Research, Division of Food Science, 10 Tuwima St., 10–747 Olsztyn, Poland.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • rats • daidzein • genistein • sulfate • glucuronide
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Isoflavones influence
steroid hormone metabolism (Loukovaara et al. 1995
),
inhibit cell proliferation and in vitro angiogenesis (Fotsis et al. 1995
), exert antioxidative activity (Wei et al. 1995
) and are potent inhibitors of tyrosine protein kinases
(Akiyama et al. 1987
). Nevertheless, some potential
adverse effects of soy isoflavones have been reported. Neonatal
exposure of rat male offspring to coumestrol through milk of rat dams
fed a diet containing coumestrol produced significant deficits in their
sexual behavior in adulthood (Whitten et al. 1995
). The
main soy isoflavones, daidzein and genistein, appear in soybeans in the
form of glucosides, daidzin and genistin, respectively. Hutchins et al. (1995)
showed that fermentation of soybeans increases
the availability of isoflavones by releasing isoflavone aglycones from
their glucosides as well as by increasing digestibility through the
structural alteration of the food matrix. Recently published reports
demonstrate the presence of ß-glucosidase activity toward flavonoid
and isoflavonoid glucosides in rat (Ioku et al. 1998
)
and human (Day et al. 1998
) small intestine. Indeed, no
differences in absorption between isoflavone glucosides and aglycones
were found except that aglycones, but not their glucosides, were
absorbed from the rat stomach (Piskula at al. 1999
).
Despite considerable interest in soy isoflavones, their absorption and
metabolism have not been well studied. In a number of papers, the total
plasma concentration or amount of excreted compound was measured, but
rarely as a function of time, and there is no information on the
pharmacokinetics of isoflavonoids conjugates, i.e., glucuronides and/or
sulfates. Although almost all isoflavones are glucuronized and/or
sulfated after absorption (Yasuda et al. 1994
and 1996
),
most of the in vitro studies demonstrating beneficial action of
isoflavones were done on nonconjugated aglycones. Moreover, the
effective plasma concentrations of these compounds are still not known.
Therefore, the aim of this study was to compare the absorption of
daidzein and genistein in fed (F) and food-deprived (FD) rats with
regard to their conjugation pattern. At present, there are still no
definite recommendations concerning the amounts of isoflavones to be
consumed to prevent diseases. On the basis of rat studies, the daily
dose of isoflavones that humans would have to consume to suppress
hepatocarcinogenesis would be 6–8 µmol/kg body
(Hendrich et al. 1994
), an amount rather difficult to
reach without dietary supplementation of isoflavones. The average daily
intake of isoflavones in high soy products consumed by the Japanese
population is estimated to be ~2.3–2.5 µmol/kg body
(Kimira et al. 1998
). In this study, rats were
administered daidzein and genistein at a dose of 7.9
µmol/kg body, and changes in their metabolites were
measured quantitatively in blood plasma as a function of time.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Daidzein and genistein were purchased from Fujicco (Kobe, Japan), sulfatase type H-5 and VIII, ß-glucuronidase type VII-A and D-saccharic acid 1.4 lactone were purchased from Sigma Chemical (St. Louis, MO). Other chemicals were of analytical or HPLC grade.
Animals, diets and treatments.
Wistar male rats (n = 10; Charles River Japan,
Atsugi, Japan) were supplied at the age of 8 wk and kept in a
temperature- (23 ± 1°C) and light- (0700–1900 h) controlled
room in the institute animal facility for ~1 wk before the
experiments, with free access to tap water and diet. Feeding the rats
nonpurified diet (standard MF, Oriental Bioservice, Chiba, Japan)
containing some soy components resulted in a concentration of
isoflavones in blood plasma of ~0.8 µmol/L.
Therefore it was necessary to switch rats to a phenolic-free
powdered
diet3
(Oriental Bioservice) (Okushio et al. 1996
) for ~1 wk
before the experiments to eliminate isoflavones from plasma to levels
below the detection limit (30 nmol/L).
The comparison of daidzein and genistein absorption and conjugation was performed on two groups of 5 rats, one of which was denied access to food at 0900 h, i.e., 24 h before the experiment. On the day of the experiment, daidzein and genistein freshly dissolved in 25 mmol/L Na2CO3 were administered orally to rats at 7.9 µmol/kg body by direct stomach intubation in a total volume of ~1.5 mL. Before (control) and after administration, blood samples (~400 µL) were collected from the tail vein at certain time intervals into heparinized tubes, and plasma was prepared by centrifugation for 20 min at 4°C and 1000 x g. Experiments were made after the experimental protocol was approved by the Institute Ethic Committee; rats received humane care consistent with institutional guidelines.
Determination of isoflavones and their conjugates in rat plasma.
Identification and plasma concentration of isoflavones and their
conjugates were studied by the method described previously
(Piskula and Terao 1998a
, Piskula et al. 1999
). Nonconjugated daidzein and genistein were determined by
HPLC after extraction from blood plasma. To 50 µL of
plasma, 50 µL of 0.2 mol/L sodium acetate buffer, pH
5, and 900 µL of methanol/acetic acid (100:5, v/v)
were added. The mixture was vortexed for 30 s, sonicated for
30 s, again vortexed for 30 s and centrifuged for 5 min at
4°C and 5000 x g. The supernatant was diluted
with 100 mmol/L of lithium acetate (1:1, v/v), centrifuged for 2 min at
4°C and 5000 x g, and 20 µL was
injected onto a HPLC column (TSKgel ODS-80TS, 5 µm,
150 x 4.6 mm, TOSOH, Tokyo, Japan). The flow of the
mobile phase composed of water/methanol/acetic acid (58:40:2, v/v/v)
containing 50 mmol/L of lithium acetate, was 0.9 mL/min. The elute was
monitored with an amperometric electrochemical detector (ICA-3062, TOA,
Tokyo, Japan) with the working potential set at + 950 mV. When
necessary, samples were diluted with the mobile phase before HPLC
analysis.
Enzymatic hydrolysis of daidzein and genistein conjugates and determination of their concentration in plasma.
Rat plasma (50 µL) was mixed with 50 µL of sulfatase type H-5 solution in 0.2 mol/L acetate buffer, pH 5 (the preparation contained 500 U of ß-glucuronidase per 25 U of sulfatase), and the mixture was incubated at 37°C in a shaking water bath for 1 h. Daidzein and genistein released during the incubation and their nonconjugated forms present in plasma before the hydrolysis were extracted with 900 µL of methanol/acetic acid (100:5, v/v) and determined as described above. The result was the total plasma concentration of daidzein and genistein.
To determine daidzein and genistein glucuronides only, 50 µL of plasma was mixed with 50 µL of ß-glucuronidase (type VII-A) solution containing 50 U of the enzyme in 0.2 mol/L acetate buffer (pH 5), and the mixture was incubated at 37°C in shaking water bath for 2 h. Plasma daidzein or genistein glucuronide concentration was calculated as the difference between the plasma concentration before and after hydrolysis with VII-A ß-glucuronidase.
For determination of daidzein and genistein sulfate conjugates only, 50 µL of plasma was incubated with 50 µL of H-5 sulfatase solution (same as above), containing in addition 100 mmol/L of D-saccharic acid 1.4 lactone as a ß-glucuronidase inhibitor. Plasma daidzein or genistein sulfate concentration was calculated as the difference between the plasma concentration before and after hydrolysis with sulfatase.
The results of subtraction of plasma concentrations of glucuronides, sulfates and nonconjugated forms of daidzein or genistein from their respective total plasma concentrations were attributed to the concentration of sulfate/glucuronide conjugates, the conjugates with both sulfate and glucuronide moieties.
Statistical analyses.
Reported values represent means ± SD
(n = 5). Comparisons were made at each time point
using paired or unpaired Student’s t test, with
P 
0.05 considered to be significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. After absorption, isoflavones are metabolized, forming glucuronide
and/or sulfate conjugates. Enzymatic hydrolysis (ß-glucuronidase
and/or sulfatase) of blood plasma taken from rats after administration
of daidzein and genistein resulted in two peaks in the HPLC
chromatogram (compared with the chromatogram of hydrolyzed control
plasma); these were identified as daidzein and genistein
(Piskula et al. 1999
). Using a combination of plasma
enzymatic hydrolysis with ß-glucuronidase and/or sulfatase, the
concentration of total plasma isoflavones, and the concentration of
their glucuronides, sulfates and sulfates/glucuronides were measured.
For determination of sulfates, sulfatase type H-5 was used. Because it
also contains 500 U of ß-glucuronidase per 25
U of sulfatase, it was necessary to add a ß-glucuronidase
inhibitor, 100 mmol/L of D-saccharic acid 1.4 lactone, to
the enzyme solution. The amount of inhibitor was significantly higher
than in a previous experiment, in which sulfatase type VIII (containing
<3 U of ß-glucuronidase per 25 U of
sulfatase) was used (Piskula and Terao 1998a
). The
effectiveness of inhibition was confirmed when the same amounts of
isoflavones were released after hydrolysis of plasma from
isoflavone-administered rats with type H-5 and VIII sulfatases,
both containing ß-glucuronidase inhibitor. Moreover, when the same
plasma was hydrolyzed with 500 U of ß-glucuronidase type
VII-A with 100 mmol/L of D-saccharic acid 1.4 lactone,
no released daidzein or genistein was found; this is in contrast to the
control hydrolysis without the inhibitor added. For each kind of
enzymatic reaction, the hydrolysis time was set as the time at which
further extension of hydrolysis did not influence the amount of
isoflavones released.
|
Because daidzein and genistein are absorbed from the rat stomach
(Piskula et al. 1999
), the compounds and their
conjugates administered were found in plasma 3 min after
administration. Moreover, 7 min later, in the FD group, plasma total
daidzein and genistein reached maximum concentrations of 20.9 ± 4.4 and 11.4 ± 3.1 µmol/L, respectively (Fig. 1B
). In the F group, the maxima for daidzein and genistein
were found at 2 and 4 h after administration, i.e., 2.4 ± 0.8 and 1.8 ± 0.2 µmol/L, respectively (Fig. 1A
). In the F group, isoflavones were found exclusively in
the conjugated form, whereas in the FD group, nonconjugated daidzein
and genistein were noted 5 min after administration at maximum
concentrations of 0.85 ± 0.35 and 0.70 ± 0.30
µmol/L, respectively, and their plasma concentrations
dropped below the detection limit within 1 h. In both groups,
despite the same molar dose administered, total plasma concentration of
daidzein was higher than that of genistein, opposite to the results
after isoflavones were administered to rats with the absorption site
restricted to the stomach (Piskula et al. 1999
).
In the FD group (Fig. 1B
), a rapid increase in plasma
isoflavone concentration was followed by its rapid decrease, which
indicates that very fast absorption is followed by efficient
elimination and/or distribution of the compounds administered. Fed rats
were also absorbing isoflavones very rapidly (Fig. 1A
).
However, the extent of absorption in this group during the first 2 h was significantly lower and, in contrast to the FD group, no strong
fluctuations in plasma isoflavone concentration were observed.
Because of the several-fold differences in the extent of absorption
between the F and FD groups as well as high individual;F2>
variation among rats, the comparison of conjugation patterns of
daidzein (Fig. 2
) and genistein (Fig. 3
) between the groups was possible only for the relative content of each
type of metabolite (i.e., glucuronides, sulfates and
sulfate/glucuronides) compared with the total plasma concentration of
daidzein or genistein in the group.
|
|
, Fig. 3A
). Furthermore, when glucuronides of daidzein and
genistein were compared within the group, in both groups, there were
always more glucuronides of genistein than of daidzein. Also,
glucuronides were the group of isoflavone conjugates whose
concentration first dropped below the detection limit, i.e., 12 h
after administration. Unlike glucuronides, sulfates of both daidzein
(Fig. 2B)
and genistein (Fig. 3B)
decreased in the F group. When
concentrations of plasma sulfates of daidzein and genistein were
compared within groups, more daidzein sulfates than genistein sulfates
were found in both groups. The last type of isoflavone conjugates
measured was the sulfate/glucuronides. Similar to the glucuronides,
feeding was also the factor increasing the plasma concentration of
sulfate/glucuronide conjugates of daidzein and genistein (Fig. 2C
, Fig. 3C
); however, this increase was found to
be significant only for a limited period after genistein administration
(Fig. 3C
). Of all the plasma genistein and daidzein
conjugates determined, genistein conjugated both with sulfate and
glucuronide moieties (Fig. 3C
) and sulfated daidzein (Fig. 2B
) were the metabolites that lasted in rat plasma for the
longest time, and this was observed in both the F and FD groups. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) in which oral genistein
administration at 79 µmol/kg body to fed rats resulted in
the maximum total plasma genistein concentration of 11
µmol/L; this is significantly higher than results in this
study, probably reflecting the 10-fold higher dosage. Because the first
measurement of plasma genistein concentration in the study of
King et al. (1996)
was made 2 h after
administration and was the highest in that experiment, it is difficult
to state whether it was the maximum.
The differences in the extent and profile of absorption between the fed
and food-deprived groups (Fig. 1)
can be attributed to several
factors. At acidic pH, isoflavone solubility is low; therefore,
isoflavones were administered completely solubilized in 25 mmol/L
Na2CO3 at pH 10.6. Because
the stomach produces acidic secreta, there was likely a decrease in
solubility of administered isoflavones there, which strongly influenced
the extent of absorption (Piskula and Terao 1998b
,
Piskula et al. 1999
). Unlike in the FD group, rats in
the F group had stomachs with low pH contents which, despite provoking
rapid precipitation of administered isoflavones, also delayed the dose
transition and limited its surface contact with the digestive tract. In
addition, interactions of the administered compounds with food
particles are among the factors influencing their absorption
(Welling 1996
).
In both groups, daidzein was present in plasma at a higher
concentration than genistein (Fig. 1)
. Similar observations were made
after daidzein and genistein glucosides were administered to rats as a
soy extract (King 1998
). Additional measurement of
urinary isoflavones in that study revealed a significantly higher
content of daidzein than of genistein metabolites; the same result was
reported in a human study by Xu et al. (1994)
in which
isoflavones were administered to adult women in the form of soy milk.
In both cases, it was concluded that daidzein was more bioavailable
than genistein. Here, from the comparison of absorption profiles of
daidzein and genistein, it is clear that daidzein plasma concentration
dropped below the detection limit before genistein (20 vs. 24 h,
respectively), suggesting that daidzein is eliminated preferentially
from the common blood circulation or is further metabolized to
derivatives other than simple conjugates. Because flavonoids enter the
enterohepatic circulation after metabolic conjugation (Hackett 1986
), it is possible that genistein is eliminated
preferentially to daidzein with bile and subsequently reabsorbed, which
results in its extended presence in blood. Extensive secretion of
genistein conjugates with bile and its enterohepatic circulation were
confirmed by Sfakianos et al. (1997)
who showed that in
female Sprague-Dawley rats, >70% of the genistein dose infused
into the duodenum was excreted with bile as genistein
7-O-ß-glucuronide within 4 h after infusion. The
genistein metabolites collected with bile and reinfused into the
mid-small intestine were again recovered at 70% from bile. The
only genistein metabolite found in that study was genistein
7-O-ß-glucuronide. That result differs from those of this
and other studies in which genistein was found as a mixture of
glucuronide and/or sulfate conjugates after its metabolic conversion.
The discrepancy might have resulted from using animals that had had no
exposure to genistein, beginning from gestation, or because genistein
was infused into rats in a manner that by-passed the stomach. In
experiments with rats, Manach et al. (1997)
showed that
the conjugation pattern of quercetin that was consumed with diet
changed after an adaptation period. Rats not adapted to quercetin
produced isorhamnetin and tamarixetin, two derivatives of quercetin,
but after adaptation for 10 d to a quercetin-rich diet, no
tamarixetin was detected. Moreover, because genistein is absorbed from
the rat stomach, conjugates that differ from those produced by
intestinal absorption may be formed. After oral administration of
genistein to rats, several genistein metabolites were isolated and
identified from urine and bile; the main ones were
4'-O-sulfate and
4'-O-sulfate/7-O-ß-glucuronide (Yasuda et al. 1996
). In this study, the majority of daidzein and
genistein conjugates had a sulfate moiety (sulfates and
sulfates/glucuronides). However, it must be pointed out that the
identity of conjugates here was based on the specificity of the enzymes
used. A number of papers report sulfation of flavonoids or other
phenolic compounds in rats. A large proportion of plasma quercetin was
sulfated (36%) after in situ perfusion of quercetin through the rat
jejunum plus ileum (Crespy et al. 1999
). Moreover, when
isolated rat liver was perfused with quercetin and catechin, three
sulfated metabolites were formed from each flavonoid (Shali et al. 1991
), i.e., quercetin gave two glucuronide/sulfate
conjugates and one sulfate, whereas catechin yielded one such double
conjugate and two sulfates. More than 98% of p-nitrophenol
infused to male Sprague-Dawley rats was excreted with urine at the
same rate as sulfates and glucuronides (Tremaine et al. 1984
).
Sulfotransferases, located in the cytoplasm, often compete with
glucuronyltransferases for substrates. The balance between sulfation
and glucuronidation of various phenolic substances may be affected by
the dose administered (Koster et al. 1981
, Mehta et al. 1978
). Generally, the capacity to conjugate with sulfate
is limited compared with glucuronidation, and at a large dose, there is
a shift from sulfation toward glucuronidation. Despite the use of the
same methodology as in this study, results of a study on
(-)-epicatechin absorption in food-deprived rats showed >85% of
plasma (-)-epicatechin was glucuronized 4 h after oral
administration of a high dose of 172 µmol of (-)-epicatechin per kg
body (Piskula and Terao 1998a
). This is clearly
different from the results of this study in which only 20 and 38% of
total isoflavone metabolites were glucuronized 4 h after daidzein
and genistein administration, respectively, to food-deprived rats.
In mice, the major urinary metabolites of orally administered phenol
were phenol sulfate and phenol glucuronide; sulfation was the dominant
pathway at all dose levels but decreased as the dose increased in favor
of glucuronidation (Kenyon et al. 1995
). Furthermore,
comparing glucuronidation and sulfation of phenolic compounds, species
differences must be considered. In ddY mice, during metabolism of
troglitazone, an antidiabetic agent, hepatic glucuronidation clearance
was 170-fold higher than sulfation clearance, whereas in rats,
sulfation was sixfold higher than glucuronidation (Izumi et al. 1997
). Using the liquid chromatography-mass spectrometry
technique for analysis of urine from humans and rats administered
genistein, 4 and 26%, respectively, of genistein metabolites were
identified as sulfate conjugates (Cimino et al. 1999
).
Apart from species differences, sex difference also has a strong effect
on the balance between sulfation and glucuronidation. Oral
administration of isoflavones to male Wistar rats resulted in high
plasma concentrations of their sulfated conjugates (Fig. 2B,C
, and Fig. 3B, C
). In a report on the
metabolic fate of acetaminophen in rats, Kane et al. (1990)
showed that males excreted more acetaminophen sulfate
than females and that these differences persisted in cultured
hepatocytes. Moreover, after the acetaminophen dose was increased, a
dose-related shift from sulfation toward glucuronidation was
observed in both genders. Similarly, a study focused on sex differences
in the excretion of glucuronide conjugates showed that female rats
administered p-nitrophenol excreted more
p-nitrophenolglucuronide in urine than males (Rush et al. 1983
).
One of the conclusions of this study is that food deprivation increases
plasma sulfate conjugates of orally administered isoflavones, with a
simultaneous decline of glucuronide conjugates. This is likely the
result of decreased production of uridine diphosphate glucuronic acid,
which in turn is a consequence of a decrease in its precursor
UDP-glucose (Price and Jollow 1998
). It was also
shown that food deprivation did not influence the rate of
harmol sulfation in isolated rat hepatocytes but inhibited the
glucuronidation rate by 50% (Sundheimer and Brendel 1984
). There was also a suggestion that starvation can induce a
shift from conjugation toward hydroxylation, which in turn can give
rise to the formation of hazardous metabolites (Banhegyi et al. 1988
). On the other hand, food deprivation increases plasma
concentration of sulfate conjugates (Fig. 2B
and Fig. 3B
), especially of daidzein. This might be important in the
protective action of dietary daidzein because daidzein sulfoconjugates,
at a micromolar concentration, were reported to be potent inhibitors of
sterol sulfatase, an enzyme involved in the evolution of breast cancer
(Wong and Keung 1997
).
The formation of isoflavone glucuronides or sulfates can affect their
biological activity profoundly; in many cases, this was demonstrated
for their nonmetabolized forms. Nonconjugated (free) and sulfated forms
of isoflavones were regarded as biologically "active," whereas
their glucuronides and sulfate/glucuronides were considered
biologically "inactive" (Adlercreutz et al. 1993
).
Recently published data demonstrate that the glucuronide derivatives of
daidzein and genistein also exhibit some biological activities.
Although conjugation with glucuronic acid decreased the ability of
isoflavones to compete with the binding of estradiol to estrogen
receptors, their 7-O-glucuronides, at nutritionally relevant
concentrations, were shown to activate human natural killer cells even
better than their parental compounds and were weakly estrogenic
(Zhang et al. 1999
).
For populations with a low consumption of soy and soy products, dietary supplementation with isoflavones might be beneficial. Conjugation enzymes such as sulfotransferase or glucuronyltransferase convert isoflavones to more water-soluble products to enhance their excretion. The balance of these conjugation reactions determines the rate of metabolism and clearance of xenobiotic agents. It is clear from this study that food deprivation is a factor altering this balance. Therefore, understanding the effect of nutritional conditions on the conjugation profile of potentially beneficial soy isoflavones might be of both fundamental and practical value. Nevertheless, to eliminate the influence of interspecies differences in metabolism, a similar study in humans is required.
|
FOOTNOTES |
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3 Composition of the diet (per kg): 
-corn starch, 489 g; sucrose,100 g; casein, 250 g; corn oil, 50 g; cellulose, 50 g; choline chloride, 1 g; CaHPO4·2H2O, 172 mg; KH2PO4, 13.7 g; NaCl, 10.2 g; Fe-citrate (17% Fe), 249 mg; MgSO4, 1.95 g; ZnCl2, 8 mg; MnSO4·4–5H2O, 48.4 mg; CuSO4·5H2 O, 62.4 mg; KI, 0.2 mg; CaCO3, 11.72 g; (NH4)6Mo7O24·4H2O,1 mg; all-trans-retinol acetate, 9320 IU; cholecalciferol, 4660 IU; all-rac--tocopherol acetate, 240 mg; quinone, 1.2 mg; thiamine, 11.8 mg; riboflavin,11.8 mg; pyridoxine, 5.8 mg; cobalmanin, 40 µg; ascorbic acid, 117.6 mg; D-biotin, 0.2 mg; calcium pantothenate, 47 mg; nicotinic acid, 58.8 mg; inositol, 235 mg.
Manuscript received November 29, 1999. Initial review completed December 27, 1999. Revision accepted March 23, 2000.
|
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