European Journal of Clinical Nutrition (2007) 61, 255–261

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ORIGINAL ARTICLE
Urinary isoflavonoid excretion and soy consumption
in three generations of Japanese women in Hawaii
G Maskarinec, R Yamakawa, S Hebshi and AA Franke

Cancer Research Center of Hawaii, Honolulu, HI, USA

Objective: To explore soy intake and urinary isoflavonoid excretion within several generations of American-Japanese women
based on the hypothesis that earlier generations excrete higher levels of urinary isoflavonoids, in particular the metabolite equol,
than later generations.
Subjects: A convenience sample of 43 women from 19 families aged 18–78 years, all of whom reported at least 50% Japanese
ancestry.
Interventions: Each woman collected overnight urine samples at baseline and after consuming one serving of soymilk, both
samples were analyzed for the isoflavonoids daidzein, genistein and equol using liquid chromatography–mass spectrometry.
Results: Median isoflavone intakes during the last year were 7.2 mg/day for the first generation, 7.3 mg/day for the second
generation and 6.3 mg/day for the third generation (P ¼ 0.36). At baseline, the median isoflavonoid excretion for the first
generation was nonsignificantly higher than for later generations (190, 86 and 42 nmol/h; P ¼ 0.20) but after intervention, the
median urinary isoflavonoid excretion was very similar for the three groups: 2465, 1895 and 2775 nmol/h (P ¼ 0.70). Following
intervention, a nonsignificantly higher proportion of older than younger women (53 vs 32 and 33%; P ¼ 0.41) excreted the
metabolite equol. The respective median equol excretion rates by generation following intervention were 39.5, 4.2 and
3.5 nmol/h (P ¼ 0.04).
Conclusions: This small investigation among three generations of Japanese-Americans detected a higher equol production
among older women after a soy challenge, but no difference in the excretion of total isoflavonoids after a standardized dose of
soymilk was observed.
European Journal of Clinical Nutrition (2007) 61, 255–261. doi:10.1038/sj.ejcn.1602511; published online 16 August 2006

Keywords: soy foods; isoflavones; ethnicity; nutrition; migrants; breast cancer risk

Introduction owing to their estrogenic and anti-estrogenic properties

Women in Japan have one of the lowest incidence rates of
breast cancer in the world, but when they migrate to the
United States, their risk increases significantly (Shimizu
et al., 1991). In recent years, breast cancer incidence in
Japanese-American women has been approximately the
same as for Caucasian women (Deapen et al., 2002; Pike
et al., 2002). The rising incidence rates among migrant
women suggest that environmental factors such as diet may
influence the development of breast cancer (Buell, 1973).
Soy foods were proposed as one of the possible sources of
protection (Ziegler et al., 1993; Yan and Spitznagel, 2004)
Correspondence: Dr G Maskarinec, Cancer Research Center of Hawaii, 1236
Lauhala Street, Honolulu, HI 96813, USA.
E-mail: gertraud@crch.hawaii.edu
Received 9 December 2005; revised 20 June 2006; accepted 28 June 2006;
published online 16 August 2006
(Adlercreutz, 1995). Most soy foods contain glycosides of
the isoflavones daidzein, genistein and glycitein, which are
hydrolyzed by intestinal glucosidases and absorbed as
aglycones following ingestion (Coward et al., 1993; Wang
and Murphy, 1994; Tsukamoto et al., 1995; Franke et al.,
1998, 2004). The isoflavone daidzein is metabolized to equol
and O-desmethylangolensin by intestinal bacteria (Axelson
et al., 1984; Atkinson et al., 2004). The extent of the
metabolism seems to be highly variable among individuals
and may be influenced by other components of the diet
(Lampe et al., 1999; Rowland et al., 2000). Approximately
30–50% of the human population produces equol (Setchell
et al., 2002; Atkinson et al., 2005), but it appears that a
greater proportion of Asian than Western populations have
the ability to produce equol (Setchell et al., 2002; Akaza et al.,
2004; Ozasa et al., 2004), possibly because they were exposed
to soy early in life. Urinary isoflavonoid excretion serves as
 Soy in Japanese-Americans
G Maskarinec et al
256
an excellent biomarker for soy intake owing to the rapid
absorption and excretion of isoflavonoids specific to soy
foods (Maskarinec et al., 1998). Observational and interven-
tion studies in humans have suggested that the ability to
produce equol may be associated with a reduced risk for
breast and prostate cancer (Setchell et al., 2002; Atkinson
et al., 2005). Women who consumed soy at least once per
week during adolescence had a lower risk of breast cancer
than women with less than monthly intakes during
adolescence in two studies (Shu et al., 2001; Wu et al.,
2002). We hypothesized that women exposed to soy early
in life, such as Japanese migrants, excrete higher levels of
urinary isoflavonoids and are more likely to produce equol
after consuming a standardized amount of soy than women
of later generations who were exposed to a more Westernized
diet. It has been proposed that intestinal bacteria are
responsible for the differences in isoflavone metabolism
(Atkinson et al., 2005) and that the development of gut
bacteria may be influenced by habitual nutrition (Lampe
et al., 1998; Rowland et al., 2000; Setchell et al., 2002).
Subjects and methods
Participants
We recruited a convenience sample through employees,
families and friends of our center. Eligible participants were
at least 18 years old, English speaking, at least 50% Japanese
ancestry, currently residing in Hawaii, free of known soy
allergies and had at least one other female relative of a
different generation willing to participate. Except for one
young woman who was taking a very low dose acne
treatment, no antibiotics were used during this study. The
older women in the study group, the grandmothers, were
over 60 years and older; the second-generation women, the
mothers, were 30–59 years old and the third-generation
participants were 30 years of age or younger. With the
exception of four women who were born in Japan, also called
Issei, the older generation women in this study were Nissei or
Sansei, that is, children and grandchildren of Japanese
immigrants to Hawaii who arrived during 1868–1924
(Nordyke, 1989). The study protocol was approved by the
Committee on Human Subjects at the University of Hawaii;
all participants gave written informed consent.
Data collection
Demographic, reproductive and medical information was
collected by questionnaire. Regular soy intake was assessed
with a 12-item questionnaire, which elicited the frequency
and portion size of soy foods consumed during the last 12
months (Williams et al., 2003). To obtain a summary score,
we multiplied the frequencies of intake for each of the 12 soy
foods by the estimated isoflavone content from the food
composition database maintained by the Nutrition Support
Shared Resource at the Cancer Research Center of Hawaii
European Journal of Clinical Nutrition
(Murphy, 2002). The total amounts from all foods were
added as an estimate of daily isoflavone intake. Isoflavone
values (genistein, daidzein and glycitein) for soy foods in this
database were largely derived from analyses of representative
local foods (Franke et al., 1999). A lifetime questionnaire
estimated soy exposure since birth (Maskarinec et al., 2004)
using the following periods: infancy (1 year), childhood (1–9
years), adolescence (10–19 years), early adulthood (20–29
years) and late adulthood (30 þ years). Participants marked
the annual frequency (never, 1/month, 2–3/month, 1/week,
2–3/week, 4–6/week, 1/day and 2 þ /day) of four categories of
soy foods (tofu, soy beans and sprouts, soybean drink or milk
and other soy products) for each of the stages. For infancy,
soy-based formula was the only choice. To obtain a summary
score, we multiplied the frequency of intake for each of the
four foods by the estimated isoflavone amount and added
the total amounts of the four foods in each of the stages of
life to determine an annual intake for each stage.
Intervention and urine collection
The 3-day study protocol included two overnight urine
collections. On day 1, participants consumed their normal
diet during the day, emptied their bladders at 1800 hours,
abstained from all soy foods until the next morning, and
collected all urine during the night and in the early morning.
On day 2, the subjects followed the same protocol but
also abstained from all soy foods other than one container of
soymilk (8.45 fl oz. of Edensoy Original Organic Soymilk or
Edensoy Extra Organic Soymilk) consumed after 1800 hours.
The two types of soymilk were purchased at one time and
only differed in their calcium content. Urine collection
containers contained 0.1 g of ascorbic acid and 0.2 g of boric
acid to prevent bacterial contamination and degradation of
analytes. The urine samples were aliquoted and stored at
801C until analyzed. The samples from day 1 constituted
the baseline measurements. Based on the collection times
recorded by the subjects, we calculated the total number of
overnight urine hours and assessed the completeness of
overnight collection.
Urine analysis
Owing to budgetary constraints, only urinary daidzein,
genistein and equol were analyzed by liquid chromatogra-
phy–mass spectrometry (electrospray ionization, negative
mode; ESI-MS) with photo diode array detection (PDA) using
a LCQ Surveyor-Advantage system (ThermoElectron Corpor.,
Madison, WI, USA) (Franke et al., 2002; Blair et al., 2003). In
brief, triply 13C-labeled internal standards of daidzein,
genistein and equol (University of St Andrews, UK) were
added to each specimen and hydrolyzed for 1 h at 371C
with glucuronidase and sulfatase (Roche Applied Sciences,
Indianapolis, IN, USA) followed by phase separation with
diethyl ether (Franke et al., 1998). The ether fractions were
dried under nitrogen and redissolved in a 1:1 mixture of

methanol/NaAc buffer (0.2 M, pH 5). Ten microliters of this
extract was analyzed by LC/PDA/ESI-MS after separation on
a HydroBond PS (100  3.0 mm; 5 mm) C18-reversed phase
column coupled to a HydroBond PS C18 (20  3.2 mm; 5 mm)
direct-connect guard column (MacMod Analytical Inc.,
Chadds Ford, PA, USA). The elution, absorbance detection
and mass spectrometric measurements were performed as
applied previously (Franke et al., 2002; Adams et al., 2004;
Cline et al., 2004). Limits of quantitation for all analytes
were 1.5 nmol/h for daidzein and genistein and 3.0 nmol/h
for equol for post-intervention samples and half of those
values for pre-intervention samples owing to differences in
concentration steps before analysis. A woman with any
measurable equol was considered an equol excretor. Be-
tween-day coefficients of variation ranged for in urine
4–12% (daidzein), 5–18% (genistein) and 3–14% (glycitein).
Results were expressed as nmol/h of urine collection. The
total number of hours covered by the urine collections
was similar among subjects and did not warrant further
adjustments.
Statistical analysis
We calculated descriptive statistics for the self-reported soy
and isoflavone intakes and for urinary isoflavonoid excretion
Soy in Japanese-Americans
G Maskarinec et al
257
by generation. Because of our small sample size with
distributions that deviated considerably from normality,
medians rather than means were computed for isoflavone
intake and urinary isoflavonoid excretion variables. For the
same reason, differences between generations were assessed
using the non-parametric Kruskal–Wallis test (SAS Institute
Inc., 2004). Soy intake during early and adult life was
categorized into low and high using three servings per day as
cutoff. We computed Spearman correlation coefficients (rs)
to explore the association between self-reported isoflavone
intake and urinary excretion.
Results
We enrolled 19 families into the study (Table 1): four families
with three generations (grandmother, mother and daughter)
and 15 families with two generations (10 families were
generation 1 and 2, five families were generation 2 and 3).
The age range was 18–78 years. Of the three-generation
families, one included a paternal grandmother and one had
two sisters. Most of the participants (41/43) were of full
Japanese or Okinawan ancestry; one subject was half-
Japanese (in addition to Chinese and Caucasian); and one

Table 1 Description of study participants

Family Generation 1 Generation 2 Generation 3 Mean isoflavone intakea

01 2 1 0 24.4
02 1 1 1 7.3
03 1 1 0 8.4
04 1 1 0 1.6
05 0 1 1 2.1
06 1 1 1 10.0
07 1 1 1 7.1
08 1 1 0 8.8
09 1 1 0 7.0
10 1 1 0 6.2
11 1 1 0 3.6
12 1 1 0 26.2
13 0 1 1 0.2
14 1 1 1 10.7
15 1 1 0 20.7
16 1 1 0 12.2
17 0 1 1 28.0
18 0 1 1 21.1
19 0 1 1 13.6

All 15 19 9 11.5712.8

Means7s.d. by generation
Age (years) 70.676.6 46.677.6 20.271.3
Body weight (kg) 58.177.3 59.5712.6 54.9711.4

Medians (IQ by generation)

Isoflavone intake (mg/day)a 7.2 (5.1; 16.5) 7.3 (3.2; 20.7) 6.3 (1.3; 6.5)
Early life soy intake (servings/day) 1.8 (0.6; 3.5) 1.6 (0.8; 2.8) 2.0 (1.6; 2.3)
Adult soy intake (servings/day) 2.7 (1.2; 4.0) 1.8 (0.9; 2.9) 0.4 (0.1; 2.5)

Abbreviations: IQ, interquartile range; s.d., standard deviation.

a
Self-reported intake during the last year.

European Journal of Clinical Nutrition

 Soy in Japanese-Americans
G Maskarinec et al
258
was three-fourth Japanese and one-fourth Korean. All
women were apparently healthy.
The most frequently eaten soy foods among all subjects
were tofu, followed by soymilk, and then miso soup. Women
in the first generation reported eating more tofu, fried tofu
(e.g., the skin of deep fried tofu used to wrap rice for ‘cone
sushi’), miso paste, miso soup, soy nuts and natto, whereas
women in the third generation reported eating more soy bars
and meat analogs made from soy compared to the other age
groups. The intake of soymilk was high in the second
generation; eight out of 19 women consumed soymilk. Mean
self-reported isoflavone intake during the previous year
varied between 0.2 and 28.0 mg among families (Table 1).
The median intake during the last year for the first
generation was 7.2 mg/day, 7.3 mg/day for women in the
second generation and 6.3 mg/day for the third generation
(P ¼ 0.36). Among women in the first generation, 20%
reported eating less than 5 mg/day of soy, whereas 47% of
second-generation women and 44% of third-generation
women consumed less than 5 mg/day. On the other hand,
40% of women in the first generation, 42% of women in the
second generation and 11% of women in the third genera-
tion consumed more than 10 mg/day (P ¼ 0.32).
The urine samples were collected over 12.070.8 h at
baseline and over 11.870.8 h after soymilk intake. At
baseline, the median isoflavonoid excretion for the first
generation was higher for the first than for the later
generations (190, 86 and 42 nmol/h; P ¼ 0.20) (Figure 1),
isoflavonoid excretion after the soy challenge when we
stratified by self-reported habitual soy intake at baseline
(P ¼ 0.92). For women with less than 5 mg daily isoflavone
intake, the median was 2211 nmol/h; for women with 5–
10 mg of intake, it was 2538 nmol/h; and for women with
intakes above 10 mg/day, it was 2332 nmol/h.
At baseline, 33% (5/15) of the first-generation women
produced equol (Figure 2), whereas 32% (6/19) of the
women in the second generation and 33% (3/9) of women
in the third generation produced equol at our detection
limit (3.0 nmol/h). Following intervention, the respective
proportions were 53, 32 and 33% (P ¼ 0.41). The respective
median equol excretion rates by generation following
intervention were 39.5, 4.2 and 3.5 nmol/h (P ¼ 0.04). There
was no significant difference in habitual soy intake between
women who produced equol and those who did not after
the soy challenge (P ¼ 0.33), but the ratio between equol
and daidzein, a measure of the ability to produce in relation
to the available amount of its source daidzein, was
60
Baseline Intervention
50
Difference between generations
p = 0.99 at baseline
p = 0.41 after intervention
40
Percent

but this difference was not statistically significant. Self- 30

reported soy intake during the last year and baseline urinary
isoflavonoid excretion were weakly correlated (rs ¼ 0.28, 20

P ¼ 0.07) for the overall population, but the relation

was stronger for the first (rs ¼ 0.57, P ¼ 0.03) than for the 10
second (rs ¼ 0.32, P ¼ 0.19) and third generation (rs ¼ 0.42,
P ¼ 0.27). After intervention, the median urinary isoflavo- 0
noid excretion increased considerably, but it was very Generation 1 Generation 2 Generation 3 All women
similar for the three groups: 2465, 1895 and 2775 nmol/h Figure 2 Equol excretor status by intervention status and genera-
(P ¼ 0.70). There was also no significant difference in urinary tion.

3000 3000
Difference between generations Difference between generations
p = 0.20 at baseline Baseline Intervention p = 0.03 at baseline
p = 0.70 after intervention p = 0.32 after intervention
2500 2500

2000
2000
nmoles/hour
nmoles/hour

1500
1500

1000
1000

500
500
0
Low intake High intake Low intake High intake
0
Generation 1 Generation 2 Generation 3 All women Baseline Intervention

Figure 1 Urinary isoflavonoid excretion by intervention status and Figure 3 Urinary isoflavonoid excretion by soy consumption during
generation (all values are medians). early life and intervention status (all values are medians).

European Journal of Clinical Nutrition


nonsignificantly higher for the first than for the later
generations at any time.
Self-reported soy intake during early life did not differ
significantly by generation; the respective values were 1.8,
1.6 and 2.0 servings per week (P ¼ 0.87). After stratification
by early life soy intake (Figure 3), women with high intake
(more than three servings per week) during early life had
higher urinary isoflavonoid excretion at baseline (P ¼ 0.03).
However, after intervention urinary excretion levels were
very similar (P ¼ 0.32).
Discussion
Although the older Japanese-American women in our study
excreted more isoflavonoids in urine than younger women,
we observed no significant difference in urinary isoflavonoid
excretion after a challenge of one serving of soymilk by
generation or by self-reported soy intake during the previous
year. The daidzein metabolite equol, which is produced
by gut bacteria, was present after the intervention in a
nonsignificantly larger proportion of women in the first
than in the later generations. The small sample size of the
study may have been responsible for the lack of statistical
significance. However, the mean equol excretion levels were
significantly higher for the first generation after the soy
challenge. This suggests that the first generation may
metabolize isoflavonoids differently from women in later
generations owing to differences in early nutrition. Other
explanations include older age because it is known that the
composition of the gut flora changes with age (Saunier and
Dore 2002; van Tongeren et al., 2005) or environmental
factors that influence equol-producing gut bacteria (Lampe
et al., 1999). The fact that studied women from one family
provides new insight into this issue because cross-sectional
studies of unrelated subjects tend to be confounded by
differences in diet and environment.
No differences were seen in soy intake between the
generations. However, women in the first generation
reported a higher consumption of traditional soy foods,
such as tofu, miso soup, miso paste and natto, whereas the
third generation consumed more of the ‘Westernized’ soy
foods such as soy bars and meat analogs made from soy. The
observation that the first generation showed the strongest
correlation between self-reported intake and baseline urinary
isoflavonoid excretion is probably a result of more accurate
reporting of soy intake and possibly owing to more frequent
and regular soy consumption. The negative correlation
between self-reported intake and baseline urinary isoflavo-
noid excretion for the youngest generation is puzzling, but
the skewed distribution of soy intake may have been
responsible. Whereas one value was greater than 50 mg, all
others were below 7 mg/day. The observation that 30% of our
second- and third-generation subjects were equol producers
agrees with published reports for Western populations
(Lampe et al., 1998; Setchell et al., 2002; Frankenfeld et al.,
Soy in Japanese-Americans
G Maskarinec et al
259
2004). Our finding that the older generation women
excreted more equol after a soy challenge than younger
women is consistent with equol producer rates of 50–60%
reported from Japan (Akaza et al., 2004; Ozasa et al., 2004).
A significant higher prevalence of equol producers among
Korean Americans than Caucasians (51 vs 36%; P ¼ 0.015)
after a soy challenge also supports the idea that consumers of
a traditional Asian diet metabolize isoflavones differently
(Song et al., 2006). As 41 out of 43 subjects reported 100%
Japanese ancestry, ethnic admixture did not play a role in the
differences.
The major limitation of this study was the small sample
size. Because there were only four families of three genera-
tions, it was not possible to explore familial and genetic
associations (Frankenfeld et al., 2004). It would be beneficial
to gather a larger random sample of Japanese-Americans to
examine the relation by family and generation as long as
Nissei or Sansei women are alive. Our recruitment strategy
may have introduced selection bias; in particular, the
younger women in the study may have consumed more
soy than the average Japanese-American woman. The dietary
assessment may have led to misclassification because the soy
questionnaire may have been missing soy foods consumed in
that age group. It is difficult to measure the accuracy of the
lifetime soy questionnaire; it has not been validated so far
and recall of dietary intake over so many years is challen-
ging. The comparison of equol producer rates across studies
is limited by the different urine collection protocols,
analytical methods and detection limits.
Because all women were instructed to abstain from other
soy foods, to consume the same amount of soymilk and to
collect overnight urine, the recovery of isoflavonoids should
have been comparable across age groups despite slight
variations in the number of hours for which urine was
collected. Urinary isoflavonoid excretion shows the highest
correlation with recent soy intake owing to the fast
pharmacokinetics of isoflavonoids (Setchell et al., 2003;
Zubik and Meydani, 2003). However, studies with large
sample sizes that used validated diet questionnaires have
consistently demonstrated significant associations in Asian
and Western populations, even when urine was collected
only once and soy intake was assessed over the previous year
(Maskarinec et al., 1998; Seow et al., 1998; Chen et al., 1999;
Atkinson et al., 2002). This small investigation among three
generations of Japanese-Americans observed a higher con-
sumption of traditional Asian soy foods and a slightly higher
equol production among older Japanese women, but no
evidence that soy intake during early and adult life affected
the ability to take up and excrete isoflavonoids after a
standardized dose of soymilk. Although there is evidence
that intestinal bacteria are responsible for the differences in
isoflavone metabolism (Atkinson et al., 2004, 2005), not
much is known about the determinants of gut bacteria and
equol excretion status (Lampe et al., 1998; Rowland et al.,
2000; Blair et al., 2003; Franke et al., 2004) or the possible
effects of equol production on health outcomes.
European Journal of Clinical Nutrition
 Soy in Japanese-Americans
G Maskarinec et al
260
Acknowledgements
We are grateful to the Meiji Foundation for supporting this
project, the study participants and Laurie Custer for her
analysis of the urine samples.
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