Phyto Estrogen
Phyto Estrogen
Phyto Estrogen
net/publication/222325632
CITATIONS READS
49 3,954
7 authors, including:
Angela A Mulligan
University of Cambridge
101 PUBLICATIONS 3,005 CITATIONS
SEE PROFILE
Some of the authors of this publication are also working on these related projects:
Toxicogenomic responses to N-Nitroso Compound exposure in relation to human Colorectal Cancer Risk View project
All content following this page was uploaded by Caterina Dell'Aquila on 30 October 2017.
Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem
Analytical Methods
a r t i c l e i n f o a b s t r a c t
Article history: Phytoestrogens are a group of non-steroidal secondary plant metabolites with structural and functional
Received 15 August 2008 similarity to 17b-oestradiol. Urinary and plasma phytoestrogens have been used as biomarkers for die-
Received in revised form 21 February 2009 tary intake, however, this is often not possible in large epidemiological studies or to assess general expo-
Accepted 1 March 2009
sure in free-living individuals. Accurate information about dietary phytoestrogens is therefore important
but there is very limited data concerning food contents. In this study, we analysed the phytoestrogen
(isoflavone, lignan and coumestrol) content in more than 240 different foods based on fresh and pro-
Keywords:
cessed fruits and vegetables using a newly developed sensitive method based on LC–MS incorporating
Phytoestrogens 13
Fruits
C3-labelled standards. Phytoestrogens were detected in all foods analysed with a median content of
Vegetables 20 lg/100 g wet weight (isoflavones: 2 lg/100 g; lignans 12 lg/100 g). Most foods contained less than
Lignans 100 lg/100 g, however, 5% of foods analysed contained more than 400 lg/100 g, in particular soya-based
Isoflavones foods and other legumes. The results published here will contribute to databases of dietary phytoestro-
Coumestrol gen content and allow the more accurate determination of phytoestrogen exposure in free-living
LC/MS individuals.
Ó 2009 Elsevier Ltd. All rights reserved.
0308-8146/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.foodchem.2009.03.002
Table 1
Phytoestrogen content of fruits and vegetables analysed. The data is the average of three samples analysed in duplicate and given in lg/100 g wet weight. Isoflavones are the sum of daidzein, genistein, glycitein, biochanin A and
formononetin, lignans the sum of secoisolariciresinol and matairesinol. Unless stated otherwise, food analysed was unprepared.
Food (taxonomic Preparation Variety Family Phytoestrogens Isoflavones Lignans Daidzein Genistein Glycitein Biochanin A Formononetin Secoisolariciresinol Matairesinol Coumestrol
name)
Apple (Malus Cored Cox Rosaceae 4 2 2 <1 <1 – 1 <1 2 <1 <1
domestica)
Apple (Malus Cored Golden Rosaceae 5 2 3 <1 <1 – <1 <1 3 <1 <1
domestica) Delicious
Apple (Malus Cored Granny Rosaceae 4 2 2 <1 <1 – <1 1 2 <1 <1
domestica) Smith
Apple (Malus Cored Red Rosaceae 3 1 2 <1 <1 <1 <1 <1 2 – –
domestica) dessert
Apple (Malus Peeled, cored & Cooking Rosaceae 9 7 2 2 <1 <1 4 <1 2 <1 –
domestica) cooked apple
Apple (Malus Peeled & cored Cooking Rosaceae 5 3 2 1 <1 <1 1 <1 1 <1 –
domestica) apple
Apple (Malus Peeled & cored Cox Rosaceae 5 2 2 <1 <1 – <1 <1 2 <1 <1
domestica)
Apple (Malus Peeled & cored Golden Rosaceae 5 3 2 <1 <1 <1 2 <1 2 <1 –
543
544
Beans, Haricot beans Cooked from dried Fabaceae 29 6 22 2 4 <1 – – 22 <1 <1
(Phaseolus vulgaris)
Beans, Kidney beans Dried Fabaceae 172 73 89 15 26 32 – – 88 <1 10
(Phaseolus vulgaris)
Beans, Kidney beans Cooked from dried Fabaceae 41 14 26 2 6 5 <1 – 26 <1 <1
(Phaseolus vulgaris)
Beans, Runner beans Trimmed & strung Fabaceae 201 164 26 64 78 22 <1 <1 26 <1 11
(Phaseolus
coccineus)
Beans, Runner beans Trimmed, strung & Fabaceae 156 132 18 45 70 16 <1 <1 17 – 7
(Phaseolus cooked
coccineus)
Beansprouts (Vigna Pre-washed Fabaceae 798 351 86 110 225 16 – <1 86 <1 361
radiata)
Beetroot (Beta vulgaris) Raw, peeled Chenopodiaceae 8 1 7 – <1 <1 1 – 6 1 –
Beetroot (Beta vulgaris) Cooked Chenopodiaceae 10 <1 10 <1 <1 <1 – <1 10 <1 –
Beetroot (Beta vulgaris) Pickled Chenopodiaceae 5 1 4 – <1 <1 <1 <1 4 <1 –
Beetroot (Beta vulgaris) Precooked Chenopodiaceae 8 1 7 – <1 <1 1 <1 7 <1 –
Blackberries (Rubus sp.) Fresh Rosaceae 57 <1 56 <1 <1 <1 <1 <1 55 1 <1
Blackberries (Rubus sp.) Stewed from fresh Rosaceae 221 <1 220 – <1 – – <1 220 – <1
Blackcurrant (Ribes Fresh Grossulariaceae 109 2 107 <1 – <1 2 <1 105 2 <1
545
546
Fennel (Foeniculum Cooked Apiaceae 85 <1 85 <1 <1 <1 <1 <1 72 13 –
vulgare)
Fig. (Ficus sp.) Moraceae 389 12 376 – 10 2 – <1 372 3 <1
Fig. (Ficus sp.) Dried Moraceae 129 14 114 – 12 <1 1 <1 113 1 1
Garlic (Allium sativum) Peeled Alliaceae 99 2 97 – – <1 2 <1 93 4 <1
Gooseberries (Ribes Grossulariaceae 72 <1 71 <1 <1 <1 <1 <1 71 <1 <1
uva-crispa)
Gooseberries (Ribes Stewed with sugar Grossulariaceae 121 <1 121 – <1 <1 <1 – 119 2 <1
uva-crispa)
Grapefruit (Citrus x Peel, pith and pips Rutaceae 39 17 21 3 2 – 11 <1 21 <1 <1
paradisi) removed
Grapefruit (Citrus x Tinned in juice Rutaceae 21 13 4 5 – – 8 <1 4 <1 4
paradisi)
Grapes, black (Vitis sp.) Seeds removed Vitaceae 19 5 14 1 4 <1 – <1 7 7 –
Grapes, dried as Dried Vitaceae 87 17 70 – – 7 10 – 36 34 <1
Currants (Vitis sp.)
Grapes, dried as Raisins Dried Vitaceae 88 7 81 – <1 <1 5 1 50 31 <1
(Vitis sp.)
Grapes, red, seedless Vitaceae 21 6 15 <1 3 <1 2 – 7 8 –
(Vitis sp.)
Grapes, white, seedless Vitaceae 18 <1 17 <1 <1 <1 <1 <1 8 9 –
547
sativum)
548
Peas, fresh (Pisum Cooked Fabaceae 1 1 <1 <1 <1 <1 <1 <1 – <1 <1
sativum)
Peas, frozen (Pisum Fabaceae 3 1 2 <1 <1 <1 <1 <1 1 <1 <1
sativum)
Peas, frozen (Pisum Cooked Fabaceae 2 1 1 <1 <1 <1 <1 <1 <1 <1 –
sativum)
Peas, garden (Pisum Tinned, drained Fabaceae 2 1 1 <1 <1 <1 <1 – <1 <1 <1
sativum)
Peas, marrowfat Tinned, drained Fabaceae 51 50 <1 <1 3 46 <1 <1 <1 <1 –
(Pisum sativum)
Peas, mushy (Pisum Tinned/frozen Fabaceae 15 14 1 <1 3 10 <1 <1 1 – –
sativum)
Peas, petit pois (Pisum Frozen Fabaceae 8 6 2 – 2 1 2 <1 <1 2 –
sativum)
Peas, split, dried Fabaceae 15 11 4 2 2 7 – <1 <1 4 <1
(Pisum sativum)
Peas, split, dried Cooked Fabaceae 13 12 <1 4 5 3 – <1 <1 <1 –
(Pisum sativum)
Peas, sugar snap Cooked Fabaceae 44 31 13 – <1 29 <1 <1 13 – <1
(Pisum sativum)
Peas, whole, dried Fabaceae 29 28 <1 7 9 9 – 3 – <1 –
549
550
Strawberries (Fragaria Rosaceae 8 <1 7 <1 – <1 – <1 7 <1 <1
ananassa)
Strawberries (Fragaria Tinned in syrup, Rosaceae 40 2 38 – <1 – 2 <1 38 <1 –
ananassa) drained
Sultanas (Vitis sp.) Vitaceae 54 11 44 – <1 <1 8 1 13 31 <1
Swede (Brassica Brassicaceae 6 1 5 <1 <1 <1 <1 <1 5 <1 –
napobrassica)
Swede (Brassica Cooked Brassicaceae 2 <1 2 <1 <1 <1 <1 <1 2 <1 –
napobrassica)
Sweet potato Convolvulaceae 259 1 258 <1 <1 <1 <1 – 136 122 <1
(Ipomoea batatas)
Sweet potato Cooked Convolvulaceae 251 1 249 <1 <1 <1 <1 – 118 132 <1
(Ipomoea batatas)
Sweetcorn (Zea mays) Boiled on the cob Poaceae 9 2 7 <1 <1 <1 2 <1 5 2 <1
Sweetcorn (Zea mays) Frozen, tinned, Poaceae <1 <1 <1 – <1 <1 <1 – <1 <1 <1
drained
Sweetcorn (Zea mays) Frozen, tinned, Poaceae 3 <1 2 – <1 <1 <1 <1 1 <1 –
drained, heated
Sweetcorn (Zea mays) Kernels from the Poaceae 2 <1 1 <1 <1 <1 <1 <1 1 <1 <1
cob
Sweetcorn, baby Poaceae 6 <1 5 <1 <1 <1 <1 <1 5 <1 <1
Wong, Welch, & Bingham, 2001; Kipnis et al., 2003), their use is of- weighed, prepared and a representative portion (approximately
ten not feasible, particularly in larger studies, and intake has to be 35 g dry weight) was taken from each of the five samples. Cooked
either calculated from dietary information provided by partici- food was boiled in water until tender and the water discarded;
pants or determined by a combination of biomarkers and dietary more details on preparation are given in Table 1. Tinned foods were
information. Accurate information on the phytoestrogen content drained unless indicated otherwise; outer leaves were removed
in foods is therefore crucial for the investigation of effects on from cabbages; lettuce was analysed as purchased. The samples
health; and to determine population levels for surveillance were frozen ( 20 °C), freeze-dried if necessary (BOC Edwards,
purposes. Crawley, Sussex, UK) and stored at 20 °C until analysis. For anal-
The main dietary sources of phytoestrogens are plant-based ysis, samples of each food were pooled (equal amounts), weighed
foods such as fruits and vegetables. In plants, where these com- and processed as described below.
pounds occur predominantly as glycosides, they act as antioxi-
dants, screen against light and most importantly act as defensive 2.3. Analysis
agents against predators (Mazur & Adlercreutz, 1998a). The princi-
pal phytoestrogen-classes are isoflavones (found mainly in le- Samples were analysed as described previously (Kuhnle, Dell’A-
gumes, e.g. chickpeas and soybean), lignans (e.g. in cereals, quila, Low, Kussmaul & Bingham, 2007). Briefly, approximately
linseed and other fruits and vegetables) and coumestans (e.g. in 100 mg freeze-dried food was extracted three times with 2.0 ml
young sprouting legumes like clover or alfalfa sprouts) (Committee 10% methanol in sodium acetate (0.1%, pH 5) and deconjugated
on Toxicity of Chemicals in Food, 2003). with a hydrolysis reagent consisting of purified Helix pomatia juice
Several detailed studies have been conducted to determine the (b-glucuronidase), cellulase and b-glucosidase. Deconjugated sam-
phytoestrogen content of food previously, amongst others in the ples were then extracted using Strata C-18E SPE cartridges (50 mg/
UK (Liggins, Bluck, Coward, & Bingham, 1998a, 1998b; Liggins ml; Phenomenex, Macclesfield, Cheshire, UK), dried, reconstituted
et al., 2000; Liggins, Grimwood, & Bingham, 2000; Liggins, Mulli- in 40% aqueous methanol and analysed using LC/MS/MS. Analysis
gan, Runswick, & Bingham, 2002), Finland (Dwyer et al., 1994; Ma- was performed on an LC/MS/MS system consisting of a Jasco HPLC
zur, 1998; Mazur et al., 1996, 1998b; Valsta et al., 2003), and the system (Jasco, Great Dunmow, UK) using a diphenyl column (Varian
US (US Department of Agriculture, 2002); however, these studies Pursuit, 3 lm, 150 2 mm, Varian, Oxford, Oxfordshire, UK) and a
provide only data for approximately 12% of the UK diet (Mulligan, Waters Quattro Ultima triple quadrupole MS instrument (Waters,
Welch, McTaggart, Bhaniani, & Bingham, 2007) and had methodo- Manchester, UK) fitted with an electrospray ion source in negative
logical limitations (Adlercreutz et al., 1993; Wähälä, Hase, & Adl- ion mode and a LC/MS/MS system consisting of an Agilent 1100
ercreutz, 1995; Wähälä & Rasku, 1997). Previously, we have CapHPLC System (Agilent, Wokingham, Berkshire, UK) and an ABI
developed a sensitive LC/MS/MS method using 13C3-labelled stan- 4000 QTRAP mass spectrometer (Applied Biosystems, Warrington,
dards to analyse phytoestrogens in plasma and urine (Grace Cheshire, UK) fitted with an electrospray ion source in negative
et al., 2003). We have adapted this method to be used for food sam- ion mode. Compounds were quantified using 13C3-labelled internal
ples and have measured the phytoestrogen content (isoflavones: standards; Compounds were quantified using 13C3-labelled internal
biochanin A, daidzein, formononetin, genistein, glycitein; lignans: standards; coumestrol was quantified using 13C3-enterolactone.
matairesinol, secoisolariciresinol; coumestrol) in more than 240 The method was validated on both LC/MS/MS systems. The in-
foods based on fruits and vegetables commonly consumed in the tra-batch CV of this method is between 3% and 14% and the in-
UK. This is one of the most comprehensive analysis of plant-based ter-batch between 1% and 6%. As quality control, a sample
phytoestrogens in the UK and elsewhere. consisting of equal amounts of red cabbage, orange and celery
was analysed with each batch. The limit of detection of this meth-
od is 1.5 lg/100 g dry weight.
2. Experimental
2.4. Data analysis
2.1. Chemicals
Each sample was prepared in triplicate and analysed twice. Data
Biochanin A, daidzein, genistein, glycitein, formononetin, seco- are presented as the average of two analyses and is in lg/100 g wet
isolariciresinol, matairesinol and coumestrol were purchased from weight. Data was analysed using SPSS 16 (SPSS Inc., Chicago, IL) for
Plantech (Reading, Berkshire, UK). 13C3-biochanin A 13C3-daidzein, Mac OS X. The data was not normally distributed and therefore
13
C3-genistein, 13C3-glycitein, 13C3-formononetin, 13C3-matairesi- non-parametric tests were used. Differences between plant-fami-
nol, 13C3-secosiolariciresinol and 13C3-enterolactone were obtained lies were analysed using the Kruskal–Wallis test, the effect of prep-
from Dr. Nigel botting (University of St. Andrews, Fife, UK) (Fryatt aration was investigated using Wilcoxon signed rank test. p < 0.05
& Botting, 2005; Haajanen & Botting, 2006; Whalley, Bond, & Bot- was considered to be statistically significant.
ting, 1998; Whalley, Oldfield, & Botting, 2000). b-Glucuronidase
(from Helix pomatia), b-glucosidase (from almonds) and cellulase 3. Results
(from Trichoderma reesi) were purchased from Sigma (Poole, Dor-
set, UK). Water, methanol, acetic acid and ammonia were pur- In all foods analysed, with the exception of microwaved mush-
chased from Sigma (Poole, Dorset, UK) and Fisher Scientific rooms and unheated tinned sweet-corn, phytoestrogens were de-
(Loughborough, Leicestershire, UK). To inhibit losses of target com- tected (Table 1). In most foods, the phytoestrogen content was
pounds by adsorption to glassware, only silanised glassware was below 100 lg/100 g wet weight (median: 20 g/100 g; IQR (inter-
used. quartile range): 7–66 lg/100 g) with less isoflavones (median:
2 lg/100 g; IQR: 1–8 lg/100 g) than lignans (median: 12 lg/
2.2. Sampling 100 g; IQR 3–47 lg/100 g) and a low amount of coumestrol (med-
ian: <1 lg/100 g). However, 5% of foods analysed contained more
Samples of each food were purchased from at least five different than 400 lg/100 g phytoestrogens (>134 lg/100 g isoflavones in
food outlets (where possible) in Cambridgeshire, UK. If possible, top 5% of foods; >218 lg/100 g lignans in top 5% of foods), with
the foods bought at each outlet were from different manufacturers, the highest content in soya flour (125,000 lg/100 g) and cooked
varieties, country of origin and/or batch numbers. Each sample was soya beans (18,000 lg/100 g).
552 G.G.C. Kuhnle et al. / Food Chemistry 116 (2009) 542–554
Table 2
Phytoestrogen content (in lg/100 g wet weight; median and inter-quartile range) and composition (% of total phytoestrogen content) in foods from different plant families. For
this table, only unprocessed foods from families with at least five samples were compared. Percentage of the phytoestrogen content in Solanaceae is too small to provide reliable
information of phytoestrogen composition.
Thompson, Boucher, Liu, Cotterchio, and Kreiger (2006) do not in- Committee on Toxicity of Chemicals in Food, Consumer Products and the
Environment (2003). Phytoestrogens and Health. London: Food Standards
clude biochanin A. Furthermore, the phytoestrogen content in
Agency.
foods depends on a large number of genetic and environmental Dang, Z. C., & Lowik, C. (2005). Dose-dependent effects of phytoestrogens on bone.
factors such as variety, harvest and processing (Eldridge & Kwolek, Trends in Endocrinology and Metabolism, 16(5), 207–213.
1983; Wang & Murphy, 1994), making a comparison difficult. For Day, N., Oakes, S., Luben, R., Khaw, K. T., Bingham, S., & Welch, A. (1999). EPIC-
Norfolk: Study design and characteristics of the cohort. European Prospective
soya-based food, fourfold differences between growth location Investigation of Cancer. British Journal of Cancer, 80(Suppl. 1), 95–103.
and varieties have been observed. Previously, we compared the ef- Day, N. E., McKeown, N., Wong, M. Y., Welch, A., & Bingham, S. A. (2001).
fect of different sources or countries of origin in nine different Epidemiological assessment of diet: A comparison of a 7-day diary with a food
frequency questionnaire using urinary markers of nitrogen, potassium and
foods and found an average variability of threefold with a coeffi- sodium. International Journal of Epidemiology, 30(2), 309–317.
cient of variation of more than 30%; however, for some foods the Duffy, C., Perez, K., & Partridge, A. (2007). Implications of phytoestrogen intake for
observed variability was much higher (Kuhnle, Dell’Aquila, Runs- breast cancer. CA: A Cancer Journal for Clinicians, 57(5), 260–277.
Dwyer, J. T., Goldin, B. R., Saul, N., Gualtieri, L., Barakat, S., & Adlercreutz, H. (1994).
wick & Bingham, 2009). A comparison of our data with Horn-Ross Tofu and soy drinks contain phytoestrogens. Journal of the American Dietetic
et al. (2000), Milder, Arts, Van De Putte, Venema, and Hollman Association, 94(7), 739–743.
(2005) and Thompson et al. (2006) using Wilcoxon’s signed rank Eldridge, A. C., & Kwolek, W. F. (1983). Soybean isoflavones: Effect of environment
and variety on composition. Journal of Agricultural and Food Chemistry, 31(2),
test showed no overall significant difference between the phytoes- 394–396.
trogen and isoflavone content and phytoestrogen composition (as Fryatt, T., & Botting, N. P. (2005). The synthesis of multiply 13C-labelled plant and
proportion of isoflavones on total phytoestrogens) found in this mammalian lignans as internal standards for LC–MS and GC–MS analysis.
Journal of Labelled Compounds and Radiopharmaceuticals, 48(13), 951–969.
study and the average content found elsewhere. However, lignan
Grace, P. B., Taylor, J. I., Botting, N. P., Fryatt, T., Oldfield, M. F., Al-Maharik, N., et al.
contents were significantly different (p < 0.01) with most values (2003). Quantification of isoflavones and lignans in serum using isotope
found in this study being higher, suggesting a better extraction dilution liquid chromatography/tandem mass spectrometry. Rapid
of these compounds from the sample matrix. Communications in Mass Spectrometry, 7(12), 1350–1357.
Grace, P. B., Taylor, J. I., Low, Y. L., Luben, R. N., Mulligan, A. A., Botting, N. P., et al.
Only limited information is available about the effect of cooking (2004). Phytoestrogen concentrations in serum and spot urine as biomarkers for
on the phytoestrogen content of foods. Milder et al. (2005) and dietary phytoestrogen intake and their relation to breast cancer risk in
Thompson et al. (2006) investigated the effect for some types of European prospective investigation of cancer and nutrition-norfolk. Cancer
Epidemiology, Biomarkers and Prevention, 13(5), 698–708.
food and found a decrease in phytoestrogen content. The protocol Haajanen, K., & Botting, N. P. (2006). Synthesis of multiply 13C-labeled furofuran
for this study was not designed to assess the effect of cooking on lignans using 13C-labeled cinnamyl alcohols as building blocks. Steroids, 71(3),
phytoestrogen levels and, although compared with previous stud- 231–239.
Horn-Ross, P. L., Barnes, S., Lee, M., Coward, L., Mandel, J. E., Koo, J., et al. (2000).
ies, this study includes a larger variety of foods, it was not possible Assessing phytoestrogen exposure in epidemiologic studies: Development of a
to control for the effect of family on the probability shown in Table database (United States). Cancer Causes and Control, 11, 289–298.
3 that there are losses during cooking. An explanation for this loss Horn-Ross, P. L., John, E. M., Lee, M., Stewart, S. L., Koo, J., Sakoda, L. C., et al. (2001).
Phytoestrogen consumption and breast cancer risk in a multiethnic population:
during cooking is the leaching of phytoestrogens into the water The bay area breast cancer study. American Journal of Epidemiology, 154(5),
which is later discarded. Although prolonged heating could also re- 434–441.
sult in the decomposition of phytoestrogen, this effect was not Kipnis, V., Subar, A. F., Midthune, D., Freedman, L. S., Ballard-Barbash, R., Troiano, R.
P., et al. (2003). Structure of dietary measurement error: Results of the open
seen in stewed fruits and it is therefore likely that these com-
biomarker study. American Journal of Epidemiology, 158(1), 14–21.
pounds are stable during preparation, at least under acidic Krebs, E. E., Ensrud, K. E., MacDonald, R., & Wilt, T. J. (2004). Phytoestrogens for
conditions. treatment of menopausal symptoms: A systematic review. Obstetrics and
In summary, this study provides so far the most comprehensive Gynecology, 104(4), 824–836.
Kuhnle, G. G., Dell’Aquila, C., Low, Y.-L., Kussmaul, M., & Bingham, S. A. (2007).
database of isoflavones, lignans and coumestrol in more than 240 Extraction and quantification of phytoestrogens in food using automated SPE
foods based on fruits and vegetables commonly consumed in the and LC/MS/MS. Analytical Chemistry, 79(23), 9234–9239.
UK. The selection of food was based on consumption data of the Kuhnle, G. G. C., Dell’Aquila, C., Runswick, S. A., & Bingham, S. A. (2009). Variability
of phytoestrogen content in foods from different sources. Food Chemistry,
EPIC-Norfolk cohort (Day et al., 1999) and will allow the more 113(4), 1184–1187.
accurate determination of phytoestrogen intake and exposure in Liggins, J., Bluck, L., Coward, W. A., & Bingham, S. A. (1998a). A simple method for
this and other studies and free-living individuals. the extraction and quantification of daidzein and genistein in food using gas
chromatography mass spectrometry. Biochemical Society Transactions, 26(2),
S87.
Acknowledgements Liggins, J., Bluck, L. J., Coward, W. A., & Bingham, S. A. (1998b). Extraction and
quantification of daidzein and genistein in food. Analytical Biochemistry, 264(1),
1–7.
This work was funded by the UK Food Standards Agency (FSA), Liggins, J., Bluck, L. J., Runswick, S., Atkinson, C., Coward, W. A., & Bingham, S. A.
Contract No. T05028 and the Medical Research Council (MRC). (2000). Daidzein and genistein content of fruits and nuts. Journal of Nutritional
Biochemistry, 11(6), 326–331.
Liggins, J., Grimwood, R., & Bingham, S. A. (2000). Extraction and quantification of
References
lignan phytoestrogens in food and human samples. Analytical Biochemistry,
287(1), 102–109.
Adlercreutz, H. (2002). Phyto-oestrogens and cancer. Lancet Oncology, 3(6), Liggins, J., Mulligan, A., Runswick, S., & Bingham, S. A. (2002). Daidzein and genistein
364–373. content of cereals. European Journal of Clinical Nutrition, 56(10), 961–
Adlercreutz, H., Fotsis, T., Lampe, J. W., Wähälä, K., Makela, T., Brunow, G., et al. 966.
(1993). Quantitative determination of lignans and isoflavonoids in plasma of Low, Y.-L., Dunning, A. M., Dowsett, M., Folkerd, E., Doody, D., Taylor, J., et al. (2007).
omnivorous and vegetarian women by isotope dilution gas chromatography– Phytoestrogen exposure is associated with circulating sex hormone levels in
mass spectrometry. Scandinavian Journal of Clinical and Laboratory Investigation, postmenopausal women and interact with ESR1 and NR1I2 gene variants.
215, 5–18. Cancer Epidemiology, Biomarkers and Prevention, 16(5), 1009–1016.
Akiyama, T., Ishida, J., Nakagawa, S., Ogawara, H., Watanabe, S., Itoh, N., et al. (1987). Low, Y.-L., Dunning, A. M., Dowsett, M., Luben, R. N., Khaw, K.-T., Wareham, N. J.,
Genistein, a specific inhibitor of tyrosine-specific protein kinases. Journal of et al. (2006). Implications of gene–environment interaction in studies of gene
Biological Chemistry, 262(12), 5592–5595. variants in breast cancer: An example of dietary isoflavones and the D356N
Anthony, M. S. (2002). Phytoestrogens and cardiovascular disease: Where’s the polymorphism in the sex hormone-binding globulin gene. Cancer Research,
meat? Arteriosclerosis, Thrombosis, and Vascular Biology, 22(8), 1245– 66(18), 8980–8983.
1247. Low, Y.-L., Taylor, J. I., Grace, P. B., Dowsett, M., Folkerd, E., Doody, D., et al. (2005a).
Bhathena, S. J., & Velasquez, M. T. (2002). Beneficial role of dietary phytoestrogens Polymorphisms in the CYP19 gene may affect the positive correlations between
in obesity and diabetes. American Journal of Clinical Nutrition, 76(6), serum and urine phytoestrogen metabolites and plasma androgen
1191–1201. concentrations in men. Journal of Nutrition, 135(11), 2680–2686.
Branham, W. S., Dial, S. L., Moland, C. L., Hass, B. S., Blair, R. M., Fang, H., et al. (2002). Low, Y.-L., Taylor, J. I., Grace, P. B., Dowsett, M., Scollen, S., & Dunning, A. M. (2005b).
Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor. Phytoestrogen exposure correlation with plasma estradiol in postmenopausal
Journal of Nutrition, 132(4), 658–664. women in European prospective investigation of cancer and nutrition-norfolk
554 G.G.C. Kuhnle et al. / Food Chemistry 116 (2009) 542–554
may involve diet–gene interactions. Cancer Epidemiology, Biomarkers and Stark, A., & Madar, Z. (2002). Phytoestrogens: A review of recent findings. Journal of
Prevention, 14(1), 213–220. Pediatric Endocrinology and Metabolism, 15(5), 561–572.
Markovits, J., Linassier, C., Fosse, P., Couprie, J., Pierre, J., Jacquemin-Sablon, A., et al. The Endogenous Hormones Breast Cancer Collaborative. (2002). Endogenous sex
(1989). Inhibitory effects of the tyrosine kinase inhibitor genistein on hormones and breast cancer in postmenopausal women: Reanalysis of nine
mammalian DNA topoisomerase II. Cancer Research, 49(18), 5111–5117. prospective studies. Journal of the National Cancer Institute, 94(8), 606–
Martin, P. M., Horwitz, K. B., Ryan, D. S., & McGuire, W. L. (1978). Phytoestrogen 616.
interaction with estrogen receptors in human breast cancer cells. Endocrinology, Thompson, L. U., Boucher, B. A., Liu, Z., Cotterchio, M., & Kreiger, N. (2006).
103(5), 1860–1867. Phytoestrogen content of foods consumed in Canada, including isoflavones,
Mazur, W. M. (1998). Phytoestrogen content in foods. Bailliere. lignans and coumestan. Nutrition and Cancer, 54(2), 184–201.
Mazur, W. M., & Adlercreutz, H. (1998a). Natural and anthropogenic environmental US Department of Agriculture (2002). USDA-Iowa State University database on the
oestrogens: The scientific basis for risk assessment; naturally occurring isoflavone content of foods.
oestrogens in food. Pure and Applied Chemistry, 70(9), 1759–1776. Valsta, L. M., Kilkkinen, A., Mazur, W. M., Nurmi, T., Lampi, A.-M., Ovaskainen, M.-L.,
Mazur, W. M., Fotsis, T., Wähälä, K., Ojala, S., Salakka, A., & Adlercreutz, H. (1996). et al. (2003). Phyto-oestrogen database of foods and average intake in Finland.
Isotope dilution gas chromatographic–mass spectrometric method for the British Journal of Nutrition, 89(Suppl. 1), S31–38.
determination of isoflavonoids, coumestrol, and lignans in food samples. Verdeal, K., Brown, R. R., Richardson, T., & Ryan, D. S. (1980). Affinity of
Analytical Biochemistry, 233, 169–180. phytoestrogens for estradiol-binding proteins and effect of coumestrol on
Mazur, W. M., Wähälä, K., Rasku, S., Salakka, A., Hase, T., & Adlercreutz, H. (1998b). growth of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.
Lignan and isoflavonoid concentrations in tea and coffee. British Journal of Journal of the National Cancer Institute, 64(2), 285–290.
Nutrition, 79(1), 37–45. Wähälä, K., Hase, T., & Adlercreutz, H. (1995). Synthesis and labeling of isoflavone
Milder, I. E. J., Arts, I. C. W., Van De Putte, B., Venema, D. P., & Hollman, P. C. H. phytoestrogens, including daidzein and genistein. Proceedings of the Society for
(2005). Lignan contents of Dutch plant foods: A database including lariciresinol, Experimental Biology and Medicine, 208(1), 27–32.
pinoresinol, secoisolariciresinol and matairesinol. British Journal of Nutrition, Wähälä, K., & Rasku, S. (1997). Synthesis of D4-genistein, a stable deutero labeled
2005(93), 3. isoflavone, by a perdeuteration – Selective dedeuteration approach. Tetrahedron
Mulligan, A. A., Welch, A. A., McTaggart, A. A., Bhaniani, A., & Bingham, S. A. (2007). Letters, 38(41), 7287–7290.
Intakes and sources of soya foods and isoflavones in a UK population cohort Wang, H.-J., & Murphy, P. A. (1994). Isoflavone composition of American and
study (EPIC-Norfolk). European Journal of Clinical Nutrition, 61(2), 248– Japanese Soybeans in Iowa: Effects of variety, crop year and location. Journal of
254. Agricultural and Food Chemistry, 42(8), 1674–1677.
Peeters, P. H. M., Keinan-Boker, L., van der Schouw, Y. T., & Grobbee, D. E. (2003). Ward, H., Chapelais, G., Kuhnle, G., Luben, R., Wareham, N. J., Khaw, K.-T., et al.
Phytoestrogens and breast cancer risk. Review of epidemiological data. Breast (2008). Risk of breast cancer in relation to biomarkers of phytoestrogen intake
Cancer Research and Treatment, 77(2), 171–183. in a population cohort study. Breast Cancer Research, 10(2), R32.
Phillips, K. P., & Tanphaichitr, N. (2008). Human exposure to endocrine disrupters Wei, H., Bowen, R., Cai, Q., Barnes, S., & Wang, Y. (1995). Antioxidant and
and semen quality. Journal of Toxicology and Environmental Health, Part B, 11(3), antipromotional effects of the soybean isoflavone genistein. Proceedings of the
188–220. Society for Experimental Biology and Medicine, 208(1), 124–130.
Setchell, K. D. R., & Adlercreutz, H. (1988). Mammalian lignans and phytoestrogens. Whalley, J. L., Bond, T. J., & Botting, N. P. (1998). Synthesis of 13C labelled daidzein
In I. R. Rowland (Ed.), The role of the gut flora in toxicity and cancer (pp. 315–346). and formononetin. Bioorganic Medicine and Chemistry Letters, 8(18), 2569–
London: Academic Press. 2572.
Shutt, D. A., & Cox, R. I. (1972). Steroid and phyto-oestrogen binding to sheep Whalley, J. L., Oldfield, M. F., & Botting, N. P. (2000). Synthesis of [4–13C]-isoflavonoid
uterine receptors in vitro. Journal of Endocrinology, 52(2), 299–310. phytoestrogens. Tetrahedron, 56(3), 455–460.