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Clinical Mass Spectrometry, Children’s Hospital Medical Center, Cincinnati, OH
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INTRODUCTION |
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 TOP INTRODUCTION REFERENCES |
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); genistein
glycoside was first isolated from soybeans almost 60 years ago
(Walter 1941
). An appreciation of the hormonal potency
of isoflavones became apparent with the recognition in the mid-1940s
that an infertility syndrome in sheep was caused by the ingestion of
clover containing high levels of the related isoflavones formononetin
and biochanin A (Bennetts et al. 1946
). These two
methoxylated isoflavones were metabolized by intestinal bacteria to
equol, a unique mammalian isoflavone that shows much greater affinity
for binding to estrogen receptors than do the clover-derived
isoflavones. The importance of intestinal bacteria for the absorption
and metabolism of isoflavones in animals was thus established. There
was little clinical or nutritional interest shown in phytoestrogens
until the chance discovery of equol in human urine and the recognition
that when soy foods were consumed, the levels of isoflavones in urine
and blood far exceeded those of endogenous estrogens (Axelson et al. 1984
, Setchell et al. 1984
). These
observations led to the hypothesis that phytoestrogens would be
biologically active at these concentrations, conferring health benefits
that could explain the relatively low incidence of
hormone-dependent diseases in countries in which soy is a dietary
staple (Setchell et al. 1984
).
Soy foods made from whole soybeans or isolated and purified soy
proteins all contain relatively high concentrations of isoflavones,
primarily in the form of various ß-glycoside conjugates
(Coward et al. 1993
, Murphy 1982
). A
plethora of soy isoflavone extracts and supplements are now
commercially available; however, little is known concerning their
metabolism and effects. Much is known about the general metabolism of
isoflavones in animals and humans, but only limited information exists
on pharmacokinetics (King and Bursill 1998
). When
ingested, these conjugated isoflavones undergo hydrolysis by
ß-glucosidases in the jejunum, releasing the principal bioactive
aglycones, daidzein and genistein. Further metabolism takes place in
the distal intestine with the formation of specific metabolites
(Joanneau et al. 1995
). Although the latter enzymes are
deficient in early life, there is adequate ß-glucosidase activity to
make isoflavones bioavailable to infants consuming soy formulas
(Setchell et al. 1997
). The aglycones and any bacterial
metabolites are absorbed from the intestinal tract and conjugated
mainly to glucuronic acid; then they undergo enterohepatic recycling.
Intestinal metabolism is essential for their subsequent absorption and
bioavailability (Setchell et al. 1984
) because there is
no evidence to support absorption of the conjugated forms of
isoflavones. Furthermore, it is the aglycones that show an affinity for
estrogen receptors and have other nonhormonal effects on the cell
machinery.
Interest in the health-related effects of soy isoflavones has
surged in recent years (Setchell 1998
, Setchell and Cassidy 1999
). Numerous dietary intervention
studies have been performed in areas related to cholesterol lowering
and cardiovascular effects, effects on bone, and use as an alternative
to conventional hormone replacement for postmenopausal women; these
studies have given conflicting results. The targeted intake of
isoflavones from soy foods has been derived empirically because there
are no guidelines for optimal levels of intake. A daily isoflavone
intake 
50 mg has generally been used in clinical studies, largely on
the basis of the early observation that a daily intake of 45 mg causes
endocrine modulation of the menstrual cycle of premenopausal women
(Cassidy et al. 1994
). Few dietary intervention studies
have attempted to quantify intake or confirm compliance from blood
measurements of isoflavones, and the effect of varying dietary intakes
of phytoestrogens is largely unknown. Concerns have been expressed that
too much isoflavone in the diet may have negative effects, yet there is
a paucity of information on the pharmacokinetics of isoflavones or on
how varying dietary intake will influence the circulating levels and
bioavailability of these bioactive phytoestrogens.
In a series of randomized crossover studies, we examined the pharmacokinetics of daidzein and genistein in healthy adults fed different amounts and types of soy foods. These studies were designed to address whether all soy isoflavone are equal in terms of their apparent bioavailability. Classical pharmacokinetics have established that the volume of distribution in adults is large, indicating a wide tissue distribution, and that the shape of plasma appearance curve is consistent with compounds that undergo enterohepatic recycling. Peak concentrations are seen generally 4–8 h after dietary intake, and the plasma appearance and disappearance in pre- and postmenopausal women are similar. Most of the daidzein and genistein is excreted within the first 24 h, with the average fractional excretion remaining relatively constant over a wide range of intakes, although there is a high individual variability, ranging from 20 to 50% of the dietary intake. Differences are observed in the elimination half-life for different foods. More rapid elimination is observed for isoflavones in a liquid matrix than in a solid matrix food. The bioavailability as determined from the area under the curve is therefore influenced by the food matrix. We have found a curvilinear relationship between the dietary intake of isoflavones and peak plasma concentration and apparent bioavailability, indicating that absorption of isoflavones from food may be saturable. It may be more difficult to attain supraphysiologic levels of isoflavones from foods than from supplements, which are more closely aligned with pharmacologic agents. These findings are relevant to the safety of phytoestrogens. On the basis of the pharmacokinetics of soy isoflavones, maintenance of high steady-state plasma concentrations will be achieved by a regular intake, particularly if phytoestrogens are ingested throughout the day. This approach may serve to maximize the efficacy of phytoestrogens in clinical studies.
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FOOTNOTES |
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2 Supported by grants R01-CA563030 and R01-CA73328 from the National Institutes of Heath National Cancer Institute.
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REFERENCES |
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TOPINTRODUCTIONREFERENCES |
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1. Axelson M., Sjovall J., Gustafsson B., Setchell K.D.R. Soya—A dietary source of the non-steroidal oestrogen equol in humans and animals. J. Endocrinol. 1984;102:49-56[Abstract]
2. Bennetts H. W., Underwood E. J., Shier F. L. A specific breeding problem of sheep on subterranean clover pastures in Western Australia. Aust. J. Agric. Res. 1946;22:131-138
3.
Cassidy A., Bingham S., Setchell K.D.R. Biological effects of isoflavones present in soy in premenopausal women: implications for the prevention of breast cancer. Am. J. Clin. Nutr. 1994;60:333-340
4. Coward L., Barnes N. C., Setchell K.D.R., Barnes S. Genistein and daidzein, and their ß-glycoside conjugates: anti-tumor isoflavones in soybean foods from American and Asian diets. J. Agric. Food Chem. 1993;41:1961-1967
5. Joannou G. E., Kelly G. E., Reeder A. Y., Waring M. A., Nelson C. A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids. J. Steroid Biochem. Mol. Biol. 1995;54:167-184[Medline]
6. King R. A., Bursill D. B. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am. J. Clin. Nutr. 1998;67:867-872[Abstract]
7. Murphy P.A. Phytoestrogen content of processed soybean products. Food Technol 1982;34:60-64
8. Setchell K.D.R. Phytoestrogens: biochemistry, physiology, and implication for human health of soy isoflavones. Am. J. Clin. Nutr. 1998;68:1333S-1348S[Abstract]
9.
Setchell K.D.R., Borriello S. P., Hulme P., Kirk D. N., Axelson M. Non-steroidal oestrogens of dietary origin: possible roles in hormone-dependent disease. Am. J. Clin. Nutr. 1984;40:569-578
10. Setchell K.D.R., Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J. Nutr. 1999;129:758S-767S
11. Setchell K.D.R., Nechemias-Zimmer L., Cai J., Heubi J. E. Exposure of infants to phytoestrogens from soy infant formulas. Lancet 1997;350:23-27[Medline]
12. Walter E. D. Genistein (an isoflavone glucoside) and its aglucone, genistein, from soybeans. J. Am. Oil Chem. Soc. 1941;63:3273-3276
13. Walz E. Isoflavon- und saponin-glucoside in Soja-Hispida. Justus Liebigs Ann. Chem. 1931;489:118-155
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