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Absorption and Metabolism of Isoflavones

By Kenneth D. R. Setchell, Ph.D.

Isoflavones represent one of the classes of the so-called "phytoestrogens." These bioactive non-nutrients are strikingly similar in chemical structure to estradiol, the main female hormone (1). Indeed, one can superimpose almost exactly the structures of estradiol and isoflavones so they become indistinguishable, and therefore they fit beautifully into the pocket representing the binding domain of the estrogen receptor. It is therefore not surprising that isoflavones share many of the properties of endogenous estrogens. Isoflavones have the ability to behave as estrogen mimics, but also have other important non-hormonal properties that have attracted the attention of many investigators.

The chemical form in which isoflavones occur is an important consideration since it can dramatically influence the biological activity, the bioavailability, and therefore the physiological effects of these dietary constituents. We showed almost two decades ago that intestinal microflora play a key role in the metabolism and bioavailability of phytoestrogens (2).

After ingestion, soybean isoflavones are hydrolyzed by intestinal glucosidases, which releases the aglycones, daidzein, genistein and glycitein. These may be absorbed or further metabolized to many specific metabolites, including equol and p-ethylphenol (3,4). The extent of this metabolism appears to be highly variable among individuals and is influenced by other components of the diet. A high carbohydrate milieu, which causes increased intestinal fermentation, results in more extensive biotransformation of phytoestrogens, with greatly increased formation of equol, a mammalian isoflavone metabolite.

This metabolic pathway may be clinically relevant to the efficacy of soybean isoflavones, because the estrogenic potency of equol is an order of magnitude higher than that of its plant precursor, daidzein. The importance of the microflora in the metabolic handling of isoflavones is well illustrated from observations that antibiotic administration blocks metabolism, germfree animals do not excrete the metabolites, and infants fed soy infant formulas in the first four months of life cannot form appreciable amounts of equol (5,6).

Like endogenous estrogens (7), isoflavones undergo an enterohepatic circulation; they are secreted in bile. This has been shown in rats (6,8,9), and our pharmacokinetic studies in humans (unpublished) indicate that absorption takes place along the entire length of the intestine, presumably by nonionic passive diffusion. There is no evidence, to my knowledge, that the glycoside conjugates, can be absorbed, and this would be consistent with observations for flavonoids. Conjugation of isoflavones to glucuronic acid, a reaction catalyzed by one of the UDP-glucuronyltransferase isozymes, occurs on first-pass. Whether this takes place exclusively in the liver, or in the intestine is uncertain. Studies in rats suggest glucuronidation takes place during transport across the intestinal wall (6,9). Isoflavone glucuronide concentrations in portal venous blood of rats are high, and older studies of sheep showed that intestinal epithelia had a higher capacity for glucuronidation of equol than hepatocytes. Like estradiol, isoflavones are found in plasma mostly in the form of glucuronide conjugates, and to a lesser extent as sulfates (10); there also occur double conjugates.

Estrogens are strongly bound to the serum proteins, albimin and sex hormone binding globulin, so that <5 percent is circulating unbound, or free. The extent of protein binding is a major factor in governing the availability of estrogen for occupancy of nuclear receptor sites. Interestingly, phytoestrogens are less avidly bound to serum proteins; equol for example shows 10-fold less affinity for serum proteins that estradiol, and therefore a greater proportion will be available to occupy the estrogen receptor, which hypothetically may bolster the effectiveness of isoflavones.

We have determined the plasma half-life of daidzein and genistein, measured from their plasma appearance and disappearance curves to be 7.9 hours in adults; peak concentrations occur 6-8 hours after ingestion. Consequently, adherence to a soy-containing diet will ultimately lead to high steady-state plasma concentrations. Plasma concentrations of 50-800 ng/mL are achieved for daidzein, genistein and equol in adults consuming modest quantities of soy-foods containing in the region of 50 mg/day of total isoflavones. These values are similar to those of Japanese consuming their traditional diet (11).

In infants fed soy formulas plasma concentrations are even higher (5). Overall, when soy is consumed on a regular basis, levels far exceed normal plasma estradiol concentrations which in men and women generally range between 40-80 pg/mL. It was this early observation that led us to the hypothesis that with such disproportional levels one could anticipate hormonal effects from phytoestrogens (2).

Elimination of isoflavones from the body occurs via the kidneys. In urine, isoflavones are found mainly as glucuronide conjugates (3). Studies in animals and humans have indicated that the urinary output of isoflavones accounts for no more than 50 percent of the ingested dose, and since fecal excretion is minimal, there is currently an unaccounted balance. It is probable that this is explained by intestinal biotransformation to metabolites which are not presently being measured by investigators, and therefore it leads to questions regarding the reliability of using urinary isoflavone excretion as an indicator of dietary intake. p-Ethyl phenol, a metabolite formed by a cleavage of the isoflavone molecule, is not being quantified by most investigators. There is also a significant proportion of the population that lack the capacity to biotransform isoflavones (3), and a very high variability in quantitative excretion among individuals. Clinical efficacy of isoflavones is almost certainly related to the plasma circulating concentration and it is this endpoint that is likely to be the most reliable one to measure in clinical studies.

In summary, considerable knowledge of the metabolism and absorption of phytoestrogens was gained during the course of their discovery, however there are still gaps in our knowledge. The optimal dose of isoflavone required to have clinical effects remains to be established. In general we believe that 50 mg per day of aglycones is sufficient to have a clinical/biological effect. This would be consistent with intakes in countries consuming soy as a staple, and is the level at which demonstrable endocrine effects occur in premenopausal women (12). Dose response relationships remain to be established and factors governing their absorption and metabolism, which will govern efficacy will no doubt be understood in the near future.


(1) Setchell KDR, Adlercreutz H. Mammalian lignans and phyto-oestrogens. Recent Studies on their formation, metabolism and biological role in health and disease. In: Rowland IA, ed. The Role of Gut Microflora in Toxicity and Cancer. New York: Academic Press 1988:315-345.

(2) Setchell KDR, Borriello SP, Hulme P, Axelson M. Non-steroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am J Clin Nutr 1984;40:569-578.

(3) Axelson M, Sjovall J, Gustafsson B, Setchell KDR. Soya- A dietary source of the non-steroidal oestrogen equol in humans and animals. J Endocrin 1984;102:49-56.

(4) Joannou GE, Kelly GE, Reeder AY, Waring MA, Nelson C. A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids. J Steroid Biochem Molec Biol 1995;54:167-184.

(5) Setchell KDR. Nechemias-Zimmer LZ, Cai J, Heubi JE. Exposure of infants to phytoestrogens from soy infant formulas. The Lancet 1997; 350:23-27.

(6) Axelson M, Setchell KDR. The excretion of lignans in rats - Evidence for an intestinal bacterial source for this new group of compounds. FEBS Lett 1981;123:337-342.

(7) Adlercreutz H, Martin F. Biliary excretion and intestinal metabolism of progesterone and estrogens in man. J Steroid Biochem 1980;13:231-244.

(8) King RA, Broadbent JL, Head RJ. Absorption and excretion of the soy isoflavone genistein in rats. J Nutr 1996;126:176-182.

(9) Sfakianos J, Coward L, Kirk M, Barnes S. Intestinal uptake and biliary secretion of the isoflavone genistein in the rat. J. Nutr 1997;127:1260-1268.

(10) Adlercreutz H, Fotsis T, Lampe J, Wahala K, Makela T, Brunow G, Hase T. Quantitative determination of lignans and isoflavones in plasma of omnivorous and vegetarian women by isotope-dilution gas chromatography-mass spectrometry. Scand J Clin Lab Invest 1993;53:5-18.

(11) Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phyto- oestrogens in Japanese men. Lancet 1993;342:1209-1210.

(12) Cassidy A, Bingham S, Setchell KDR. Biological effects of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-340.

About the author

Kenneth D.R. Setchell, Ph.D. is a professor in the Department of Pediatrics, College of Medicine, University of Cincinnati. He obtained his doctorate in steroid biochemistry from the University of London. Formerly, he was a fellow at the Royal Society for post-doctoral studies at the Karolinska Institute in Stockholm, Sweden.

Reprinted with permission from The Soy Connection newsletter, Volume 6, No. 2, Spring 1998. More information about the newsletter can be obtained by writing to:

Editor, The Soy Connection
P.O. Box 237
Jefferson City, MO 65102

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