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September 15-18, 1996
Brussells, Belgium

(Oral Abstracts)

Overview of Isoflavone Structure, Metabolism and Pharmacokinetics
Kenneth D., Setchell.
Children's Hospital and Medical Center, Cincinnati, Ohio.

There has been a veritable explosion of interest in phytoestrogens, and in particular in the potential health benefits that a diet rich in these compounds might confer on many hormone-related diseases (Setchell et. al. 1984 Setchell 1985; Setchell & Aldercreutz 1988; Aldercreutz 1990). While there are many classes of bioactive non-nutrients with weak estrogenic activity, much of the current interest in the pharmacology and physiology of phytochemicals has focused on the group of compounds belonging to the isoflavone class.

These phenolic compounds possess in addition to estrogenic activity, a myriad of biological properties that can impact of many biochemical and physiological processes. While isoflavones are widely distributed in the plant kingdom, the concentrations of these compounds are relatively high in legumes, and in particular the soybean (Coward 1993). As a result, it is not surprising that most soy proteins commonly used by the food industry contain isoflavones in varying concentrations, ranging 0.1-3.0 mg/g.

The principal isoflavones found in soy proteins and soy foods are daidzein, genistein and glycitein, which for the most part usually exist as various forms of glycosidic conjugates, depending upon the extent of processing or fermentation of the soybean (Famakalidis & Murphy 1985; Barnes et. al. 1994). From a dietary perspective, what may be of greatest relevance is the total intake of isoflavone, rather than the chemical composition.

The 6"-O-malonylglucosides and 6"-O-acetlyglucosides are relatively heat sensitive and will readily convert to the more stable b-glucosides, but with negligible quantitative loss of the aglycone moiety. Furthermore, because of the abundance of intestinal b-glucosidase activity the initial metabolic fate of isoflavones inevitably leads to cleavage of the glycosidic moiety and release of the aglycone for subsequent absorption from the intestinal tract. Irrespective off the fate of the isoflavone conjugates, it should be realized that it is the aglycones that have demonstrable biological potency. The presence of the conjugate group may serve to influence the metabolic fate and pharmacokinetic behavior of dietary isoflavones, as we have recently shown in comparisons of daidzein, genistein and their respective b-glucosides.

On ingestion of dietary isoflavones, these compounds are metabolized by intestinal bacteria, absorbed from the intestinal tract and transported via the portal venous system to the liver. The high capacity of hepatic glucuronyltransferases dictates that, in common with endogenous steroid hormones, the isoflavones and their metabolites are efficiently conjugated with glucuronic acid, and to a lesser extent are found as sulfate conjugates.

Our recent studies where the pharmacokinetics of the pure isoflavones was examined in premenopausal women following single-bolus oral administration of 50 mg of each isoflavone suggests that conjugation may also occur in the intestine during the absorption phase. Maximum plasma concentrations of daidzein or genistein range 130-640 ng/mL following the administration of 50 mg of either glycosides or aglycones and these values are which is several orders of magnitude higher than the levels for endogenous estrogens (30-200 pg/mL). The plasma half-life for daidzein and genistein is similar at 7-8 hr, but the bioavailability of the glycosides is greater than that of the aglycones.

Our discovery of the unique mammalian isoflavone, equol, in human urine and blood, and its association with dietary soy protein intake (Axelson et. al. 1984; Setchell et. al. 1984), established the role of intestinal bacteria in the biotransformation of isoflavones, and led to the recognition that soy protein was a key dietary source of its origin. This relatively simple isoflavone is formed following deoxygenation and reduction, and more recent studies have shown a large number of intermediates are also formed from daidzein and genistein.

The formation of equol is highly variable with a relatively high proportion of the population (30-40%) being unable to produce equol even when challenged with soy protein (Setchell 1984). Our recent studies indicate that equol is formed from daidzein rather than genistein, and both the residence time in the intestine, and the extent of intestinal fermentation influence its formation. Elimination of isoflavones by urinary excretion accounts for 10-30% of the dietary intake of isoflavones and fecal excretion is relatively low.

Our studies in animals and humans have shown that isoflavones can be detected in many tissues, including brain, where it rapidly appears after i.p. administration, however, there is presently a relatively high proportion of the ingested isoflavone that cannot be accounted for. We have recently identified 4-ethylphenol in human plasma in rat brain and it is possible that this simple phenol, originally shown to be a metabolite of genistein in sheep, may account for a significant proportion of the biotransformation of products of isoflavones.

The successful synthesis of isoflavone tracers incorporating stable-isotopes of [13C] would greatly facilitate the elucidation of the biotransformation of isoflavones in humans. Nevertheless, the data thus far indicates that consuming modest quantities of soy protein results in relatively high circulating concentrations of these estrogen mimics. We have already demonstrated significant hormonal effects of premenopausal women of a diet that included modest amounts of soy protein containing isoflavones (Cassidy 1994, 1995). Based on the biological potency, the physiological effects and the pharmacokinetics of isoflavones, negative effects could be anticipated from high doses of these compounds, and this is likely to occur as they become available as nutrichemical supplements and pills.

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