Glycitein is an oxygen (O)-methylated isoflavone (synonyms: methoxyisoflavone, -isoflavonoid) and belongs to the large group of phytochemicals (bioactive substances with health-promoting effects – “anutritive ingredients”). Chemically, glycitein belongs to the polyphenols – a disparate group of substances based on the structure of phenol (compound with an aromatic ring and one or more bound hydroxyl (OH) groups). Glycitein is a 3-phenylchroman derivative with the molecular formula C16H12O5, which has two hydroxyl (OH) groups and one oxygen-containing methyl (OCH3) group attached. Its exact name is 4́,7-dihydroxy-6-methoxyisoflavone or 7-hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4-chromenone according to the International Union of Pure and Applied Chemistry (IUPAC). The molecular structure of glycitein is similar to that of the steroid hormone 17ß-estradiol (female sex hormone). This enables glycitein to interact with estrogen receptors (ER). Two human ER subtypes can be distinguished – ER-alpha and ER-beta (ß), which share the same basic structure but are localized in different tissues. While ER-alpha receptors (type I) are mainly located in the endometrium (endometrium), breast and ovary (ovary) cells, testes (testis), and the hypothalamus (section of the diencephalon), ER-ß receptors (type II) are mainly found in kidney, brain, bone, heart, lung, intestinal mucosa (intestinal mucosa), prostate and endothelium (cells of the innermost wall layer of lymph and blood vessels facing the vascular lumen). Isoflavones preferentially bind to ER-ß receptors, with the binding affinity of glycitein being lower than that of genistein, daidzein, and equol (4′,7-isoflavandiol synthesized from daidzein by intestinal bacteria). In vitro studies (studies outside a living organism) with soybean extracts show an affinity (binding strength) of isoflavones to the progesterone and androgen receptor in addition to a clear interaction with estrogen receptors. Due to its hormonal character, glycitein belongs to the phytoestrogens. However, its estrogenic effect is lower by a factor of 100 to 1,000 than that of the 17ß-estradiol formed in the mammalian organism. However, the concentration of glycitein in the body can be many times higher than that of the endogenous (endogenous) hormone. Compared to the isoflavones genistein, daidzein, and equol, glycitein has weak estrogenic activity.The effect predominated by glycitein depends on both the individual amount of circulating endogenous (endogenous) estrogen and the number and type of estrogen receptors. In adult premenopausal women (women before menopause) who have high estrogen levels, glycitein exerts an antiestrogenic effect because the isoflavone blocks the ER for endogenous (endogenous) 17ß-estradiol by competitive inhibition. In contrast, in childhood to puberty and in postmenopausal women (women after menopause), in whom estrogen levels are decreased, glycitein develops a more estrogenic effect. The tissue-specific effects of glycitein are due in part to ligand-induced conformational changes at the receptor, which can modulate (alter) gene expression and physiological response in a tissue-specific manner. In vitro studies with human endometrial cells confirm the estrogenic and antiestrogenic potential of isoflavones at ER-alpha and ER-ß receptors, respectively. Accordingly, glycitein can be classified as a natural SERM (Selective Estrogen Receptor Modulator). Selective estrogen receptor modulators, such as raloxifene (drug for the treatment of osteoporosis), lead to inhibition of ER-alpha and stimulation of ER-ß receptors, thereby inducing (triggering) estrogen-like effects on bone, for example (→ prevention of osteoporosis (bone loss)), and antagonizing (opposite) effects to estrogen in reproductive tissues, in contrast (→ inhibition of hormone-dependent tumor growth, such as mammary (breast), endometrial (endometrial), and prostate carcinoma).
Synthesis
Glycitein is synthesized (produced) exclusively by plants, especially tropical legumes (pulses).Soybeans have the highest content of glycitein (10-14 mg/100 g fresh weight), followed by tofu (0-5 mg/100 g fresh weight) and soymilk (0-2 mg/100 g fresh weight). Of all isoflavones in soybean, glycitein accounts for about 5-10%. The highest isoflavone concentrations are found directly in or under the seed coat – where glycitein is many times more concentrated than in the cotyledon (cotyledon). In Western countries, consumption of soybeans and products made from them has traditionally been low. For example, in Europe and the United States, the average intake of isoflavones is <2 mg per day. In contrast, in Japan, China and other Asian countries, due to the traditionally high consumption of soy products, such as tofu (soy curd or cheese made from soybeans and produced by the coagulation of soymilk), tempeh (fermentation product from Indonesia, (fermentation product from Indonesia produced by inoculating cooked soybeans with various Rhizopus (mold) species), miso (Japanese paste made from soybeans with variable amounts of rice, barley or other grains) and natto (Japanese food made from cooked soybeans fermented under the action of the bacterium Bacillus subtilis ssp. natto fermented), ingested between 25-50 mg of isoflavones per day. In the plant organism, the phytoestrogen is present primarily in conjugated form as glycoside (binding to glucose) – glycitin – and only to a small extent in free form as aglycone (without sugar residue) – glycitein. In fermented soy products, such as tempeh and miso, genistein aglycones predominate because the sugar residue is enzymatically cleaved by the microorganisms used for fermentation.
Resorption
The absorption (uptake) of glycitein can occur in both the small intestine and the colon (large intestine). Whereas unbound glycitein is absorbed by passive diffusion into the mucosa cells (mucosal cells) of the small intestine, glycitein glycosides are first absorbed by salivary enzymes, such as alpha-amylase, by gastric acid, or by glycosidases (enzymes, (enzymes that break down glucose molecules by reacting with water) of the brush border membrane of the enterocytes (cells of the small intestinal epithelium), so that they can then be passively absorbed as free glycitein in the small intestine. Absorption of glycosidically bound glycitein can also occur in an intact form via the sodium/glucose cotransporter-1 (SGLT-1), which transports glucose and sodium ions into the cell by means of a symport (rectified transport). Aglycone and glycoside forms of glycitein that are not absorbed in the small intestine are taken up in the colon (large intestine) by passive diffusion into the mucosa cells (mucosal cells) after hydrolysis of glycitein glycosides by beta-glucosidases (enzymes that cleave glucose molecules by reaction with water) of various bifidobacteria. Before absorption, the glycitein aglycones can be metabolized (metabolized) by microbial enzymes. This process produces, among others, as a result of demethoxylation (cleavage of the OCH3 group) of glycitein, the isoflavone daidzein, which can be converted to equol (4′,7-isoflavandiol) and is absorbed in this or its original form together with other glycitein metabolites. Antibiotic therapy has negative effects on both the quantity (number) and quality (composition) of the colonic flora and thus may affect the metabolism of glycitein. The bioavailability of glycitein ranges from 13-35%. Okabe et al (2011) studied the bioavailability of isoflavones from fermented (aglycone-rich) and non-fermented soybeans (glycoside-rich) and concluded that free glycitein is absorbed faster and in greater amounts compared to the glycoside-bound form, resulting in significantly higher serum concentration and AUC (English : Area under the curve, area under the concentration-time curve → measure for the absorbed amount of a substance and for the speed of absorption) and has a significantly higher concentration in the urine. In addition to the chemical mode of binding, the bioavailability of isoflavones is also dependent on age. For example, according to Halm et al (2007), the rate of absorption of glycitein – as measured by the renal excretion rate (rate of excretion by the kidneys) – is significantly greater in children than in adults. In addition, the presence of dietary fats plays a significant role.Fatty acids serve as transporters of lipophilic (fat-soluble) molecules and stimulate the secretion of bile acids. The latter are necessary in the intestinal tract for the formation of mixed micelles (aggregates of bile salts and amphiphilic lipids), which induce the uptake of lipophilic substances into the intestinal mucosa cells (mucosal cells of the intestine). Because glycitein is lipophilic, concomitant intake of dietary fats promotes absorption of the isoflavone.
Transport and distribution in the body
Absorbed glycitein and its metabolites enter the liver via the portal vein and are transported from there to peripheral organs and tissues. To date, little is known about the distribution and storage of glycitein in the human organism. Studies in rats administered radiolabeled isoflavones have shown that they are preferentially stored in mammary tissue, ovaries (ovaries), and uterus (uterus) in females and in the prostate gland in males. Gilani et al (2011) studied the tissue distribution of isoflavones – daidzein, equol, genistein, glycitein – in rats and pigs and found that it differed between sexes as well as between species. In male rats, for example, isoflavone serum concentrations rose significantly higher after feeding a soy product than in female rats, while the picture was reversed with regard to the liver. Here, equol showed the highest levels in the blood serum, liver and mammary gland of rats, followed by genistein, daidzein and glycitein. In pigs, appreciable isoflavone concentrations – daidzein, equol – were detectable in the mammary gland only when crystalline genistein was administered in addition to the soy product. In tissues and organs, 50-90% of glycitein is present as aglycone, the biologically active form. In blood plasma, on the other hand, an aglycone content of only 1-2 % is detectable. The isoflavone plasma concentration is about 50 nmol in an average mixed diet, while this can increase to about 870 nmol with a diet rich in soy products. The maximum isoflavone concentration in blood plasma was reached approximately 6.5 hours after the intake of soy products. After 24 hours, virtually no levels were detectable.
Excretion
To convert glycitein into an excretable form, it undergoes biotransformation.Biotransformation occurs in the liver and can be divided into two phases:
- In phase I, glycitein is hydroxylated (insertion of an OH group) by the cytochrome P-450 system to increase solubility.
- In phase II, conjugation with strongly hydrophilic (water-soluble) substances takes place – for this purpose, glucuronic acid, sulfate and the amino acid glycine are transferred to the previously inserted OH group of glycitein with the help of enzymes, whereby it mainly comes to glucuronidation of glycitein
The conjugated glycitein metabolites, mainly glycitein-7-O-glucuronides, are excreted primarily by the kidneys and to a lesser extent by the bile. Biliary secreted glycitein is metabolized in the colon by bacterial enzymes and reabsorbed. Thus, similar to endogenous (endogenous to the body) steroid hormones, the phytoestrogen is subject to enterohepatic circulation (liver-gut circulation).
