Genistein: Definition, Synthesis, Absorption, Transport, and Distribution

Genistein, along with daidzein and glycitein, is a typical representative of isoflavones (synonym: isoflavonoids), which belong to the group of secondary plant compounds (bioactive substances with health-promoting effects – “anutritive ingredients”). Chemically, genistein 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). Genistein is a 3-phenylchroman derivative with the molecular formula C15H10O5, which has three OH groups attached. Its exact name is 4′,5,7-trihydroxyisoflavone or 5,7-dihydroxy- 3-(4-hydroxyphenyl) chromen-4-one according to the International Union of Pure and Applied Chemistry (IUPAC). Genistein has a molecular structure similar to the steroid hormone 17ß-estradiol (female sex hormone) and for this reason can interact with estrogen receptors (ER). Two human ER subtypes can be distinguished – ER-alpha and ER-beta (ß), which have the same basic structure but are localized in different tissues. While ER-alpha receptors (type I) are mainly located in breast, endometrium (uterine mucosa), ovaries (ovaries) and hypothalamus (section of diencephalon), ER-ß receptors (type II) are mainly detectable 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 (binding strength) of genistein being higher compared to that of daidzein, equol (4′,7-isoflavandiol synthesized from daidzein by intestinal bacteria), and glycitein [1-3, 8, 10, 15, 17, 19, 21]. In vitro studies (studies outside a living organism) with soybean extracts show an affinity of isoflavones for the progesterone and androgen receptor in addition to a clear interaction (interaction) with estrogen receptors. Due to its hormonal activity, genistein belongs to the phytoestrogens. However, its estrogenic effect is lower by a factor of 100 to 1,000 compared to that of 17ß-estradiol formed in the mammalian organism. However, the concentration of genistein in the body can be up to 1,000-fold higher than that of the endogenous (endogenous) hormone [1-3, 8, 10, 12, 13, 19, 21].The predominant effect of genistein depends on both the individual amount of circulating endogenous (endogenous) estrogens and the number and type of estrogen receptors. In adult premenopausal women (women before menopause) who have high estrogen levels, genistein 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, genistein develops a more estrogenic effect [1-3, 8, 10, 19, 21]. The tissue-specific effects of genistein 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, genistein can be classified as a natural SERM (Selective Estrogen Receptor Modulator). Selective estrogen receptor modulators, such as raloxifene, lead to downregulation of ER-alpha and stimulation of ER-ß receptors, inducing, for example, estrogen-like effects on bone (→ prevention of osteoporosis (bone loss)) and, in contrast, effects antagonizing (opposing) estrogen in reproductive tissues (→ inhibition of hormone-dependent tumor growth, such as mammary (breast), endometrial (endometrial), and prostate carcinoma).

Synthesis

Genistein is synthesized (produced) exclusively by plants, especially tropical legumes (pulses).Soybeans (30-92 mg/100 g fresh weight) and products made from them, such as soymilk (3-17 mg/100 g fresh weight) and tofu (8-20 mg/100 g fresh weight), contain the most significant amount of genistein in terms of quantity. Of all isoflavones, genistein is the most quantitatively relevant component of soybean (> 50%), followed by daidzein (> 40%) and glycitein (> 5-10%) – ratio genistein: daidzein: glycitein = 10: 8: 1. The highest isoflavone concentrations are found directly in or under the seed coat – where genistein is 5- to 6-fold more concentrated than in the cotyledon (cotyledon). In Europe and the USA, the average intake of isoflavones is < 2 mg per day. In Japan, China and other Asian countries, on the other hand, 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 by the bacterium Bacillus subtilis ssp. natto fermented), ingested between 25-50 mg of isoflavones per day, with the daily genistein intake in Japan being 7.8-12.4 mg per capita. In the plant organism, the phytoestrogen is present primarily in conjugated form as a glycoside (binding to the sugar glucose) – genistin – and only to a small extent in free form as an aglycone (without sugar residue) – genistein. On average, 50 mg of genistin contains about 30 mg of genistein. 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 genistein can occur in both the small intestine and the colon (large intestine). While unbound genistein is absorbed into the mucosa cells (mucosal cells) of the small intestine via passive diffusion, genistein glycosides are first cleaved by salivary enzymes, such as alpha-amylase, by gastric acid, or by glycosidases (enzymes that cleave glucose molecules by reaction with water) of the brush border membrane of enterocytes (cells of the small intestinal epithelium), respectively, to be subsequently passively absorbed as free genistein in the small intestine. Absorption of glycosidically bound genistein 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 genistein not absorbed in the small intestine are taken up in the colon (large intestine) by passive diffusion into mucosa (mucosal) cells after hydrolysis of genistein glycosides by bacterial beta-glucosidases (enzymes that cleave glucose molecules by reaction with water). Prior to absorption, genistein aglycones may be metabolized (metabolized) by microbial enzymes. Antibiotic therapy has negative effects on both the quantity (number) and quality (composition) of the colonic flora and thus may affect the metabolism of genistein. The bioavailability of genistein ranges from 13-35%. Studies on the biokinetics of genistein aglycones and glycosides have shown that the aglycones are absorbed more rapidly than the glycoside derivatives. The extent to which the total availability of free and glycoside-bound genistein differs has not been conclusively determined.

Transport and distribution in the body

Absorbed genistein and its metabolites enter the liver via the portal vein and are transported from there to organs and tissues. To date, little is known about the distribution and storage of genistein in the human body. Studies with rats administered radiolabeled isoflavones have shown that they are preferentially stored in mammary tissue, ovaries (ovaries) and uterus (uterus) in female animals and in the prostate in male animals. In the intervention study by Bolca et al with healthy women, a distribution of isoflavones in the fatty and glandular tissues of the breast of 40:60 was detectable after ingestion of soy milk and soy supplements.In tissues and organs, 50-90% of genistein 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 genistein into an excretable form, it undergoes biotransformation.Biotransformation occurs in the liver and can be divided into two phases:

  • In phase I, genistein 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 genistein with the help of enzymes, whereby it mainly comes to glucuronidation of genistein (98%)

The conjugated genistein metabolites, mainly genistein-7-O-glucuronides, are excreted primarily by the kidneys and to a lesser extent by the bile. Biliary secreted genistein 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 (livergut circulation).