Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 51-52
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Phytoestrogens: Basic Aspects

M.C. Navarro Moll

Department of Pharmacology, School of Pharmacy, University of Granada, Spain

Extensive studies on the effects of diet on different pathological processes (1) have led to evidence of the protective effects of certain compounds found in fruit and other vegetables. A new category for these agents was recently added: phytoestrogens. They are compounds with nonsteroidal structures obtained from different vegetable species (2) and/or from the intestinal metabolic conversions of their precursors (3).

The benefits that phytoestrogens bring to health have been shown in several epidemiological studies, as well as in experimental and clinical research. Their estrogenic activity, derived from their capacity to interact with 17b-estradiol receptors, has been demonstrated (4).

The known phytoestrogens are diphenolic compounds with some structural similarity to estrogens (5) that belong to some of the following types of chemicals: lignans, coumestans, resorcinol derivatives and isofla-vones (genistein and daidzein). Of these four groups, isoflavones are of the most interest (6, 7).

With respect to its pharmacokinetic parameters, the elimination half-life (t_1/2) varies depending on the isoflavone and the treatment duration (8). The maximum serum levels are observed after 7.42 ± 0.79 h for daidzein and 8.42 ± 0.69 h for genistein (9). The half-life values are 8.36 h and 5.79 h for genistein and daidzein, respectively (10). Daidzein (t_1/2 of excretion = 4.4) is excreted much faster than genistein (t_1/2 of excretion = 6.7 h). The isoflavones bioavailability could be affected by several factors: individual metabolism, dietary fiber, sex and duration of treatment (10, 11). There are several mechanisms whereby isoflavones exert their effects, as outlined below.

INTERACTION WITH ESTROGENIC RECEPTORS (4, 12)

The capacity of isoflavones to bind to estrogenic receptors leads to a link-receptor complex that is functionally equivalent to the one formed by 17b-estradiol, which in turn causes a transcriptional activity increase. The response obtained with isoflavone is not as intense as the one with 17b-estradiol due to isoflavones having less affinity to estrogenic receptors (13). This varies depending on the estrogenic receptor under consideration (a and b) with specific tissue location. The isoflavones affinity is notable in the case of type b receptors and very low towards type a receptors. It is therefore supposed that its actions are more marked in those target organs and tissues in which b receptors predominate (central nervous system, bone, vascular wall and urogenital tract).

With regard to the estrogenic strength of the isoflavones, other factors play a key role: the presence of coactivator or repressor factors in the target cells, the specific isoflavone type and the greater facility of access to the estrogenic receptors in comparison with the 17b-estradiol of the isoflavones (14).

ENZYMATIC INHIBITION

Initially, the inhibitory action of genistein over the family of tyrosine kinases was demonstrated (15.) This factor gave rise to its possible use as an anticancerous agent, given the long series of events in which tyrosine kinases are involved: i) inhibition of oncogene expression; ii) reduction in the number of receptors for different growth factors involved in the process of cellular proliferation/differentiation (16); iii) the reduction in tyrosine phosphorylation causes an inhibition of platelet aggregation (17); and iv) inhibition of acid metabolism in osteoclasts, which gives rise to a reduction of these bone cells activity that are responsible for the bone reabsorption (18).

ANTIOXIDANT ACTIVITY

Isoflavones have antioxidant properties, which are more intense for genistein, followed by equol (19). This antioxidant activity leads to a reduction in free oxygen radicals.

OTHERS

Genistein favors a reduction in Ca²⁺ [c] through reduced Ca²⁺ entrance to the cell and an increase incation capture by the endoplasmic reticule. Isoflavones inhibit the linking of the thromboxane A₂ to its platelet receptor (20), thus causing a reduction in the platelet aggregation process. After administration of genistein, an increase in the sex hormone binding globulin (SHBG) was observed (21), with a subsequent decrease in the free circulating fraction of 17b-etradiol.

The isoflavones, in particular genistein, favor cellular differentiation processes (22), and are capable of inducing the apoptosis of cancer cells by mechanisms that do not involve enzymatic inhibition.

As a result of these actions, isoflavones produce some effects that justify their interest for therapeutic purposes in climacteric symptoms, as well as a possible role in the treatment of cancerous diseases.

REFERENCES

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2. Brzezinski, A., Debi, A. Phytoestrogens: The "natural" selective estrogen receptor modulators? Eur J Obstet Gynecol Reprod Biol 1999, 85(1): 47-51.

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9. 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(5): 867-72.

10. Watanabe, S., Yamaguchi, M., Sobue, T. et al. Pharmacokinetics of soybean isoflavones in plasma, urine and feces of men after ingestion of 60 g baked soybean powder (kinako). J Nutr1998, 128(10): 1710-5.

11. Wiseman, H. The bioavailability of non-nutrient plant factors: Dietary flavonoids and phyto-oestrogens. Proc Nutr Soc 1999, 58(1): 139-46.

12. Barnes, S. Phytoestrogens and breast cancer. Baillieres Clin Endocrinol Metab 1998, 12(4):559-79.

13. Breithofer, A., Graumann, K., Scicchitano, M.S., Karathanasis, S.K., Butt, T.R., Jungbauer, A. Regulation of human estrogen receptor by phytoestrogens in yeast and human cells. J Steroid Biochem Mol Biol 1998, 67(5-6): 421-9.

14. Nagel, S.C., vom Saal, F.S., Welshons, W.V. The effective free fraction of estradiol and xenoestrogens in human serum measured by whole cell uptake assays: Physiology of delivery modifies estrogenic activity. Proc Soc Exp Biol Med 1998, 217(3): 300-9.

15. Akiyama T, Ishida J, Nakagawa S. et al Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987, 262(12): 5592-5.

16. Peterson, G., Barnes, S. Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ 1996, (10): 1345-51.

17. Yan, C., Han, R. Genistein suppresses adhesion-induced protein tyrosine phosphorylation and invasion of B16-BL6 melanoma cells. Cancer Lett 1998, 129(1): 117-24.

18. Knight, D.C., Eden, J.A. A review of the clinical effects of phytoestrogens. Obstet Gynecol 1996, 87(5 Pt 2): 897-904.

19. Mitchell, J.H., Gardner, P.T., McPhail, D.B., Morrice, P.C., Collins, A.R., Duthie, G.G. Antioxidant efficacy of phytoestrogens in chemical and biological model systems. Arch Biochem Biophys 1998, 360(1): 142-8.

20. McNicol, A. The effects of genistein on platelet function are due to thromboxane receptor antagonism rather than inhibition of tyrosine kinase. Prostaglandins Leukot Essent Fatty Acids 1993, 48(5): 379-84.

21. Adlercreutz, H., Mousavi, Y., Clark, J. et al. Dietary phytoestrogens and cancer: In vitro and in vivo studies. J Steroid Biochem Mol Biol 1992, 41(3-8): 331-7.

22. Adlercreutz, C.H., Goldin, B.R., Gorbach, S.L. et al. Nutr 1995, 125 (Suppl. 3): 757S-70S.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 51-52
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com