genistein

Sei-Jung Lee

** Genistein: Phytoestrogen from Soy **

Phytoestrogens are the plant-derived chemicals that possess the estrogenic activities. Although many plants with estrogenic activity have been used worldwide throughout history, the concrete concept of phytoestrogen came when the bioassay for estrogen by Allen Doisy was published in 1923. About two decades later, ‘the clover disease’ in the 1940s brought the intensive attention to phytoestrogen because sheep in Western Australia suffered infertility as they grazed on clover-rich pasture. 1 By early 1980s, phytoestrogen’s biological effect in humans became clear, yet, the soaring interest on phytoestrogen since 1990s was due to reports on Japanese women who showed less menopausal symptoms such as hot flushes, osteoporosis, or cardiovascular disease than Western women. Both Japanese men and women also appeared to have low incidents of sex hormone-related cancer such as breast cancer or prostate cancer. This phenomenon showed the strict correlation with their traditional soy-rich diet. 2

Phytoestrogens are divided in four main classes: isoflavones from soy or whole grain cereals; coumestans from bean sprouts like alfalfa; lignans from fruits, vegetables or seeds; and stilbenes from grapes. The position of hydroxyl groups, attached to a benzene ring, is considered to the determinant of estrogenic activities of theses phytoestrogen. Among these, isoflavones are the most common, and Genistein (5,7,4’-trihydroxyisoflavone), one of isoflavones, appeared to have the highest estrogenic properties. 3

Due to the similar shape to the endogenous estrogen as shown in figure 1, genistein has high affinity to the estrogen receptor, which explains its estrogenic properties. Compared to 17-β-estradiol (E2), the endogenous sex hormone present in females, genistein shares almost identical molecular weight, and a similar hydroxylation pattern and position, with two key hydroxyl groups at C7 and C4’. In addition, the distance (∼11.5 Å) between the C7 and C4′ hydroxyl groups allows for optimal binding of genistein to the estrogen receptor (ER). 4

 Figure 1. The shape of Genistein, similar to endogenous estradiol, contributes to the high affinity to estrogen receptor 5

There are two different estrogen receptors, ER- a and ER- b, through which the biological effect of Estradiol (E2) is carried out. Binding of estrogen to ER is responsible for the classical estrogenic activities such as puberty, sexual differentiation, and breast development as well as non-classic effect on bone growth, memory or arthrosclerosis. During menopause, estrogen is also responsible of certain cancers. ER alpha and ER beta are different in localization and concentration in ovary, uterus, breast, bones, cardiovascular system, and brain. Genistein has a low affinity for binding to ER alpha, which explains its weaker estrogenic activities than natural estrogens, however, they express the preferential binding to ER beta. The Classic ER related action induced by genistein is complexly branching out (dichotomous), which might explain conflicting researches of genistein for its agonistic as well as antagonistic activity on certain cancer cells

Epidemiological and case control studies have reported a negative correlation between breast cancer and intake of soy products. Some animal studies showed that genistein suppressed the number of breast tumors by 50%. In cell cultures, genistein inhibited the proliferation of ER positive breast cancer, yet, when estrogen is absent, genistein increased the proliferation of mammary cancer cell. These suggest the pre-pubertal exposure to genistein is critical for preventing breast cancer. 6

Although recent meta-analysis of eight studies found that genistein consumption was associated with a reduction in risk of prostate cancer, evidences of many studies are inconsistent. 7

Since estrogen works against atherosclerosis and bone loss, the rate of cardiovascular disease and osteoporosis in menopausal and postmenopausal women increases dramatically. Large epidemiological and animal studies found that genistein consumption have demonstrated beneficial effect for cardiovascular disease via decrease in the Low Density Lipoprotein-Cholesterol (LDL-C) and increase in HDL-C level. Positive correlations between genistein intake and Bone Mineral Density (BMD) also have shown in many researches, yet long-term studies are necessary to confirm these beneficial effects. 8

Due to the estrogen’s beneficial effects on the brain such as protection against oxidative damage or enhancement on cognitive activities, estrogen therapy through genistein consumption might prevent dementia or Alzheimer Disease. However, scientific research on the effect of genistein for cognitive function is limited. 9

Genistein has two known synthesis routes: deoxybenzoin route and chalcone route. Deoxybenzoin route uses friedel-craft reaction, and chalcone route uses aldol condensation as shown in figure 2. Developing synthesis of genistein allows the access to the affordable therapy as well as mass production of commercial genistein supplements. However, it would be recommended to consult with the health care provider and discuss the pros and cons before the use since the effects of genistein on human body are not fully understood yet as discussed above.

 Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

1. Haneef, J., & Sreeja, S. (2009). Phytoestrogens: An Overview. //The Icfai University Journal of Biotechnology, vol. 3, No. 2.// Retrieved from EBSCOhost database. 2. Albertazzi, P. (2005). Phytoestrogen in Human Health: What are the Evidences. //Curr.Med. Chem.-Immun., Endoc. & Metab. Agents,vol. 5, No.2.// Retrieved from EBSCOhost database. 3. Haneef, J., & Sreeja, S. (2009). Phytoestrogens: An Overview. //The Icfai University Journal of Biotechnology, vol. 3, No. 2.// Retrieved from EBSCOhost database. 4. Pavese, M., Farmer, Rebecca L., and Bergan, Raymond C. (2010). Inhibition of cancer cell invasion and metastasis by genistein. doi: 10.1007/s10555-010-9238-z Retrieved from http://www.springerlink.com/content/6l6t22m6u01n767k/fulltext.pdf 5. http://www.emeraldinsight.com/journals.htm?articleid=1463286&show=html 6. Haneef, J., & Sreeja, S. (2009). Phytoestrogens: An Overview. //The Icfai University Journal of Biotechnology, vol. 3, No. 2.// Retrieved from EBSCOhost database. 7. Higdon, J. (2006, January, Last updated 2009, December). Soy Isoflavone. Retrieved from http://lpi.oregonstate.edu/infocenter/phytochemicals/soyiso/ 8. Haneef, J., & Sreeja, S. (2009). Phytoestrogens: An Overview. //The Icfai University Journal of Biotechnology, vol. 3, No. 2.// Retrieved from EBSCOhost database. 9. Higdon, J. (2006, January, Last updated 2009, December). Soy Isoflavone. Retrieved from http://lpi.oregonstate.edu/infocenter/phytochemicals/soyiso/ 10. http://www.springerlink.com/content/6l6t22m6u01n767k/fulltext.pdf