Screening of estrogenic and antiestrogenic activities from medicinal plants
Introduction
The estrogen, androgen and progesterone receptors, members of the nuclear receptor (NRs) superfamily, act as nuclear transport proteins, cell cycle components, and transcription factors (Fu et al., 2003). Most cellular actions of sex steroid hormones are mediated through binding to nuclear receptors that act as ligand-inducible transcription factors (Aranda and Pascual, 2001). Estrogen plays an important role in the growth, differentiation and function of many bodily targets, including the female and male reproductive systems. Estrogen also has a variety of pharmacological functions, such as maintenance of bone mass, cardiovascular protection, and brain protection (Ciocca and Roig, 1995, Smith et al., 1996). Estrogen deficiency during menopause can lead to risk for many health problems, such as hot flushes, sleeping disorders, vaginal dryness, joint pain, mood swings, reduced bone density, cardiovascular disease, etc. (Eaker et al., 1993, Palacios, 1999, Rymer et al., 2003).
Phytoestrogens are a new category of therapeutic agents available for the prevention and treatment of diseases such as osteoporosis and breast cancer (Jordan, 2004). It has been found that natural compounds known as phytoestrogens, obtained from certain plants and possessing estrogen-like activity (Paola and David, 2002), can be used for the management of menopausal symptoms with few side effects (Thompson, 1993, Glazier and Bowman, 2001). However, many phytoestrogens and environmental xenoestrogens also have been shown to increase the risk of breast cancer in women and to affect the reproductive systems in general (Hileman, 1996). Early studies noted adverse effects on fertility in animals that had been grazing on plants rich in phytoestrogens. Today, there is a wide interest in phytoestrogens for their potential health benefits in countering menopausal symptoms (Bennetts et al., 1946, Adlercreutz and Mazur, 1997). Phytoestrogens share the basic frame of other steroid hormones, although their potencies are estimated to be approximately 1000-fold weaker than that of 17β-estradiol (Lindner, 1976). To date, more than 300 plants have been found that possess compounds with estrogenic activity (Farnsworth et al., 1975, Price and Fenwich, 1985). Several classes of phytoestrogens have been identified and studied: the hormone-like bisphenolic phytoestrogens, the isoflavonoids daidzein and genistein, coumestrol, and the lignans and matairesinols are of great interest because of their respective estrogenic, antiestrogenic, anti-carcinogenic, and antioxidant activities (Adlercreutz, 1984, Adlercreutz et al., 1982, Setchell et al., 1980, Setchell et al., 1981, Whitten and Naftolin, 1991). Moreover, these phytoestrogens are structurally and functionally similar to estrogen (Knight and Eden, 1996).
Among the in vivo and in vitro assays that have been developed to test estrogenic substances, the binding of a ligand to estrogen receptor is the simplest and is suitable for screening of estrogen and antiestrogenic substances. Yeast cells carrying the human estrogen receptor (hER) gene, estrogen response elements (ERE) and Escherichia coli β-galactosidase gene (lacZ) are very suitable for large-scale screening and sensitive analysis of estrogenic compounds, and this model system has proven useful for the assay and discovery of novel estrogenic substances in Oriental medicinal plants (Routledge and Sumpter, 1996, Breithofer et al., 1998, Zhang et al., 2005).
In this study, 94 medicinal plants commonly used in Asia were screened to determine their ability to regulate estrogenic activity, and 14 plants showed significant effects. In addition, the estrogenic activities of solvent fractions from eight selected estrogenic and two selected antiestrogenic plants, which are not well reported for estrogenic or antiestrogenic effects, were investigated in order to better assess their largely undetermined effects.
Section snippets
Preparation of test samples
A total of 94 oriental medicinal plants (95% EtOH extracts) were purchased from the Plant Extract Bank of Korea (Daejeon, Korea). Voucher specimens were preserved in College of Pharmacy, SungKyunKwan University, Korea. The voucher numbers are shown in Table 1. The plant extracts were dissolved in dimethylsulfoxide (DMSO) and used as substrates for screening tests. 17β-Estradiol or tamoxifen was dissolved in DMSO and used as a positive and a negative control, respectively.
Plant materials and fractionation
Screened plants of the
Estrogenic and antiestrogenic activities of medicinal plants
The 95% EtOH extracts of 94 Oriental medicinal plants were assayed for selective estrogen replacement modulator activities by a recombinant yeast-estrogen receptor modulating assay system. The test extracts in DMSO were added to yeast cultures (OD420 = 0.1) to achieve final concentrations between 0.001 and 1000 μg/ml and they were incubated for 24 h, after which β-galactosidase activities were assayed. As shown in Table 1, the β-galactosidase assay results we obtained indicated that 14 of the 94
Acknowledgement
The authors wish to acknowledge the financial supports from Nuclear R&D program of the Ministry of Science and Technology (MOST) of the Republic of Korea.
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