phytoestrogens and glabridin

Glabridin, a prenylated isoflavonoid of G. glabra L. roots (European licorice, Fabaceae), has been associated with a wide range of biological properties such as antioxidant, anti-inflammatory, anti-atherogenic, regulation of energy metabolism, estrogenic, neuroprotective, anti-osteoporotic, and skin-whitening. While glabridin is one of the most studied licorice flavonoids, a comprehensive literature survey linked to its numerous bioactivities is unavailable. The present review provides a comprehensive description of glabridin as a key chemical and biological marker of G. glabra, by covering both its phytochemical characterization and reported biological activities. Both glabridin and standardized licorice extracts have significant impact on food, dietary supplements (DSs) and cosmetic markets, as evidenced by the amount of available patents and scientific articles since 1976, when glabridin was first described. Nevertheless, a thorough literature survey also reveals that information about the isolation and chemical characterization of this important marker is scattered and less detailed than expected. Accordingly, the first part of this review gathers and provides all analytical and spectroscopic data required for the comprehensive phytochemical characterization of glabridin. The four most frequently described and most relevant bioactivities of glabridin are its anti-inflammatory, anti-atherogenic, estrogenic-like effects, and its capacity to regulate energy metabolism. While all bioactivities reported for glabridin belong to a wide array of targets, its principal biological properties are likely interconnected. To this end, the current state of the literature suggests that the biological activity of glabridin mainly results from its capacity to down-regulate intracellular reactive oxygen species, bind to antioxidant effectors, and act on estrogen receptors, potentially as a plant-based Selective Estrogen Receptor Modulator (phytoSERM).

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Energy Metabolism; Glycyrrhiza; Humans; Isoflavones; Phenols; Phytoestrogens; Plant Extracts; Selective Estrogen Receptor Modulators

Estrogen replacement therapy is commonly used to replace the loss of estrogen in post-menopausal women. However, it is not suitable to be used in women taking tamoxifen as both of the drugs increase the risk of endometrial cancer. This project aimed to study the potential of using the natural compound glabridin in combination with tamoxifen as a drug for estrogen replacement therapy. Ishikawa and MCF-7 cells were used to investigate the estrogenic activities stimulated by the combination of tamoxifen and glabridin through ALP and MTT assays. The expressions of the ESR1 and bcl-2 genes have also been determined using RT-PCR. The results indicated that the combination of 1 x 10(-5)M tamoxifen and 1 x 10(-6)M glabridin exhibited estrogenic activities and suppressed cell growth in both cell lines. The relative expressions of ESR1 and bcl-2 genes indicated that the estrogenicity expressed by the combinatory drug was regulated by estrogen receptor a; however, the reduction in cell proliferation was not modulated by bcl-2 anti-apoptotic proteins. These results suggested that the combination of tamoxifen and glabridin has potential to be used as an estrogen replacement drug with a reduced risk of endometrial cancer that has arisen from the intake of tamoxifen.

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Drug Therapy, Combination; Endometrial Neoplasms; Estrogens; Female; Humans; Isoflavones; Phenols; Phytoestrogens; Selective Estrogen Receptor Modulators; Tamoxifen

The risk of death from cardiovascular diseases (CVDs), which are exacerbated by oxidative stress, is higher in diabetic women. This phenomenon has been attributed to the loss of estradiol-vascular protection. Such knowledge led us to examine the potential of glabridin, a phytoestrogen, to substitute estradiol up-regulation of antioxidant enzymes under high glucose conditions. Chronic glucose stress was found to down-regulate catalase (CAT) and paraoxonase 2 (PON2) mRNA expression by 20% and 17%, respectively, and to decrease PON2 activity by 83% in macrophages. Inflammatory conditions had an additive effect on PON2 expression in a time-dependent manner. Treatment with glabridin, under high glucose stress, increased PON2 activity by 60% and up-regulated its mRNA expression by 3.5 fold. Furthermore, glabridin up-regulated the expression of manganese superoxide dismutase (Mn-SOD) and CAT in monocytes. In conclusion, glabridin has the potential of strengthening the antioxidant defense mechanism and may serve as an antiatherogenic agent in diabetes.

Topics: Animals; Antioxidants; Aryldialkylphosphatase; Catalase; Cell Line; Estradiol; Female; Glucose; Glycyrrhiza; Humans; Isoflavones; Macrophages; Mice; Monocytes; Oxidative Stress; Phenols; Phytoestrogens; Plant Roots; Reactive Oxygen Species; Stress, Physiological; Superoxide Dismutase; Up-Regulation

Ovarian steroid hormones, estrogen and progestin, affect the function of the serotonin neural system by inhibiting serotonin re-uptake through allosteric interaction with the serotonin transporter (SERT) in a nongenomic mechanism. Blocking or reducing serotonin re-uptake at the synapse alleviates depression. The aim of this study was to test the effect of compounds of the isoflavan and isoflavene groups, subclasses of the flavonoids family, on serotonin re-uptake and to compare the results with the effect of other known phytoestrogens like genistein and daidzein to relate the activity of these compounds to their structure. The effect of these compounds on the re-uptake of radioactive serotonin was assayed in HEK-293 cells stably expressed the recombinant human serotonin transporter (hSERT). The results demonstrated that the isoflavans glabridin and 4'-O-methylglabridin (4'-OMeG) and the isoflavene glabrene inhibited serotonin re-uptake by 60, 53 and 47%, respectively, at 50 microM, whereas resorcinol, the isoflavan 2'-O-methylglabridin (2'-OMeG), and the isoflavones genistein and daidzein were inactive. The inhibition of serotonin re-uptake is dose dependant with glabridin and estradiol. These results emphasize the importance of the lipophilic part of the isoflavans, as well as the hydroxyl at position 2' on ring B. In conclusion, this study showed that several isoflavans are unique phytoestrogens, which like estradiol, affects the serotonergic system and inhibits serotonin re-uptake and, thus, potentially may be beneficial for mild to moderate depression in pre- and postmenopausal women.

Topics: Carrier Proteins; Cells, Cultured; Depressive Disorder; Dose-Response Relationship, Drug; Estradiol; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Glycyrrhiza; Humans; Isoflavones; Membrane Glycoproteins; Membrane Transport Proteins; Menopause; Molecular Structure; Nerve Tissue Proteins; Phenols; Phytoestrogens; Plant Extracts; Plant Preparations; Resorcinols; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins

Licorice root extract and its major isoflavan, glabridin, exhibited varying degrees of estrogen receptor (ER) agonism in different tissues in vitro and in vivo. Animals fed with licorice extract, compared with estradiol and glabridin, showed an increase in creatine kinase (CK) activity, a known marker for estrogen responsive genes, which was higher than expected from the levels of glabridin in the extract. This led us to test for other components that may contribute to this strong estrogen agonist activity. Results indicated that glabrene and isoliquiritigenin, (2',4',4-three hydroxy chalcone) (ILC) in the licorice extract can bind to the human ER with higher affinity (IC50, 1 and 0.5 microM) than glabridin (IC50, 5 microM). The stimulatory effects of glabrene in vivo were tissue specific and similar to those of estradiol. The effect of increasing concentrations of glabrene and ILC on the growth of breast tumor cell were biphasic. Both showed an ER-dependent growth-promoting effect at low concentrations (10 nM-10 microM), and ER-independent antiproliferative activity at concentrations >15 microM. This is the first study to indicate that glabrene, an isoflavene exerted varying degrees of ER agonism in different tissues.

Topics: Animals; Breast Neoplasms; Cell Division; Estradiol; Estrogen Receptor Modulators; Estrogens, Non-Steroidal; Female; Glycyrrhiza; HeLa Cells; Humans; Isoflavones; Organ Specificity; Phenols; Phytoestrogens; Phytotherapy; Plant Preparations; Rats; Rats, Wistar; Receptors, Estrogen; Tamoxifen; Transcription, Genetic; Tumor Cells, Cultured