After the Women's Health Initiative found that the risks of hormone therapy outweighed the benefits, a need for alternative drugs to treat menopausal symptoms has emerged. We explored the possibility that botanical agents used in Traditional Chinese Medicine for menopausal symptoms contain ERbeta-selective estrogens. We previously reported that an extract containing 22 herbs, MF101 has ERbeta-selective properties. In this study we isolated liquiritigenin, the most active estrogenic compound from the root of Glycyrrhizae uralensis Fisch, which is one of the plants found in MF101. Liquiritigenin activated multiple ER regulatory elements and native target genes with ERbeta but not ERalpha. The ERbeta-selectivity of liquiritigenin was due to the selective recruitment of the coactivator steroid receptor coactivator-2 to target genes. In a mouse xenograph model, liquiritigenin did not stimulate uterine size or tumorigenesis of MCF-7 breast cancer cells. Our results demonstrate that some plants contain highly selective estrogens for ERbeta.
ABSTRACT:Liquiritigenin [2,3-dihydro-7-hydroxy-2-(4-hydroxyphenyl)-(S)-4H-1-benzopyran-4-one] is one of the major active compounds of MF101, an herbal extract currently in clinical trials for the treatment of hot flashes and night sweats in postmenopausal women. MF101 is a selective estrogen receptor  agonist but does not activate the estrogen receptor ␣. Incubation with pooled human liver microsomes yielded a single metabolite. Its structure was elucidated using tandem mass spectrometry in combination with analysis of the fragmentation patterns. The metabolite resulted from the loss of two hydrogens and rearrangement to the stable 7,4-dihydroxyflavone. The structure was also confirmed by comparison with authentic standard material. Maximum apparent reaction velocity (V max ) and Michaelis-Menten constant (K m ) for the formation of 7,4-dihydroxyflavone were 32.5 nmol/g protein/min and 128 M, respectively. After correction for protein binding (free fraction ؍ 0.84), the apparent intrinsic clearance (CL int ) for 7,4-dihydroxyflavone formation was 0.3 ml/g/min. Liquiritigenin was almost exclusively metabolized by CYP3A enzymes. Comparison of liquiritigenin metabolism in human liver microsomes isolated from 16 individuals showed 9.5-fold variability in metabolite formation (3.4-32.2 nmol/g protein/min). An estrogen receptor luciferase assay indicated that the metabolite was a 3-fold more potent activator of the estrogen receptor  than the parent compound and did not activate the estrogen receptor ␣.Flavonoids have been recognized for their anticarcinogenic, antioxidant, and anti-inflammatory properties. Over 4000 flavonoids have been isolated and identified from many types of fruits, vegetables, and herbs. Chemically, they can be categorized into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones. Liquiritigenin is the 7,4Ј-dihydroxyflavanone and is found most notably in licorice. Licorice is one of the oldest and most commonly used Chinese herbal medicines and is used in many different medications. Usually, it is found concomitantly with liquiritin, which is the 4Ј-glycoside of liquiritigenin (Wang and Nixon, 2001;Moon et al., 2006).Liquiritigenin is an active ingredient of MF101, an herbal extract currently in clinical trials for the relief of postmenopausal symptoms in women. MF101 is an ethanol/aqueous extract of 22 herbal species used in traditional Chinese medicine (Cvoro et al., 2007). Because of its effects on the estrogen receptor, MF101 belongs to a class of compounds referred to as selective estrogen receptor modulators. Most clinically used estrogen receptor agonists or antagonists similarly affect both estrogen receptor ␣ and . Selective estrogen receptor modulators discriminate between estrogen receptor ␣ and  (Riggs and Hartmann, 2003). MF101 is a potent agonist of estrogen receptor  but does not activate estrogen receptor ␣ (Cvoro et al., 2007). Most importantly, it is not implicated in tumor formation as a result of estrogen receptor ␣ activation (Cvoro e...
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