phytoestrogens and 8-isopentenylnaringenin

Bioassay-guided fractionation of a methanolic extract of a Thai crude drug, derived from heartwood of Anaxagorea luzonensis A. Gray (Annonaceae), resulted in the isolation of 8-isopentenylnaringenin (1) as an estrogen agonist with a activity of about an order of magnitude greater than genistein. Various flavonoids possessing isopentenyl side chains in the A-ring have been prepared and evaluated for their ability to bind estrogen receptor. In addition, enantiomers of 1 were separated and the respective enantiomers were assayed. These studies have demonstrated that the presence of an 8-isopentenyl group is an important factor for binding. Flavones, flavanones and flavonols having an isopentenyl substituent at C-8 exhibited an appreciable affinity for estrogen receptor. Conversely, isoflavones possessing an 8-isopentenyl substituent at C-8 did not show this activity. Movement of the isopentenyl group from position 8 to 6 resulted in loss of the activity. No significant difference was observed between 2(S)- and 2(R)-enantiomers of 1 in their binding affinity. Prenylflavonoids are reported to possess a wide range of biological activities; however, estrogenic activity has not been described.

Topics: Breast Neoplasms; Cell Division; Estradiol; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Medicine, East Asian Traditional; Molecular Structure; Phytoestrogens; Plant Extracts; Plant Preparations; Plants, Medicinal; Receptors, Estradiol; Stereoisomerism; Structure-Activity Relationship; Thailand; Tumor Cells, Cultured

In order to examine whether 8-isopentenylnaringenin (1), which has been proven to possess estrogen agonist activity in in vitro tests, also produces in vivo estrogenic properties, the effects of 1 on uterus and on bone metabolism were determined in ovariectomized rats. Rats were ovariectomized and treated with 1 at 30 mg/kg/day subcutaneously for two weeks or 17 beta-estradiol at 0.01 mg/kg/day subcutaneously for two weeks. Ovariectomy resulted in an increase in urinary excretion of bone resorption markers (hydroxyproline, pyridinoline and deoxypyridinoline) and a decrease in bone mineral density of the proximal tibia as well as reduced uterine weight. Treatment with 1 or 17 beta-estradiol completely suppressed these ovariectomy-induced bone and uterine changes in a qualitatively similar manner. These results demonstrate that 1 acts as an estrogen agonist in the uterus as well as in bone in vivo.

Topics: Amino Acids; Animals; Biomarkers; Bone Density; Bone Resorption; Estradiol; Estrogens, Non-Steroidal; Female; Hydroxyproline; Isoflavones; Organ Size; Ovariectomy; Phytoestrogens; Plant Preparations; Rats; Rats, Sprague-Dawley; Tibia; Uterus