Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms

Wipawee Winuthayanon; Pawinee Piyachaturawat; Apichart Suksamrarn; Mathurose Ponglikitmongkol; Yukitomo Arao; Sylvia C Hewitt; Kenneth S Korach

doi:10.1289/ehp.0900613

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Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms

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Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms

Wipawee Winuthayanon, Pawinee Piyachaturawat, Apichart Suksamrarn, Mathurose Ponglikitmongkol, Yukitomo Arao, Sylvia C Hewitt and Kenneth S Korach

Environmental health perspectives, Vol.117(7), pp.1155-1161

07/2009

DOI: https://doi.org/10.1289/ehp.0900613

Handle:

https://hdl.handle.net/2376/110953

PMCID: PMC2717144

PMID: 19654927

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Abstract

Plant Extracts - chemistry

Transcription, Genetic - drug effects

Diarylheptanoids - chemistry

Estradiol - analogs & derivatives

Plant Extracts - pharmacology

Humans

Phytoestrogens - chemistry

Uterus - drug effects

Phytoestrogens - isolation & purification

Estrogen Receptor beta - genetics

Mice, Mutant Strains

Polymerase Chain Reaction

Female

Estrogen Receptor alpha - physiology

Estrogen Receptor beta - antagonists & inhibitors

Estradiol - pharmacology

Phytoestrogens - pharmacology

Estrogen Receptor beta - physiology

Plants, Medicinal - chemistry

Receptors, Estrogen - genetics

Diarylheptanoids - pharmacology

Ovariectomy

Mice, Inbred C57BL

Receptors, Estrogen - antagonists & inhibitors

Estrogen Receptor alpha - antagonists & inhibitors

Plant Extracts - isolation & purification

Mice, Knockout

Organ Size - drug effects

Animals

Estrogen Receptor alpha - genetics

Diarylheptanoids - isolation & purification

Cell Line, Tumor

Uterus - cytology

Cell Proliferation - drug effects

Mice

Transcription, Genetic - genetics

Curcuma - chemistry

Receptors, Estrogen - physiology

Diarylheptanoids isolated from Curcuma comosa Roxb. have been recently identified as phyto estrogens. However, the mechanism underlying their actions has not yet been identified. We characterized the estrogenic activity of three active naturally occurring diarylheptanoids both in vitro and in vivo. We characterized mechanisms of estrogenic action of the diarylheptanoids (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D1), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (D3) by using a real-time polymerase chain reaction assay, a mammalian transfection model, and a uterotrophic assay in mice. All diarylheptanoids up-regulated estrogen-responsive genes in estrogen-responsive breast cancer cells (MCF-7). In HepG2 cells transfected with estrogen receptor (ER) beta or different ERalpha functional receptor mutants and the Vit-ERE-TATA-Luc reporter gene, all diarylheptanoids induced transcription through a ligand-dependent human ERalpha-ERE-driven pathway, which was abolished with ICI 182,780 (ER antagonist), whereas only D2 was active with ERbeta. An ERalpha mutant lacking the functional AF2 (activation function 2) region was not responsive to 17beta-estradiol (E(2)) or to any of the diarylheptanoids, whereas ERalpha lacking the AF1 domain exhibited wild-type-like activity. D3 markedly increased uterine weight and proliferation of the uterine epithelium in ovariectomized mice, whereas D1 and D2 were inactive. D3, like E(2), up-regulated lactoferrin (Ltf) gene expression. The responses to D3 in the uterus were inhibited by ICI 182,780. In addition, D3 stimulated both classical (Aqp5) and nonclassical (Cdkn1a) ER-mediated gene regulation. The results suggest that the D3 diarylheptanoid is an agonist for ER both in vitro and in vivo, and its biological action is ERalpha selective, specifically requiring AF2 function, and involves direct binding via ER as well as ERE-independent gene regulation.

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Title: Diarylheptanoid phytoestrogens isolated from the medicinal plant Curcuma comosa: biologic actions in vitro and in vivo indicate estrogen receptor-dependent mechanisms
Creators: Wipawee Winuthayanon - Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
Pawinee Piyachaturawat
Apichart Suksamrarn
Mathurose Ponglikitmongkol
Yukitomo Arao
Sylvia C Hewitt
Kenneth S Korach
Publication Details: Environmental health perspectives, Vol.117(7), pp.1155-1161
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: Intramural NIH HHS
Identifiers: 99900547273701842
Language: English
Resource Type: Journal article