The natural estrogenic compound diarylheptanoid (D3): in vitro mechanisms of action and in vivo uterine responses via estrogen receptor α

Wipawee Winuthayanon; Pawinee Piyachaturawat; Apichart Suksamrarn; Katherine A Burns; Yukitomo Arao; Sylvia C Hewitt; Lars C Pedersen; Kenneth S Korach

doi:10.1289/ehp.1206122

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The natural estrogenic compound diarylheptanoid (D3): in vitro mechanisms of action and in vivo uterine responses via estrogen receptor α

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The natural estrogenic compound diarylheptanoid (D3): in vitro mechanisms of action and in vivo uterine responses via estrogen receptor α

Wipawee Winuthayanon, Pawinee Piyachaturawat, Apichart Suksamrarn, Katherine A Burns, Yukitomo Arao, Sylvia C Hewitt, Lars C Pedersen and Kenneth S Korach

Environmental health perspectives, Vol.121(4), pp.433-439

04/2013

DOI: https://doi.org/10.1289/ehp.1206122

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https://hdl.handle.net/2376/112770

PMCID: PMC3620745

PMID: 23552522

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https://doi.org/10.1289/ehp.1206122View

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Abstract

Cell Line

Estradiol - metabolism

Ovariectomy

Humans

Uterus - drug effects

Environmental Exposure

Receptors, Progesterone - metabolism

Microscopy, Confocal

Diarylheptanoids - metabolism

Plant Extracts - metabolism

Animals

Estrogen Receptor alpha - genetics

Rhizome - chemistry

Polymerase Chain Reaction

Estrogen Receptor alpha - metabolism

Female

Phytoestrogens - metabolism

Mice

Curcuma - chemistry

Diarylheptanoid (D3) isolated from the medicinal plant, Curcuma comosa, has estrogenic activity. We aimed to elucidate the mechanism(s) of D3 action and compare it with that of 17β-estradiol (E2) using both in vitro and in vivo uterine models. We used human uterine (Ishikawa) cells to determine the estrogenic action of D3 on the activation and nuclear translocation of estrogen receptor α (ERα). In addition, we further characterized the uterine response to D3 treatment in vivo. D3 activated an estrogen responsive element (ERE) luciferase reporter through ERα, and molecular modeling suggested that D3 could be accommodated in the ERα binding pocket. Using modified ERα to assay ligand-dependent nuclear translocation, we observed D3-dependent ERα interaction and translocation. In mouse uteri, early- and late-phase estrogen-regulated gene responses were increased in D3-treated ovariectomized wild-type animals, in a manner similar to that of E2; no response was seen in ERα knockout animals. We observed a divergence in estrogen responses after D3 treatment: D3 induced robust DNA synthesis in uterine epithelial cells, linked to an increase in cell-cycle-related genes; however, no increase in uterine weight was observed 24 hr after treatment. D3 also affected uterine progesterone receptor expression patterns similar to E2. When D3 and E2 were administered together, we observed no additive or antagonistic effects of D3 on E2. Our findings suggest that D3 is a weak estrogenic agonist compound. D3 is a weakly acting phytoestrogen that mimics the mitogenic responses produced by E2 in an ERα-dependent manner, but it is unable to increase uterine weight or enhance or antagonize the effects of estrogen.

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Title: The natural estrogenic compound diarylheptanoid (D3): in vitro mechanisms of action and in vivo uterine responses via estrogen receptor α
Creators: Wipawee Winuthayanon - Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA
Pawinee Piyachaturawat
Apichart Suksamrarn
Katherine A Burns
Yukitomo Arao
Sylvia C Hewitt
Lars C Pedersen
Kenneth S Korach
Publication Details: Environmental health perspectives, Vol.121(4), pp.433-439
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: Z01-ES70065 / NIEHS NIH HHS Z01-ES102645 / NIEHS NIH HHS Z01 ES070065 / Intramural NIH HHS
Identifiers: 99900548276001842
Language: English
Resource Type: Journal article