Terpenoids found in the Umbelliferae family act as agonists/antagonists for ERα and ERβ: Differential transcription activity between ferutinine-liganded ERα and ERβ

Phytoestrogens are assumed to affect the endocrine system of animal species similarly to other man-made endocrine disrupters and to exert their effects through estrogen receptors, specifically ERα and ERβ. However, these molecular mechanisms are not fully understood. In this study, 19 phytochemicals were surveyed for agonist and antagonist activities of ERα and ERβ using an ERE-luciferase reporter assay. The results showed that ferutinine is an agonist for ERα and an agonist/antagonist for ERβ, tschimgine is an agonist for both ERα and ERβ, and tschimganidine is an agonist for only ERα. Ferutinine and tschimganidine are sesquiterpenoids, and tschimgine is a monoterpenoid derived from the Umbelliferae family. A competitive binding assay showed that ferutinine has higher binding affinities than tamoxifen for both ERs. Cotransfections of coactivators such as SRC-1, TIF2, AIB1, and TRAP220 in 293T cells and use of the luciferase assay revealed that TRAP220 failed to enhance the transcription mediated by ERβ in the presence of ferutinine. Moreover, a GST pull-down assay showed that TRAP220 marginally bound to ERβ ligand binding domain in the presence of ferutinine. These results suggest that the conformation of ferutinine-liganded ERβ is difficult for TRAP220 to recognize. Taken together, this suggests that some terpenoids can modulate estrogen signaling as ER subtype-selective phytoestrogens similar to SERMs (selective estrogen receptor modulators).