The major cyclic trimeric product of indole-3-carbinol is a strong agonist of the estrogen receptor signaling pathway

Biochemistry. 2000 Feb 8;39(5):910-8. doi: 10.1021/bi9919706.


Indole-3-carbinol (I3C), a component of Brassica vegetables, is under study as a preventive agent of cancers of the breast and other organs. Following ingestion, I3C is converted to a series of oligomeric products that presumably are responsible for the in vivo effects of I3C. We report the effects of the major trimeric product, 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b' ']triindole (CTr), on the estrogen receptor (ER) signaling pathways. Tumor-promoting effects of high doses of I3C may be due to activation of aryl hydrocarbon receptor (AhR)-mediated pathways; therefore, we also examined the effects of CTr on AhR activated processes. We observed that CTr is a strong agonist of ER function. CTr stimulated the proliferation of estrogen-responsive MCF-7 cells to a level similar to that produced by estradiol (E(2)) but did not affect the growth of the estrogen-independent cell line, MDA-MD-231. CTr displaced E(2) in competitive-binding studies and activated ER-binding to an estrogen responsive DNA element in gel mobility shift assays with EC(50)s of about 0.1 microM. CTr activated transcription of an E(2)-responsive endogenous gene and exogenous reporter genes in transfected MCF-7 cells, also with high potency. CTr failed to activate AhR-mediated pathways, consistent with the low-binding affinity of CTr for the AhR reported previously. Comparisons of the conformational characteristics of CTr with other ER ligands indicated a remarkable similarity with tamoxifen, a selective ER antagonist used as a breast cancer therapeutic agent and suggest an excellent fit of CTr into the ligand-binding site of the ER.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cell Division / drug effects
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Indoles / agonists*
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology
  • Mice
  • Models, Molecular
  • Receptors, Aryl Hydrocarbon / physiology
  • Receptors, Estrogen / agonists*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism
  • Receptors, Estrogen / physiology*
  • Signal Transduction* / drug effects
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / chemistry
  • Transcriptional Activation / drug effects
  • Tumor Cells, Cultured


  • Indoles
  • Receptors, Aryl Hydrocarbon
  • Receptors, Estrogen
  • Tamoxifen
  • afimoxifene
  • 5,6,11,12,17,18-hexahydrocyclononatriindole
  • indole-3-carbinol