Identification of the Brominated Flame Retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an Androgen Agonist

J Med Chem. 2006 Dec 14;49(25):7366-72. doi: 10.1021/jm060713d.

Abstract

To investigate androgen receptor (AR) activation by exogenous compounds, we used a combination of experimental analysis and theoretical modeling to compare a set of brominated flame retardants (BFRs) to dihydrotestosterone (DHT) with regard to ligand docking, AR binding, and AR activation in human hepatocellular liver carcinoma cells, as well as interacting energy analysis. Modeling of receptor docking was found to be a useful first step in predicting the potential to translocate to the ligand pocket of the receptor, and the computed interaction energy was found to correlate with the observed binding affinity. Flexible alignment studies of the BFR compounds demonstrated that 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (BCH) closely overlap DHT. Combining the theoretical modeling with in vitro ligand-binding and receptor-activation assays, we show that BCH binds to and activates the human AR. The remaining BFRs did not successfully interact with the ligand pocket, were not able to replace a synthetic androgen from the receptor, and failed to activate the receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens*
  • Binding, Competitive
  • Cell Line, Tumor
  • Cyclohexanes / chemistry*
  • Cyclohexanes / toxicity
  • Endocrine Disruptors / chemistry*
  • Endocrine Disruptors / toxicity
  • Flame Retardants / toxicity*
  • Humans
  • Ligands
  • Models, Molecular
  • Receptors, Androgen / chemistry*

Substances

  • Androgens
  • Cyclohexanes
  • Endocrine Disruptors
  • Flame Retardants
  • Ligands
  • Receptors, Androgen
  • 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane