INDOLE-3-CARBINOL AND DIINDOLYLMETHANE AS ARYL-HYDROCARBON (AH) RECEPTOR AGONISTS AND ANTAGONISTS IN T47D HUMAN BREAST-CANCER CELLS

Indole-3-carbinol (I3C) is a major; component of Brassica vegetables, and diindolylmethane (DIM) is the major acid-catalyzed condensation pr oduce derived from 13C. Both compounds competitively bind to the aryl hydrocarbon (Ah) receptor with relatively low affinity. In Ah-responsi ve T47D human breast cancer cells, I3C and DIM did not induce signific antly CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity or CYP1A1 mRNA levels at concentrations as high as 125 or 31 mu M, respe ctively. A 1 nM concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin ( TCDD) induced EROD activity in these cells, and cotreatment with TCDD plus different concentrations of I3C (1-125 mu M) or DIM (1-31 mu M) r esulted in a > 90% decrease in the induced response at the highest con centration of I3C or DIM. I3C or DIM also partially inhibited (< 50%) induction of CYP1A1 mRNA levels by TCDD and reporter gene activity, us ing an Ah responsive plasmid construct in transient transfection assay s. In T47D cells cotreated with 5 nM [H-3]TCDD alone or in combination with 250 mu M I3C or 31 mu M DIM, there was a 37 and 73% decrease, re spectively, in formation of the nuclear Ah receptor. The more effectiv e inhibition of induced EROD activity by I3C and DIM was due to in vit ro inhibition of enzyme activity. Thus, both I3C and DIM are partial A h receptor antagonists in the T47D human breast cancer cell line.