We have investigated the interaction of plant-derived dietary compounds with the aryl hydrocarbon receptor(AhR)pathway in MCF-7 human breast cancer cells. The AhR is a cytosolic protein which mediates signal transduction in response to aryl hydrocarbons, a class of potent carcinogens. The AhR causes the transcriptional activation of a number of genes,i.e.CYP1A1. CYP1A1 encodes the enzyme cytochrome P4501A1, which causes the metabolic activation of aryl hydrocarbons, which interact with DNA and lead to carcinogenic mutations. The known ligands of the AhR are man-made; thus, the normal function of the AhR pathway is unknown. We have examined the effect of polyphenolic plant-derived compounds on the activation of AhR and the activity of cytochrome P4501A1, as well as the interaction of metabolites of the aryl hydrocarbon and mammary carcinogen dimethylbenzanthracene DMBA) with DNA. Curcumin is a polyphenolic compound found in the spice tumeric, extensively used in Indian cuisine and in traditional medicine, and recent studies have shown that it is an effective chemopreventive agent in animal models of cancer. We found that curcumin inhibits the formation of DMBA-DNA adducts and protects the cells from DMBA-induced cytotoxicity. Curcumin inhibits cytochrome P4501A1 enzymatic activity induced by DMBA in a competitive fashion. Surprisingly, curcumin also caused an increase in enzymatic activity, and induced mRNA of CYP1A1 in the cells. Electromobility shift assays and ligand binding assays demonstrated that curcumin is a ligand of the AhR. These results indicate that curcumin is a natural ligand and substrate of the AhR pathway. Similar results have been obtained with some of the flavonoids, polyphenolic compounds widely distributed in edible plants. The AhR pathway, therefore, may function in the metabolism of dietary compounds, and the chemopreventive activity of these dietary compounds may be the fortuitous result of a shared metabolic pathway with carcinogens.
