EFFECT OF CURCUMIN ON THE ARYL-HYDROCARBON RECEPTOR AND CYTOCHROME-P450 1A1 IN MCF-7 HUMAN BREAST-CARCINOMA CELLS

We examined the interaction of curcumin,a dietary constituent and chem opreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial car cinoma cells. Curcumin caused a rapid accumulation.of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and C YP1A1 monooxygenase activity increased as measured by ethoxyresorufin- O-deethylation. Curcumin activated the DNA-binding capacity of the AhR for the xenobiotic responsive element of CYP1A1 as measured by the el ectrophoretic-mobility shift assay (EMSA). Curcumin was able to compet e with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the AhR in isolated MCF-7 cytosol, indicating that it interacts directly with the receptor. Although curcumin could activate the AhR on its own, it partially inhibited the activation of AhR, as measured by EMSA, and partially decreased the accumulation of CYP1A1 m RNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Cu rcumin competitively inhibited CYP1A1 activity in DMBA-treated cells a nd in microsomes isolated from DMBA-treated cells. Curcumin also inhib ited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These resu lts suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the A hR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway. (C) 1998 Elsevier Science Inc.