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Curcumin Activates the Aryl Hydrocarbon Receptor yet Significantly Inhibits (-)-Benzo(a)pyrene-7R-trans-7,8-dihydrodiol Bioactivation in Oral Squamous Cell Carcinoma Cells and Oral Mucosa¹

College of Dentistry, Departments of Orthodontics and Oral Maxillofacial Surgery and Pathology [A. L. R., H. W. F., D. A. R., P. P., R. J. R., S. R. M.] and Division of Environmental Health Sciences, School of Public Health [M. A. M., K. A. R.], College of Medicine, Ohio State University, Columbus, Ohio, and The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210 [M. A. M., S. R. M.]

The development of oral squamous cell carcinoma (SCC) shows a positive correlation with the carcinogen exposure that occurs during tobacco and alcohol use. The purpose of this study was to investigate whether the naturally occurring chemopreventive agent, curcumin, modulates expression and function of carcinogen- metabolizing enzymes in human keratinocytes isolated from oral SCC tumors. Dose-response studies demonstrated that curcumin concentrations of 25 µM were cytotoxic for oral SCC cells. Curcumin increased both expression (reverse transcription-PCR analyses) and function (high-performance liquid chromatography determination of ethoxyresorufin metabolism) of cytochrome P-450 (CYP) 1A1 and/or CYP1B1. The aryl hydrocarbon receptor (AhR), which up-regulates a battery of genes associated with carcinogen metabolism, is activated by polycyclic aromatic hydrocarbons such as the tobacco-associated carcinogen benzo(a)pyrene. Electromobility shift assays demonstrated that similar to the established AhR ligand 2,3,7,8,-tetrachlorodibenzo-p-dioxin, curcumin inclusion resulted in AhR nuclear translocation and formation of the transcriptionally active AhR-aryl hydrocarbon receptor nuclear translocator complex. Cellular capacity to bioactivate the tobacco-associated carcinogen (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiodiol was determined by evaluating conversion of the carcinogenic metabolite diol epoxide to stable tetrols via high-performance liquid chromatography. Results of our metabolism studies showed that curcumin significantly inhibited CYP1A1-mediated benzo(a)pyrene diol bioactivation in both oral SCC cells and intact oral mucosa. Because CYP1A1 is one of the primary carcinogen-activating enzymes in oral mucosa, the use of curcumin as an oral cavity chemopreventive agent could have significant clinical impact via its ability to inhibit carcinogen bioactivation.

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