title: 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 mucosa.
abstract: 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 >or=25 micro M 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.
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004268:DNA-Binding Proteins; D004101:Dihydroxydihydrobenzopyrenes / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C497396:ARNT protein, human; D000970:Antineoplastic Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D004101:Dihydroxydihydrobenzopyrenes; D010078:Oxazines; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; C017228:benzo(a)pyrene 7,8-dihydrodiol; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C014180:resorufin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D005978:Glutathione; D003474:Curcumin