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 chemopreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial carcinoma cells. Curcumin caused a rapid accumulation of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and CYP1A1 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 electrophoretic-mobility shift assay (EMSA). Curcumin was able to compete 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 mRNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Curcumin competitively inhibited CYP1A1 activity in DMBA-treated cells and in microsomes isolated from DMBA-treated cells. Curcumin also inhibited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These results suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the AhR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway.
Cellular Defense and Carcinogenesis Section, National Cancer Institute-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, MD 21702-1201, USA. hciolino@mail.ncifcrf.gov
H P
HP
Ciolino
P J
PJ
Daschner
T T
TT
Wang
G C
GC
Yeh
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000493:pharmacokinetics; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002273:Carcinogens / Q000493:pharmacokinetics; D003474:Curcumin / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene; D019363:Cytochrome P-450 CYP1A1; D003474:Curcumin