Elsevier

Biochemical Pharmacology

Volume 56, Issue 2, 15 July 1998, Pages 197-206
Biochemical Pharmacology

Original Articles
Effect of Curcumin on the Aryl Hydrocarbon Receptor and Cytochrome P450 1A1 in MCF-7 Human Breast Carcinoma Cells

https://doi.org/10.1016/S0006-2952(98)00143-9Get rights and content

Abstract

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.

Section snippets

Materials

RPMI 1640, glutamine, fetal bovine serum, trypsin/EDTA, PBS, and TBE buffer were obtained from BioFluids. Curcumin, DMBA, HEPES, EDTA, dithiothreitol (DTT), glycerol, poly(dI-dC), sodium molybdate, ethyoxyresorufin, resorufin, Tris–HCl, sulforhodamine, salmon sperm, and protease inhibitors were from the Sigma Chemical Co. α-Naphthoflavone was from Indofine. [32P]CTP and [32P]dATP were from DuPont/NEN. The RT–PCR kit was from Stratagene. TBE gels, TBE running buffer, and high-density sample

Effect of Curcumin on CYP1A1 mRNA

We measured CYP1A1 mRNA in MCF-7 cells treated with DMBA in the presence or absence of curcumin using RT–PCR. Treatment of cells with 1 μM of DMBA for 24 hr caused a 15-fold increase in CYP1A1 mRNA accumulation (Fig. 1). Curcumin at 5 μM of partially inhibited the DMBA-induced increase. Surprisingly, treatment with curcumin alone caused an approximately six-fold increase in CYP1A1 mRNA. We therefore examined the effect of curcumin in the absence of other treatment on CYP1A1 mRNA. Treatment

Discussion

We examined the effect of curcumin on the AhR and the major carcinogen-activating enzyme in MCF-7 cells, CYP1A1 [25]. Using RT–PCR, we found that the mammary carcinogen DMBA caused an increase in CYP1A1 mRNA in MCF-7 cells that was partially antagonized by simultaneous treatment of the cells with curcumin (Fig. 1). It has been shown previously that the ability of the liganded AhR to induce transcription of genes depends on its ability to bind enhancer sequences, called the XRE, flanking the

Acknowledgements

The authors would like to thank Dr. Miriam Poirier for her critical reading of the manuscript.

References (32)

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