Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells |
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Authors: | Somchaiya Surichan Vasilis P. Androutsopoulos Stavros Sifakis Eleni Koutala Aristidis Tsatsakis Randolph R.J. Arroo Michael R. Boarder |
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Affiliation: | 1. De Montfort University, Leicester School of Pharmacy, Leicester LE1 9BH, UK;2. University of Crete, Centre for Toxicology, Medical School, Heraklion 71003, Greece;3. University of Crete, Department of Gynecology and Obstetrics, Medical School, Heraklion 71003, Greece |
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Abstract: | Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells. Incubation of nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the flavone moiety. Among the three CYP1 isoforms, CYP1A1 exhibited the highest rate of metabolism of nobiletin in recombinant CYP microsomal enzymes. The intracellular CYP1-mediated bioconversion of the flavone was reduced in the presence of the CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and acacetin. In addition nobiletin induced CYP1 enzyme activity, CYP1A1 protein and CYP1B1 mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with nobiletin and CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of CYP1A1 inhibitor. Taken together the data suggests that the dietary flavonoid nobiletin induces its own metabolism and in turn enhances its cytostatic effect in MCF7 breast adenocarcinoma cells, via CYP1A1 and CYP1B1 upregulation. |
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Keywords: | CYP, cytochrome P450 TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin NADPH, β-nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt EROD, 7-ethoxyresorufin-O-deethylase AhR, aryl hydrocarbon receptor ARNT, aryl hydrocarbon nuclear translocator |
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