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Novel bioavailable inhibitors of benzo[a]pyrene‐induced cytochrome P450 1B1 mRNA in human oral epithelial cells
Author(s) -
Walle Thomas,
Walle U. Kristina,
Carter Louisa G.,
Wen Xia
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a262-a
Subject(s) - flavones , cyp1b1 , chemistry , curcumin , cytochrome p450 , bioavailability , biochemistry , polyphenol , pharmacology , quercetin , messenger rna , benzo(a)pyrene , enzyme , carcinogen , antioxidant , biology , gene , chromatography
Previous studies in our laboratory have shown methoxylated flavones to be potential inhibitors of the carcinogen‐bioactivating CYP1A1 and 1B1 enzymes. These findings initiated a more systematic search for compounds capable of inhibiting BaP‐induced CYP1B1 mRNA expression in oral epithelial cells. Initial screening of 18 methoxylated flavones, using Hep G2 cells and the EROD assay, identified 7 inhibitory compounds for further studies in BaP‐treated human oral epithelial SCC‐9 cells. For this purpose we used CYP1B1 mRNA bDNA technology, previously shown to be quantitative and reproducible. Four of the tested compounds, i.e. 3′,4′‐DMF, 7,3′‐DMF, 7,4′‐DMF and 5,7,4′‐trimethoxyflavone, were clear inhibitors of CYP1B1 mRNA expression, with 7,4′‐DMF being the most potent with > 90% inhibition at 25 μM. We also investigated the inhibitory effects of some common dietary nonmethylated polyphenols on CYP1B1 mRNA expression. Curcumin was the most potent of these compounds, followed by quercetin. Epigallocatechin gallate and ellagic acid were without inhibitory effect. The methoxylated flavonoids all showed high cellular uptake in the oral cells, with a 20–80‐fold accumulation factor. In addition, one of the methoxylated flavones, i.e. 7,4′‐DMF, showed remarkable resistance to hepatic metabolism. In summary, we have found potent inhibitors of CYP1B1 mRNA expression in BaP‐treated oral cancer cells. These phytochemicals should be promising candidates as chemopreventive agents against tobacco smoke‐induced oral and maybe other cancers. Supported by DOD (N6311602MD200), NIH (GM55561) and AICR (02A095).