Novel methoxylated flavone inhibitors of cytochrome P450 1B1 in SCC-9 human oral cancer cells

J Pharm Pharmacol. 2007 Jun;59(6):857-62. doi: 10.1211/jpp.59.6.0012.

Abstract

Dietary polyphenols, including flavonoids, have been implied to have cancer preventive properties. Suggested mechanisms include inhibition of carcinogen-activating cytochrome P450 (CYP) transcription and activities. These studies have focused mainly on CYP1A1. However, CYP1B1 has recently been shown to be of particular importance in smoking-induced oral and oesophageal cancer. Previous observations in our laboratory demonstrated that methoxylated flavonoids may be effective inhibitors of CYP1A1 transcription and activity as well as being orally bioavailable. In this study, an initial screening of 19 methoxylated flavones, using the ethoxyresorufin de-ethylation assay in human oral squamous cell carcinoma SCC-9 cells pretreated with 1 microM benzo[a]pyrene, identified six strongly inhibitory compounds for further studies. The effect of these flavones on CYP1B1 mRNA expression was measured with quantitative branched DNA methodology. Four of the compounds--3',4'-dimethoxyflavone and 5,7,4'-trimethoxyflavone and, in particular, 7,3'-dimethoxyflavone and 7,4'-dimethoxyflavone--were potent inhibitors of CYP1B1 mRNA expression. Two of the more common unmethylated polyphenols--curcumin and quercetin--were also potent inhibitors. Whereas most unmethylated polyphenols, such as curcumin and quercetin, have very poor bioavailability, the high metabolic stability of the methoxylated flavones studied here suggests that these CYP1B1 inhibitors may also be effective in-vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Anticarcinogenic Agents / pharmacology*
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Benzo(a)pyrene / pharmacology
  • Carcinoma, Squamous Cell
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1B1
  • Flavones / pharmacology*
  • Flavonoids / pharmacology
  • Humans
  • Mouth Neoplasms
  • Phenols / pharmacology
  • Polyphenols
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / biosynthesis

Substances

  • Anticarcinogenic Agents
  • Flavones
  • Flavonoids
  • Phenols
  • Polyphenols
  • RNA, Messenger
  • Benzo(a)pyrene
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1