Identification of novel bioactive metabolites of 5-demethylnobiletin in mice

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Abstract
Scope Biotransformation of dietary components is important for their in vivo biological activities after oral ingestion. Herein, we investigated biotransformation of 5-demethylnobiletin (a polymethoxyflavone found in citrus fruits) in mice, and its implication in the inhibition of human colon cancer cells. Methods and results Urine samples were collected from mice fed with 5-demethylnobiletin (1) and analyzed by LC-ESI-MS and HPLC coupled with an electrochemical detector. Three major metabolites were identified as 5,3′-didemethylnobiletin (2), 5,4′-didemethylnobiletin (3), and 5,3′,4′-tridemethylnobiletin (4) by comparing their ESI-MS and HPLC profiles with those of authentic standards synthesized by a multistep route. Cell viability assay in human colon cancer cells demonstrated that all three metabolites of 5-demethylnobiletin, especially 5,3′-didemethylnobiletin (2), showed much stronger inhibitory effects on cancer cell growth than 5-demethylnobiletin. For example, metabolites (2–4) showed IC50 of 0.12, 5.5, and 4.2 μM in SW620 cells, respectively, while 5-demethylnobiletin at 10 μM only caused 37% inhibition after 72 h of treatment. Conclusion Three novel metabolites were identified in mice after oral administration of 5-demethylniobiletin. These metabolites exhibited strong inhibitory effects against human colon cancer cells. Our results provide a first report on these bioactive metabolites and warrant further investigation on their molecular mechanism of actions.
Funding Information
  • NIH (CA139174)
  • AICR
  • USDA Special

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