title: Identification of novel bioactive metabolites of 5-demethylnobiletin in mice.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA, USA.
authors.forename: Jinkai
authors.initials: J
authors.lastname: Zheng
authors.forename: Mingyue
authors.initials: M
authors.lastname: Song
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.forename: Peiju
authors.initials: P
authors.lastname: Qiu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Guo
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Zhong
authors.forename: Shiming
authors.initials: S
authors.lastname: Li
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D002957:Citrus / Q000737:chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D047309:Flavones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D047309:Flavones; D010936:Plant Extracts; C509545:5-O-demethylnobiletin
keywords: 5,3′-Didemethylnobiletin; 5-Demethylnobiletin; Cancer inhibition; Metabolites