title: Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes.
abstract: METHODS
  Flavonoids are generally studied in vitro, in isolation, and as unmetabolized precursor structures. However, in the habitual diet, multiple flavonoids are consumed together and found present in the circulation as complex mixtures of metabolites. Using a unique study design, we investigated the potential for singular or additive anti-inflammatory effects of flavonoid metabolites relative to their precursor structures.
  
  
  RESULTS
  Six flavonoids, 14 flavonoid metabolites, and 29 combinations of flavonoids and their metabolites (0.1-10 μM) were screened for their ability to reduce LPS-induced tumor necrosis factor-α (TNF-α) secretion in THP-1 monocytes. One micromolar peonidin-3-glucoside, cyanidin-3-glucoside, and the metabolites isovanillic acid (IVA), IVA-glucuronide, vanillic acid-glucuronide, protocatechuic acid-3-sulfate, and benzoic acid-sulfate significantly reduced TNF-α secretion when in isolation, while there was no effect on TNF-α mRNA expression. Four combinations of metabolites that included 4-hydroxybenzoic acid (4HBA) and/or protocatechuic acid also significantly reduced TNF-α secretion to a greater extent than the precursors or metabolites alone. The effects on LPS-induced IL-1β and IL-10 secretion and mRNA expression were also examined. 4HBA significantly reduced IL-1β secretion but none of the flavonoids or metabolites significantly modified IL-10 secretion.
  
  
  CONCLUSIONS
  This study provides novel evidence suggesting flavonoid bioactivity results from cumulative or additive effects of circulating metabolites.
authors: School of Pharmacy, University of East Anglia, Norwich, UK.|Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK.
authors: Jessica L
authors: JL
authors: di Gesso
authors: School of Pharmacy, University of East Anglia, Norwich, UK.|Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK.
authors: Jason S
authors: JS
authors: Kerr
authors: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors: Qingzhi
authors: Q
authors: Zhang
authors: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors: Saki
authors: S
authors: Raheem
authors: School of Pharmacy, University of East Anglia, Norwich, UK.
authors: Sai Krishna
authors: SK
authors: Yalamanchili
authors: School of Chemistry, University of St. Andrews, St. Andrews, UK.
authors: David
authors: D
authors: O'Hagan
authors: Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK.
authors: Colin D
authors: CD
authors: Kay
authors: School of Pharmacy, University of East Anglia, Norwich, UK.
authors: Maria A
authors: MA
authors: O'Connell
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D009000:Monocytes / Q000187:drug effects*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010226:Parabens / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D062385:Hydroxybenzoates; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010226:Parabens; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C009091:protocatechuic acid; C038193:4-hydroxybenzoic acid
keywords: Cytokine; Inflammation; Metabolism; Phase 2 conjugates; Polyphenol