title: Flavonoid metabolites transport across a human BBB model.
abstract: This study aimed to evaluate the transmembrane transport of different flavonoids (flavan-3-ols, anthocyanins and flavonols) and some of their metabolites (methylated and conjugated with glucuronic acid) across hCMEC/D3 cells (a blood-brain barrier (BBB) model). Further metabolism of the tested compounds was assayed and their transport modulated in an attempt to elucidate the mechanisms behind this process. The transport across hCMEC/D3 cells was monitored in basolateral media at 1, 3 and 18 h by HPLC-DAD/MS. All the flavonoids and their metabolites were transported across hCMEC/D3 cells in a time-dependent manner. In general, the metabolites showed higher transport efficiency than the native flavonoid. No further biotransformation of the metabolites was found as consequence of cellular metabolism. Anthocyanins and their metabolites crossed this BBB cell model in a lipophilicity-dependent way. Quercetin transport was influenced by phosphatase modulators, suggesting a phosphorylation/dephosphorylation regulation mechanism. Overall, this work suggests that flavonoids are capable of crossing the BBB and reaching the central nervous system.
authors.affiliation: Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; Chemistry Investigation Centre (CIQ), Department of Chemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; Faculty of Nutrition and Food Sciences, University of Porto, 4200-465 Porto, Portugal. Electronic address: anafaria@med.up.pt.
authors.forename: Ana
authors.initials: A
authors.lastname: Faria
authors.forename: Manuela
authors.initials: M
authors.lastname: Meireles
authors.forename: Iva
authors.initials: I
authors.lastname: Fernandes
authors.forename: Celestino
authors.initials: C
authors.lastname: Santos-Buelga
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalez-Manzano
authors.forename: Montserrat
authors.initials: M
authors.lastname: Dueñas
authors.forename: Victor
authors.initials: V
authors.lastname: de Freitas
authors.forename: Nuno
authors.initials: N
authors.lastname: Mateus
authors.forename: Conceição
authors.initials: C
authors.lastname: Calhau
mesh_terms: D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D005419:Flavonoids / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D005419:Flavonoids; D010744:Phosphoric Monoester Hydrolases
keywords: ALP; Anthocyanins; BBB; Blood-brain barrier; CNS; Flavanoids; Flavonoids metabolites; RBE4; Transport; alkaline phosphatase; blood–brain barrier; central nervous system; hCMEC/D3; hCMEC/D3 cells; human brain endothelial cell; rat brain endothelial cell