title: Sustained inhibition of proton-coupled folate transporter by myricetin.
abstract: Myricetin is a flavonoid that has recently been suggested to interfere with the intestinal folate transport system. To examine that possibility, focusing on its sustained inhibitory effect on proton-coupled folate transporter (PCFT), the uptake of folate was examined in Caco-2 cells, in which PCFT is known to be in operation, in the absence of myricetin in the medium during uptake period after preincubation of the cells with the flavonoid (100 μM) for 1 h. This pretreatment induced an extensive and sustained reduction in the carrier-mediated component of folate uptake, which was attributable to a reduction in the maximum transport rate (Vmax). Although the affinity of the transporter for folate was increased at the same time as indicated by a reduction in the Michaelis constant (Km), the change in Km was overwhelmed in extent by that in Vmax. Consistent with the finding, folate transport by human PCFT stably expressed in Madin-Darby canine kidney II cells was reduced in a similar manner with simultaneous reductions in Vmax and Km by myricetin pretreatment. Attention may need to be given for a possibility that such a sustained inhibition of PCFT could potentially be a cause of the malabsorption of folate and also antifolate drugs.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Department of Biopharmaceutics, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors: Mai
authors: M
authors: Furumiya
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors: Takahiro
authors: T
authors: Yamashiro
authors: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors: Katsuhisa
authors: K
authors: Inoue
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors: Chihiro
authors: C
authors: Nishijima
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors: Kinya
authors: K
authors: Ohta
authors: Department of Biopharmaceutics, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors: Yayoi
authors: Y
authors: Hayashi
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan. Electronic address: yuasa@phar.nagoya-cu.ac.jp.
authors: Hiroaki
authors: H
authors: Yuasa
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008954:Models, Biological; D058979:Proton-Coupled Folate Transporter / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D005419:Flavonoids; D058979:Proton-Coupled Folate Transporter; C505058:SLC46A1 protein, human; C040015:myricetin; D005492:Folic Acid
keywords: Caco-2 cells; Drug interaction; Flavonoid; Folate; Methotrexate; Myricetin; Proton-coupled folate transporter; Sustained inhibition