title: Kinetic and time-dependent features of sustained inhibitory effect of myricetin on folate transport by proton-coupled folate transporter.
abstract: Myricetin is a flavonoid that has recently been suggested to induce sustained inhibition of proton-coupled folate transporter (PCFT/SLC46A1), which operates for intestinal folate uptake. The present study was conducted to characterize the inhibitory effect in more detail, using human PCFT stably expressed in Madin-Darby canine kidney II cells, to gain information to cope with problems potentially arising from that. The kinetics of saturable folate transport was first assessed in the absence of myricetin in the cells pretreated with the flavonoid for 60 min. The pretreatment induced PCFT inhibition in a manner dependent on the concentration of myricetin, where the maximum transport rate was reduced by 35.5% and 83.1%, respectively, at its concentrations of 20 μM and 50 μM. The inhibitory effect was, however, less extensive at lower folate concentrations, because the Michaelis constant was also reduced similarly in a manner dependent on myricetin concentration. The inhibition was induced depending on the time of pretreatment and, after removal of myricetin (50 μM) upon the manifestation of an extensive inhibition at 60 min, reversed almost completely in 90 min. This rather short time required for recovery may suggest that the sustained inhibition of PCFT is of a reversible type.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamashiro
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Biopharmaceutics, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Furumiya
authors.affiliation: Department of Biopharmaceutics, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan. Electronic address: yuasa@phar.nagoya-cu.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058979:Proton-Coupled Folate Transporter / Q000037:antagonists & inhibitors*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D005419:Flavonoids; D005493:Folic Acid Antagonists; D047428:Protein Kinase Inhibitors; D058979:Proton-Coupled Folate Transporter; C505058:SLC46A1 protein, human; C040015:myricetin; D005492:Folic Acid; D000077191:Wortmannin
keywords: Drug interaction; Flavonoid; Folate; Intestinal transport; Myricetin; Proton-coupled folate transporter; Sustained inhibition