title: Functional Identification of Plasma Membrane Monoamine Transporter (PMAT/SLC29A4) as an Atenolol Transporter Sensitive to Flavonoids Contained in Apple Juice.
abstract: The intestinal absorption of atenolol has recently been reported to be reduced by simultaneous ingestion of fruit juices, such as apple juice. This finding implies a possibility that an unidentified carrier-mediated transport system, which could be interfered by some components of those juices, might be involved in atenolol absorption. In an attempt to explore that possibility, we successfully identified plasma membrane monoamine transporter (PMAT/SLC29A4) as a transporter that can operate for cellular atenolol uptake in the intestine, using Madin-Darby canine kidney II cells stably expressing PMAT. The specific uptake of atenolol by PMAT was greatest at around pH 6.0 and decreased with an increase in pH. At pH 6.0, the PMAT-specific uptake of atenolol was saturable with a Michaelis constant of 0.907 mM. Moreover, PMAT-specific atenolol uptake was extensively inhibited by phloretin and quercetin, which are the major flavonoids contained in apple juice, with the half maximal inhibitory concentrations of 33.3 and 116.3 μM, respectively. PMAT-specific atenolol uptake was also inhibited by several ß-blockers, suggesting that they may also be recognized and transported by PMAT. These results suggest that PMAT is an atenolol transporter that may be involved in intestinal atenolol absorption and sensitive to flavonoids contained in apple juice.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Mimura
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan. Electronic address: yasujima@phar.nagoya-cu.ac.jp.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yasujima
authors.affiliation: College of Pharmacy, Kinjo Gakuin University, Moriyama-ku, Nagoya, 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, Hachioji, Tokyo, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
mesh_terms: D000818:Animals; D001262:Atenolol / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D033705:Equilibrative Nucleoside Transport Proteins / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D000067030:Fruit and Vegetable Juices / Q000032:analysis*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007668:Kidney / Q000378:metabolism; D027845:Malus / Q000737:chemistry*; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D033705:Equilibrative Nucleoside Transport Proteins; D005419:Flavonoids; C495988:SLC29A4 protein, human; D001262:Atenolol
keywords: atenolol; flavonoid; fruit juice; intestinal absorption