title: Synchronized activity of organic cation transporter 3 (Oct3/Slc22a3) and multidrug and toxin extrusion 1 (Mate1/Slc47a1) transporter in transplacental passage of MPP+ in rat.
abstract: The aim of the present study was to investigate the expression, localization, and function of organic cation transporter 3 (Oct3, Slc22a3) and multidrug and toxin extrusion protein 1 (Mate1, Slc47a1) in the rat placenta. Using qRT-PCR and Western  blotting techniques, we demonstrated abundant Oct3 and Mate1 mRNA and protein expression achieving significantly higher levels than those in the maternal kidney (positive control). Immunohistochemical visualization revealed preferential localization of Oct3 on the basolateral, i.e., fetus facing side of the placenta, whereas Mate1 positivity was located in the labyrinth area predominantly on the apical, i.e., maternal side of the placenta. To investigate the role of these transporters in the transplacental  pharmacokinetics, the in situ method of dually perfused rat term placenta was employed in open- and closed-circuit arrangements; 1-methyl-4-phenylpyridinium (MPP(+)) was used as a model substrate of both Oct3 and Mate1. We provide evidence that Oct3 and Mate1 cause considerable asymmetry between maternal-to-fetal and fetal-to-maternal transport of MPP(+) in favor of fetomaternal direction. Using closed-circuit experimental setup, we further describe the capacity of Oct3 and Mate1 to transport their substrate from fetus to mother even against a concentration gradient. We conclude that Oct3, in a concentration-dependent manner, takes up MPP(+) from the fetal circulation into the placenta, whereas Mate1, on the other side of the barrier, is responsible for MPP(+) efflux from placenta to the maternal circulation. These two transport proteins, thus, form an efficient transplacental eliminatory pathway and play an important role in fetal protection and detoxication.
authors.affiliation: Department of Pharmacology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Davoud
authors.initials: D
authors.lastname: Ahmadimoghaddam
authors.forename: Jakub
authors.initials: J
authors.lastname: Hofman
authors.forename: Lenka
authors.initials: L
authors.lastname: Zemankova
authors.forename: Petr
authors.initials: P
authors.lastname: Nachtigal
authors.forename: Eva
authors.initials: E
authors.lastname: Dolezelova
authors.forename: Lukas
authors.initials: L
authors.lastname: Cerveny
authors.forename: Martina
authors.initials: M
authors.lastname: Ceckova
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics*; D000818:Animals; D017920:Antiporters / Q000502:physiology*; D002460:Cell Line; D005260:Female; D007150:Immunohistochemistry; D008431:Maternal-Fetal Exchange; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099254:Organic Cation Transporter 3
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D017920:Antiporters; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3; C515734:Slc47a1 protein, rat