title: Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells.
abstract: The mechanism that removes homovanillic acid (HVA), an end metabolite of dopamine, from the brain is still poorly understood. The purpose of this study is to identify and characterize the brain-to-blood HVA efflux transporter at the rat blood-brain barrier (BBB). Using the Brain Efflux Index method, the apparent in vivo efflux rate constant of [3H]HVA from the brain, k(eff), was determined to be 1.69 x 10(-2) minute(-1). This elimination was significantly inhibited by para-aminohippuric acid (PAH), benzylpenicillin, indoxyl sulfate, and cimetidine, suggesting the involvement of rat organic anion transporter 3 (rOAT3). rOAT3-expressing oocytes exhibited [3H]HVA uptake (K(m) = 274 micromol/L), which was inhibited by several organic anions, such as PAH, indoxyl sulfate, octanoic acid, and metabolites of monoamine neurotransmitters. Neurotransmitters themselves did not affect the uptake. Furthermore, immunohistochemical analysis suggested that rOAT3 is localized at the abluminal membrane of brain capillary endothelial cells. These results provide the first evidence that rOAT3 is expressed at the abluminal membrane of the rat BBB and is involved in the brain-to-blood transport of HVA. This HVA efflux transport system is likely to play an important role in controlling the level of HVA in the CNS.
authors.affiliation: Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Mori
authors.forename: Hitomi
authors.initials: H
authors.lastname: Takanaga
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Deguchi
authors.forename: Young-Sook
authors.initials: YS
authors.lastname: Kang
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hosoya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002927:Cimetidine / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006719:Homovanillic Acid / Q000493:pharmacokinetics*; D007200:Indican / Q000494:pharmacology; D008297:Male; D009865:Oocytes / Q000502:physiology; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D010400:Penicillin G / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014316:Tritium; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000494:pharmacology
chemical_list: D003292:Convulsants; D004791:Enzyme Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D014316:Tritium; D002927:Cimetidine; D007200:Indican; D010400:Penicillin G; D006719:Homovanillic Acid; D010130:p-Aminohippuric Acid