Organic anion transport in choroid plexus from wild-type and organic anion transporter 3 (Slc22a8)-null mice.
The choroid plexus actively transports endogenous, xenobiotic, and therapeutic compounds from cerebrospinal fluid to blood, thereby limiting their exposure to the central nervous system (CNS). Establishing the mechanisms responsible for this transport is critical to our understanding of basic choroid plexus physiology and will likely impact drug targeting to the CNS. We recently generated an organic anion transporter 3- (Oat3)-null mouse, which exhibited loss of PAH, estrone sulfate, and taurocholate transport in kidney and of fluorescein (FL) transport in choroid plexus. Here, we measured the uptake of four Oat3 substrates by choroid plexus from wild-type and Oat3-null mice to establish 1) the contribution of Oat3 to the apical uptake of each substrate and 2) the Na dependence of transport by Oat3 in the intact tissue. Mediated transport of PAH and FL was essentially abolished in tissue from Oat3-null mice. In contrast, only a 33% reduction in estrone sulfate uptake was observed in tissue from Oat3-null mice and, surprisingly, no reduction in taurocholate uptake could be detected. For PAH, FL, and estrone sulfate, all Oat3-mediated transport was Na dependent. However, estrone sulfate and taurocholate also exhibited additional mediated and Na-dependent components of uptake that were not attributed to Oat3, demonstrating the complexity of organic anion transport in this tissue and the need for further examination of expressed transporters and their energetics.
Sykes
Destiny
D
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Sweet
Douglas H
DH
Lowes
Simon
S
Nigam
Sanjay K
SK
Pritchard
John B
JB
Miller
David S
DS
D000818:Animals; D000838:Anions / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000502:physiology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism*; D003287:Contrast Media / Q000493:pharmacokinetics; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D019793:Fluorescein / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism; D014316:Tritium; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D000838:Anions; D003287:Contrast Media; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D014316:Tritium; D004970:Estrone; D013656:Taurocholic Acid; D012964:Sodium; C017296:estrone sulfate; D019793:Fluorescein; D010130:p-Aminohippuric Acid