Multiple components of 2,4-dichlorophenoxyacetic acid uptake by rat choroid plexus.
Initial rates of uptake of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D; 20 microM) were measured in intact lateral choroid plexus from rat. Although inhibition of uptake by millimolar concentrations of estrone sulfate (ES) and unlabeled 2,4-D was maximal at 85%, inhibition by p-aminohippurate (PAH) saturated at about 50%. Inhibition by ES plus PAH was no greater than by ES or 2,4-D alone. Thus, inhibition studies indicated three distinct components of uptake; two mediated and one not. The sodium-dependent component of 2,4-D uptake coincided with the PAH-sensitive component, indicating uptake mediated by organic anion transporter subtype (Oat) 3. Consistent with this, efflux of 2,4-D from preloaded tissue was accelerated by all Oat3 substrates tested, and 2,4-D increased the efflux of the Oat3 substrate, PAH. Consistent with the inhibition data, kinetic analysis showed three components of 2,4-D uptake: a nonmediated component (linear kinetics), a high-affinity component, and a low-affinity component. The high-affinity component appeared to coincide with the PAH-sensitive and sodium-dependent component characterized in inhibition studies. The PAH-insensitive, low-affinity component was inhibited by ES, dehydroepiandrosterone sulfate, and taurocholate but not by 5-hydroxyindole acetic acid. Thus, the first step in transport of 2,4-D from cerebrospinal fluid to blood involves two transporters: Oat3 and a PAH-insensitive, sodium-independent transporter. Based on inhibitor profile, the latter may be Oatp3.
Lowes
Simon
S
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Sykes
Destiny
D
Breen
Christopher M
CM
Ragone
Leigh J
LJ
Miller
David S
DS
D015084:2,4-Dichlorophenoxyacetic Acid / Q000378:metabolism*; D000818:Animals; D002831:Choroid Plexus / Q000378:metabolism*; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology
D029362:Organic Anion Transporters, Sodium-Independent; C421143:Slco1a5 protein, rat; D015084:2,4-Dichlorophenoxyacetic Acid; D012964:Sodium