Saturable accumulation of the anionic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), by rabbit choroid plexus: early developmental origin and interaction with salicylates

Abstract

Transport of the anionic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) was examined in vitro via the isolated choroid plexus of adult and neonatal rabbits and in vivo via ventriculocisternal perfusion. In vitro, the facilitated transport of 2,4-D by the choroid plexus was established in the rabbit by as early as 3 days of age. Uptake in both adults and neonates took place against a concentration gradient via a saturable process that was inhibited by ouabain and hypothermia (0 degrees C). Probenecid and hippuric acid were effective dose-dependent inhibitors of 2,4-D transport in vitro. The major metabolite of salicylate, salicyluric acid, was also an effective inhibitor, more than its precursor, salicylate, or gentisic acid, a second salicylate metabolite. Neither phenol, acetaminophen nor glycine inhibited 2,4-D transport. Thus, the effects appear specific for those compounds which share the organic acid transport system. The role of carrier-mediated transport in the clearance of 2,4-D from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 2,4-D from CSF exceeded that of inulin and was reduced in a dose-dependent fashion in the presence of salicylate. Neither CSF formation nor absorption rates were changed. These results indicate that 2,4-D is transported from the CSF via the organic anion transport system, and that inhibitors of this transport system may block its elimination from the brain in vivo, just as they block its transport by the isolated choroid plexus.