title: Thyroxine (T4) transfer from CSF to choroid plexus and ventricular brain regions in rabbit: contributory role of P-glycoprotein and organic anion transporting polypeptides.
abstract: This study investigated the transfer of T4 from cerebrospinal fluid (CSF) into the choroid plexuses (CP) and ventricular brain regions, and the role of P-glycoprotein (P-gp), multidrug resistance protein 1 (mrp1) and organic anion transporting polypeptides (oatps). During in vivo ventriculo-cisternal (V-C) perfusion in the anesthetized rabbit (meditomidine hydrochloride 0.5 mg kg(-1), pentobarbitone 10 mg kg(-1) i.v.), 125I-T4 was perfused continuously into ventricular CSF with reference molecules 14C-mannitol and blue dextran. Over 2 h, 36.9+/-4.6% 125I-T4 was recovered in cisternal CSF. Addition of P-gp substrate verapamil increased CSF 125I-T4 recovery to 51.4+/-2.8%, although mrp1 and oatp substrates had no significant effect. In brain, 125I-T4 showed greatest accumulation in the CP (1.52+/-0.31 ml g(-1)), followed by ventricular regions (caudate putamen, ependyma, hippocampus, 0.05-0.14 ml g(-1)). At the CP, verapamil and probenecid (but not indomethacin) significantly increased 125I-T4 accumulation, implicating a role for P-gp and oatps. Of other brain regions, all three drugs increased accumulation in caudate putamen 3-5 times, and indomethacin and probenecid increased accumulation in ependyma 4-5 times. The role of P-gp was investigated further in isolated incubated CPs using 5 microg/ml C219 anti-P-gp antibody. Both 125I-T4 and 3H-cyclosporin accumulation increased by 80%, suggesting that P-gp is functional in the CP and has a role in removal of T4. Combined with the in vivo results, these studies suggest that P-gp provides a local homeostatic mechanism, maintaining CSF T4 levels. We conclude that P-gp and oatps contribute to the transfer of 125I-T4 between the CSF, CP and brain, hence regulating 125I-T4 availability in CSF.
authors.affiliation: King's College London, Pharmaceutical Sciences Research Division, Hodgkin Building, Guy's Campus London SE1 1UL, UK. nouhad.kassem@kcl.ac.uk
authors.forename: Nouhad A
authors.initials: NA
authors.lastname: Kassem
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Malcolm B
authors.initials: MB
authors.lastname: Segal
authors.forename: RuoLi
authors.initials: R
authors.lastname: Chen
authors.forename: Jane E
authors.initials: JE
authors.lastname: Preston
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D002831:Choroid Plexus / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D027361:Organic Anion Transporters / Q000502:physiology*; D011817:Rabbits; D018709:Statistics, Nonparametric; D013974:Thyroxine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D013974:Thyroxine