title: Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue.
abstract: Transporters in the choroid plexus (CP) regulate transport of numerous compounds of physiological and therapeutic interest between blood and CSF and thus likely play a key role in determining CNS levels of drugs, toxins and metabolites. Here, high CP expression was noted for the organic anion transporters, Oat1 (SLC22A6 or NKT) and Oat3 (SLC22A8) which are also the principal Oats in the renal proximal tubule, as well as SLC22A17, hypothesized to be involved in iron transport. Because Oat1 and Oat3 have overlapping substrate specificity, ex vivo preparations of CP from Oat1((-/-)) and Oat3((-/-)) mice were used to isolate the individual transport function of each, respectively. Tissue from either knockout mouse mediated the probenecid-inhibitable transport of the Oat substrate, 6-carboxyfluorescein (6CF), confirming the presence of Oat1 and Oat3 function. Because many antiviral medications are Oat substrates, including those crucial in the treatment of HIV infections, the interaction of the antivirals zidovudine, acyclovir, tenofovir, lamivudine, and stavudine, with Oat1 and Oat3 in CP, was investigated by determining the inhibition of 6CF uptake. All the antivirals tested manifested significant interaction with both Oat1 and Oat3, with the exception of stavudine which did not significantly affect Oat1 function. These results could have important implications for antiretroviral (and other drugs) penetration into or retention within the CNS, a major reservoir for virus during HIV infection. Apart from any effect at the blood brain barrier (BBB), designing specific inhibitors of Oat1 and Oat3 may be helpful in altering CNS drug levels by blocking organic anion transporters in the CP. The role of SLC22A17 in the CP deserves further exploration. The ability of Oats to regulate the movement of small molecules across the BBB, CP, proximal tubule and other tissues may also be important for their role in remote sensing and signaling [1,21]).
authors.affiliation: Department of Pediatrics, UCSD, La Jolla, CA 92093, United States.
authors.forename: Megha A
authors.initials: MA
authors.lastname: Nagle
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Satish A
authors.initials: SA
authors.lastname: Eraly
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000378:metabolism*; D001692:Biological Transport; D002831:Choroid Plexus / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D027362:Organic Anion Transport Protein 1 / Q000235:genetics* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D044966:Anti-Retroviral Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C105033:Slc22a6 protein, mouse; C114338:organic anion transport protein 3; C024098:6-carboxyfluorescein