ROLE OF TRANSTHYRETIN IN THE TRANSPORT OF THYROXINE FROM THE BLOOD TO THE CHOROID-PLEXUS, THE CEREBROSPINAL-FLUID, AND THE BRAIN

T4 is bound to transthyretin (TTR; 75%) and albumin (Alb; 25%) in rat serum and only to TTR in cerebrospinal fluid (CSF). In addition to the liver, TTR is synthesized in large amounts in the choroid plexus and then secreted into the CSF, suggesting that serum T4 could be transported to the CSF and brain via the choroid plexus. We determined whether serum T4 bound to TTR is transported into the choroid plexus and CSF. N-Bromoacetyl-L-[I-125]T4, a derivative of T4 that binds covalently to TTR, was used as the affinity label for the T4-binding site on TTR. Rats were injected with [I-125]T4, acetyl-[I-125]T4 covalently bound to human TTR ([I-125]T4Ac.human hTTR), or acetyl-[I-125]T4 covalently bound to human Alb ([I-125] T4Ac.hAlb). The quantities of [I-125]T4Ac.hTTR and [I-125]T4Ac.hAlb present in the choroid plexus, CSF, and brain 90 min later were barely detectable. In contrast, [I-125]T4 injected as the unbound form accumulated in the choroid plexus and CSF to levels 6-11 times higher than with [I-125]T4Ac.hTTR (P < 0.005). We then used a synthetic flavonoid (EMD) that competitively inhibits binding of T4 to serum TTR and transiently increases serum free T4 to determine the role of choroid plexus TTR and CSF TTR in the transport of T4 from serum to brain. Rats were given 110-mu-Ci [I-125]T4 15 min after the injection of vehicle, a low (0.3-mu-mol/100 g BW) or high dose of EMD (2.0-mu-mol/100 g BW). Rats were killed 60 min later. In serum, the percentage of [I-125] T4 bound to TTR decreased and free T4 increased similarly in the low and high dose EMD-treated rats. In contrast, the percentage of [I-125]T4 bound to TTR in choroid plexus and, subsequently, CSF was significantly decreased in rats given the high dose of EMD, but was not affected by the low dose of EMD, suggesting that in high doses, EMD crossed from serum to choroid plexus and CSF and occupied TTR-binding sites for T4. There was a significant decrease (P < 0.05) in the percentage of injected [I-125]T4 in the high dose vs. the low dose EMD-treated rats in total choroid plexus (61%), 1 ml CSF (94%), and 1 g cerebral cortex (46%) and cerebellum (46%). In conclusion, these data demonstrate 1) that serum T4 bound to TTR is not transported into the CSF either directly or via the choroid plexus, and thus, TTR generated by the liver is probably not a significant source of TTR in CSF; 2) that T4 transfer from serum via choroid plexus to CSF depends upon both the free T4 concentration in serum and the binding of T4 to TTR in the choroid plexus and subsequently in the CSF; and 3) that CSF T4 transported from serum via the choroid plexus may contribute to the brain T4 supply in the rat. Specific binding sites