Does thyroxine (T4) cross the blood‑brain barrier, and if so, how is it transported into the central nervous system?

Thyroxine (T4) Transport Across the Blood-Brain Barrier

Yes, T4 crosses the blood-brain barrier via specific transporter proteins, primarily OATP1C1 (organic anion-transporting polypeptide 1C1), which is expressed on brain capillary endothelial cells and facilitates active transport of T4 into the central nervous system. 1, 2

Primary Transport Mechanism

• OATP1C1 is the principal T4 transporter at the blood-brain barrier, expressed specifically on cerebral capillary endothelial cells where it mediates selective uptake of T4 into brain tissue 1, 3
• OATP1C1 demonstrates high specificity for T4 and T4 sulfate (T4S), with minimal transport of reverse T3 (rT3) and essentially no transport of T3 or T3 sulfate 3
• The transporter belongs to the SLC superfamily (specifically SLCO1C1/SLC21 family) and functions as an ATP-independent, sodium-independent polypeptide that regulates drug and hormone movement across brain barriers 4

Structural and Functional Characteristics

• Recent cryo-EM structures at 2.3 Å resolution reveal OATP1C1 bound to both T4 and T3, demonstrating distinct thyroid hormone recognition mechanisms 2
• OATP1C1 contains an extracellular allosteric site, which is uncommon among SLC transporters and may modulate its transport function 2
• The transporter is rate-limiting for subsequent intracellular T4 metabolism: when OATP1C1 is co-expressed with deiodinases, metabolism of T4, T4S, and rT3 is greatly augmented, indicating it controls substrate access to intracellular enzymatic conversion sites 3

Developmental Expression Pattern

• During brain development, OATP1C1 expression extends beyond barrier structures to include neuronal progenitors and specific neuronal populations 5
• At embryonic day 15, OATP1C1 co-localizes with TBR2, a marker of neuronal progenitors, suggesting direct T4 uptake by developing neurons 5
• Transient neuronal expression occurs in cortical layer 2/3 and hippocampus during development, making these populations particularly sensitive to hypothyroxinemia 5
• Propylthiouracil-induced hypothyroxinemia in pregnant dams decreases the number of OATP1C1-expressing neurons in newborn cortical layer 2/3, demonstrating the functional significance of this developmental expression 5

Clinical Consequences of Transporter Deficiency

• Loss of OATP1C1 function causes severe brain-specific hypothyroidism despite normal peripheral thyroid hormone levels 1
• The first reported human OATP1C1 deficiency (homozygous D252N mutation) presented with normal early development followed by progressive dementia, spasticity, cold intolerance, gray and white matter degeneration, and severe brain glucose hypometabolism starting after the first year of life 1
• The D252N mutation impairs plasma membrane localization and decreases cellular T4 uptake by approximately 50% in vitro 1
• Animal models (oatp1c1-/- zebrafish) demonstrate hyperactivity of the hypothalamic-pituitary-thyroid axis, increased locomotor activity, structural alterations in radial glial cells, shorter neuronal axons, and goiter formation 6

Comparison with MCT8 Transporter

• MCT8 (monocarboxylate transporter 8) is another critical thyroid hormone transporter at the blood-brain barrier, but MCT8 deficiency causes Allan-Herndon-Dudley syndrome with a different clinical phenotype characterized by severe intellectual and motor disability plus peripheral hyperthyroidism 1, 2
• Both transporters have been structurally characterized at high resolution (2.9 Å for MCT8), revealing distinct mechanisms for thyroid hormone recognition and transport 2

Treatment Implications

• T4 supplementation alone is ineffective for OATP1C1 deficiency because the defective transporter cannot deliver T4 into the brain 1
• Triiodothyroacetic acid (Triac), a T3 analogue, can bypass the defective OATP1C1 transporter and improve clinical outcomes in multiple domains, as demonstrated in the first human case 1
• In zebrafish models, thyroid hormone analogues (but not native thyroid hormones) reduce goiter size and improve thyroid gland appearance in oatp1c1-/- mutants 6

Common Genetic Variants

• The OATP1C1-intron3C>T, Pro143Thr, and C3035T polymorphisms are relatively common but show no consistent association with serum thyroid hormone levels and do not affect transport function in vitro 3
• This suggests that common genetic variation in OATP1C1 does not significantly impact thyroid hormone homeostasis in the general population, though rare loss-of-function mutations cause severe disease 3