Hormonas Tiroideas y Cerebro. Notas Sobre La Relación Bocio y ...

T3
T4
D2
T4
D3
T3
D1
rT3
D3
T2
D2
TR
Figure. 1. Thyroid hormone transport, metabolism and action
in a T3 target cell.
TRE
mRNA
Protein
RXR
Nucleus
Indeed much evidence has
been published over the last three
decades that cellular uptake and
efflux of thyroid hormone do not take
place by simple diffusion but are
mediated by transporters (Fig. 1)
(7). In vitro studies using isolated
cells and perfusion of isolated tissue
and in vivo studies in rats and
humans have also strongly
suggested that plasma membrane
transport plays a rate-determining
role in the hepatic metabolism of
thyroid hormone, including the
conversion of T4 to T3 (7).
During the last few years thyroid hormone transporters have been characterized at the
molecular level (7-11), including the Na + -taurocholate cotransporting polypeptide (NTCP), different
members of the Na + -independent organic anion transporting polypeptide (OATP) family, the
heterodimeric L-type amino acid transporters LAT1, LAT2, and the monocarboxylate transporters
MCT8 and MCT10. Most of these transporters accept a variety of ligands, but OATP1C1, MCT8 and
MCT10 show a high specificity towards iodothyronines (10, 12, 13).
OATP1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the
transport of the prohormone T4 across the blood-brain barrier (13, 14). MCT8 is also expressed -
among other tissues - in the brain, in particular in neurons (14, 15). MCT8 appears especially
important for the uptake of the active hormone T3 into these cells, which is essential for optimal brain
development. This T3 is produced from T4 by D2 in adjacent astrocytes. The neurons express D3
which terminates T3 activity.
The MCT8 gene is located on chromosome Xq13.2 and mutations in MCT8 have recently been
associated with a syndrome combining severe X-linked psychomotor retardation, low serum T4 and
strongly elevated T3 levels (16, 17). The mechanism of this disease involves a defect in the neuronal
entry of T3, and thus in the action and metabolism of T3 in these cells, resulting in an impaired
neurological development as well as a decrease in T3 clearance (16). This syndrome has now been
documented in over 20 families and represents a novel mechanism of thyroid hormone resistance due
to an impaired uptake of T3 in target cells.
MCT8 null mice have been investigated by two groups with the same surprising results,
showing exactly the same changes in thyroid hormone levels as affected patients but without any
obvious neurological impairment (18, 19). MCT8 null mice show high liver and kidney D1, high brain
and pituitary D2, and low brain D3 activities, changes which contribute to the abnormal serum thyroid
parameters. MCT8 is importantly expressed in the hypothalamic area which explains the defect in
negative feed-back action of thyroid hormone on TRH production and secretion (19, 20). Perhaps the
most impressive demonstration of the function of MCT8 is the dramatic decrease in brain T3 uptake in
MCT8 null versus wild-type mice (19).
14