G. Hennemann et al., Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability, ENDOCR REV, 22(4), 2001, pp. 451-476
Although it was originally believed that thyroid hormones enter target cell
s by passive diffusion, it is now clear that cellular uptake is effected by
carrier-mediated processes. Two stereospecific binding sites for each T-4
and T-3 have been detected in cell membranes and on intact cells from human
s and other species. The apparent Michaelis-Menten values of the high-affin
ity, low-capacity binding sites for T-4 and T-3 are in the nanomolar range,
whereas the apparent Michaelis-Menten values of the low-affinity, high-cap
acity binding sites are usually in the lower micromolar range. Cellular upt
ake of T-4 and T-3 by the high-affinity sites is energy, temperature, and o
ften Na+ dependent and represents the translocation of thyroid hormone over
the plasma membrane. Uptake by the low-affinity sites is not dependent on
energy, temperature, and Na+ and represents binding of thyroid hormone to p
roteins associated with the plasma membrane. In rat erythrocytes and hepato
cytes, T-3 plasma membrane carriers have been tentatively identified as pro
teins with apparent molecular masses of 52 and 55 kDa. In different cells,
such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblast
oma cells, uptake of T-4 and T-3 appears to be mediated largely by system L
or T amino acid transporters. Efflux of T-3 from different cell types is s
aturable, but saturable efflux of T-4 has not yet been demonstrated. Satura
ble uptake of T-4 and T-3 in the brain occurs both via the blood-brain barr
ier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone upt
ake in the intact rat and human liver is ATP dependent and rate limiting fo
r subsequent iodothyronine metabolism. In starvation and nonthyroidal illne
ss in man, T-4 uptake in the liver is decreased, resulting in lowered plasm
a T-3 production. Inhibition of liver T-4 uptake in these conditions is exp
lained by liver ATP depletion and increased concentrations of circulating i
nhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indo
xyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several or
ganic anion transporters and L type amino acid transporters have been shown
to facilitate plasma membrane transport of thyroid hormone. Future researc
h should be directed to elucidate which of these and possible other transpo
rters are of physiological significance, and how they are regulated at the
molecular level.