DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1138 whereas dairy products and fish are relatively high in
iodine.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Iodine has been used empirically for the treatment of iodinedeficiency
goiter for 150 years; however, its modern use evolved
from extensive studies using iodine to prevent goiter in school children
in Akron, Ohio, where endemic iodine-deficiency goiter was
prevalent. The success of these experiments led to the adoption of
iodine prophylaxis and therapy in many regions throughout the
world where iodine-deficiency goiter was endemic.
The most practical method for providing small supplements
of iodine for large segments of the population is the addition of
iodide or iodate to table salt; iodate is now preferred. The use of
iodized salt is required by law in some countries, but in others such
as the U.S., the use is optional. In the U.S., iodized salt provides
100 μg of iodine per gram. Although the U.S. population remains
iodine sufficient, iodine intake has steadily decreased over the last
20 years (Hollowell et al., 1998). The most recent data indicate that
iodine intake has stabilized, although pregnant women remain a susceptible
population for iodine insufficiency (Haddow et al., 2007;
Hollowell and Haddow, 2007). Other vehicles for supplying iodine
to large populations who are iodine deficient include oral or intramuscular
injection of iodized oil (Elnagar et al., 1995), iodized
drinking water supplies, iodized irrigation systems, and iodized animal
feed.
Thyroid Hormone Transport Into and Out of Cells. Thyroid
hormone crosses the cell membrane primarily via specific
transporter proteins (Visser et al., 2008). Multiple
such transporters likely exist, each expressed in overlapping
but different subsets of tissues. To date, the only
transporter of proven importance in humans is monocarboxylic
acid transporter 8 (MCT8, SLC16A2).
Ectopic expression in cultured cells demonstrates that
MCT8 transports T 4
and T 3
bidirectionally across the
cell membrane. MCT8 is widely expressed, including
in liver, heart, and brain. MCT8 mutations cause Allan-
Herndon-Dudley syndrome, characterized by a severe
neurological phenotype and abnormal circulating thyroid
hormone levels. The serum T 3
typically is about
2-fold elevated, associated with a slight increase in TSH
and slight decrease in T 4
.
MCT10 also transports T 4
and T 3
and is widely
expressed, but there are no mutation studies to demonstrate
its importance for thyroid hormone transport
in vivo. The organic anion transporter OATP1C1
preferentially transports T 4
rather than T 3
, is highly
expressed in brain capillaries, and has been hypothesized
to be responsible for the transport of T 4
across the
blood-brain barrier (Chapter 5).
Actions of Thyroid Hormones
Classical Nuclear-Mediated Effects. Thyroid hormone
action is mediated largely by the binding of T 3
to thyroid
hormone receptors (TRs), which are members of the
nuclear receptor superfamily of transcription factors
(Bassett et al., 2003; Yen et al., 2006). This superfamily
includes the receptors for steroid hormones, vitamin
D, retinoic acid, and a variety of small molecule metabolites
such as certain fatty acids and bile acids. The
nuclear receptor superfamily also includes a number of
“orphan receptors” that have no known ligands and may
be regulated by posttranslational modifications or other
events. The TRs have the classic nuclear receptor structure
consisting of an amino terminal domain, a centrally
located zinc finger DNA binding domain, and a ligand
binding domain that occupies the carboxyl terminal half
of the protein (Figure 39–8).
T 3
binds to TRs with ~10-fold greater affinity
than does T 4
, and T 4
is not thought to be biologically
active in normal physiology. TRs bind to specific
DNA sequences (thyroid hormone response elements,
TREs) in the promoter/regulatory regions of target
genes. The transcription of most target genes is
repressed by unliganded TRs and induced following
the binding of T 3
. The mechanisms of these effects
have been well studied (Yen, 2001, Yen et al., 2006).
In the unliganded state, the TR ligand binding domain
interacts with a co-repressor complex that includes
TRβ1
TRβ2
TRβ3
TRβ4
Hypervariable
region
DNA binding
domain
0% 100% 100%
0%
0%
84%
84%
Ligand binding
domain
461
80%
80%
514
410
370 492
Figure 39–8. Thyroid hormone receptor isoforms. The percent amino acid identities of the amino terminal, DNA binding, and ligand
binding domains relative to TRβ1 are shown. TRβ1 is 461 amino acids in length. TRα2 does not bind T 3
or any other known ligand.
0%