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

6. recycling of the iodine within the thyroid cell via
de-iodination of mono- and diiodotyrosines and
reuse of the I –
7. conversion of thyroxine (T 4
) to triiodothyronine
(T 3
) in peripheral tissues as well as in the thyroid
1131
Figure 39–2. Structural formula of 3,5-diiodothyronine, drawn to
show the conformation in which the planes of the aromatic rings
are perpendicular to each other. (Adapted from Jorgensen, 1964.)
and Asn 331 in TRβ). GC-1, a TRβ-specific agonist, stabilizes the
ligand binding domain by promoting hydrogen bonding between
Asn331 and Arg282. GC-1 has a 10-fold greater affinity for TRβ,
the predominant TR isoform in the liver, than TRα, the predominant
TR isoform in the heart, and lowers cholesterol without stimulating
the heart. Cholesterol lowering with cardiac sparing by GC-1 and
other TRβ-selective agonists, however, is also the result of much
higher distribution in the liver and less in the heart compared with T 3
.
Similar compounds, such as KB-141, lower cholesterol in clinical
studies (Baxter and Webb, 2009). Interestingly, none of these newer
thyroid hormone analogs contains iodine or any halogen.
Biosynthesis of Thyroid Hormones. The synthesis of
the thyroid hormones is unique, complex, and seemingly
inefficient. The thyroid hormones are synthesized
and stored as amino acid residues of
thyroglobulin, a protein constituting the vast majority
of the thyroid follicular colloid (Rubio and Medeiros-
Neto, 2009). The thyroid gland is unique in storing
great quantities of potential hormone in this way, and
extracellular thyroglobulin can represent a large portion
of the thyroid mass. Thyroglobulin is a complex
glycoprotein made up of two apparently identical subunits,
each of 330,000 Da. Interestingly, molecular
cloning has revealed that thyroglobulin belongs to a
superfamily of serine hydrolases, including acetylcholinesterase
(Chapter 10).
The major steps in the synthesis, storage, release,
and interconversion of thyroid hormones are as follows:
1. uptake of iodide ion (I – ) by the gland
2. oxidation of iodide and the iodination of tyrosyl
groups of thyroglobulin
3. coupling of iodotyrosine residues by ether linkage
to generate the iodothyronines
4. resorption of the thyroglobulin colloid from the
lumen into the cell
5. proteolysis of thyroglobulin and the release of thyroxine
and triiodothyronine into the blood
These processes are summarized in Figure 39–3
and described in the correspondingly labeled sections
that follow.
1. Uptake of Iodide. Iodine ingested in the diet reaches
the circulation in the form of iodide ion (I − ). Under
normal circumstances, the I − concentration in the blood
is very low (0.2-0.4 μg/dL; ~15-30 nM), but the thyroid
efficiently and actively transports the ion via a
specific membrane-bound protein, termed the sodiumiodide
symporter (NIS) (Dohan et al., 2003). As a
result, the ratio of thyroid to plasma iodide concentration
is usually between 20 and 50 and can exceed
100 when the gland is stimulated. The iodide transport
mechanism is inhibited by a number of ions such
as thiocyanate and perchlorate (Figure 39–3).
Thyrotropin (thyroid-stimulating hormone [TSH])
stimulates NIS gene expression and promotes insertion
of NIS protein into the membrane in a functional configuration.
Thus decreased stores of thyroid iodine
enhance iodide uptake, and the administration of
iodide can reverse this situation by decreasing NIS protein
expression (Eng et al., 1999).
NIS has been identified in many other tissues, including the
salivary glands, gastric mucosa, midportion of the small intestine,
choroid plexus, skin, mammary gland, and perhaps the placenta, all
of which maintain a concentration of iodide greater than that of the
blood. Iodide accumulation by the placenta and mammary gland
may provide adequate supplies for the fetus and infant. Iodine accumulation
throughout the body is mediated by a single NIS gene.
Individuals with congenital NIS gene mutations have absent or
defective iodine concentration in all tissues known to concentrate
iodine.
2. Oxidation and Iodination. Consistent with the conditions
generally necessary for halogenation of aromatic
rings, the iodination of tyrosine residues requires the
iodinating species to be in a higher state of oxidation
than is the anion. The iodinating species is hypoiodite,
either as hypoiodous acid or as an enzyme-linked
species (Magnusson et al., 1984).
The oxidation of iodide to its active form is accomplished
by thyroid peroxidase, a heme-containing enzyme that uses hydrogen
peroxide (H 2
O 2
) as the oxidant (Dunn and Dunn, 2001). The
peroxidase is membrane bound and appears to be concentrated at
or near the apical surface of the thyroid cell. The reaction results
in the formation of monoiodotyrosyl and diiodotyrosyl residues in
CHAPTER 39
THYROID AND ANTI-THYROID DRUGS