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

1132
Basolateral
membrane
Apical
membrane
Colloid
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Na + Na +
A NIS
I – I –
I –
I –
Pendrin
Na +
Dehalogenase I –
I –
K + ATPase
DIT
E MIT
D
T 4 T 3
T
T 4
4 , T 3
T
D1, D2
3
F
KEY
METABOLIC STEP
Iodine transport
thyroglobulin just prior to its extracellular storage in the lumen of
the thyroid follicle. The formation of the H 2
O 2
that serves as a substrate
for the peroxidase probably occurs near its site of utilization
and is stimulated by a rise in cytosolic Ca 2+ (Takasu et al., 1987).
The TSH receptor is notably promiscuous in its coupling, stimulating
members of four G protein families including G q
, which couples
to the PLC-IP 3
-Ca 2+ pathway (Laugwitz et al., 1996); thus, a
Ca 2+ -dependent effect on H 2
O 2
production may be a means by
which TSH stimulates the organification of iodide in thyroid cells
(Figure 39–3).
3. Formation of Thyroxine and Triiodothyronine from
Iodotyrosines. The remaining synthetic step is the coupling
of two diiodotyrosyl residues to form thyroxine or
of monoiodotyrosyl and diiodotyrosyl residues to form
triiodothyronine. These oxidative reactions apparently
are catalyzed by the same thyroid peroxidase. The
mechanism involves the enzymatic transfer of groups,
perhaps as iodotyrosyl free radicals or positively
charged ions, within thyroglobulin.
Although many other proteins can serve as substrates for the
peroxidase, none is as efficient as thyroglobulin in yielding thyroxine.
Presumably, conformation of thyroglobulin facilitates this
coupling reaction. Thyroxine formation primarily occurs near the
amino terminus of the protein, whereas most of the triiodotyrosine
is synthesized near the carboxy terminus (Dunn and Dunn, 2001).
The relative rates of synthetic activity at the various sites depend on
the concentration of TSH and the availability of iodide. Iodine
A
B
C
D
E
F
TPO
+
H 2 O 2
I – or
HOI
or
EOI
Tg
Iodination
Coupling
Colloid Resorption
Deiodination of
DIT + MIT
Deodination of T 4
Tg
TPO
+
H 2 O 2
INHIBITOR
ClO – 4 , SCN
PTU, MMI
PTU, MMI
Colchicine, Li + , I –
Dinitrotyrosine
Figure 39–3. Major pathways of thyroid hormone biosynthesis and release. Abbreviations: Tg, thyroglobulin; DIT, diiodotyrosine; MIT,
monoiodotyrosine; TPO, thyroid peroxidase; HOI, hypoiodous acid; EOI, enzyme-linked species; D1 and D2, deiodinases (see Table
39–1); PTU, propylthiouracil; MMI, methimazole.
B
DIT
MIT
PTU
deficiency is associated with an increase in thyroidal T 3
relative to
T 4
content (Zimmerman, 2009). Because triiodothyronine is the transcriptionally
active iodothyronine and contains only three-fourths as
much iodine, a decrease in the quantity of available iodine need have
little impact on the effective amount of thyroid hormone elaborated
by the gland. Although a decrease in the availability of iodide and
the associated increase in the proportion of monoiodotyrosine favor
the formation of triiodothyronine over thyroxine, a deficiency in
diiodotyrosine ultimately can impair the formation of both compounds.
Intrathyroidal and secreted T 3
are also generated by the
5′-deiodination of thyroxine.
4. Resorption; 5. Proteolysis of Colloid; and, 6. Secretion
of Thyroid Hormones. Because T 4
and T 3
are synthesized
and stored within thyroglobulin, proteolysis is an
important part of the secretory process. This process is
initiated by endocytosis of colloid from the follicular
lumen at the apical surface of the cell, with the participation
of a thyroglobulin receptor, megalin. This
“ingested” thyroglobulin appears as intracellular colloid
droplets, which apparently fuse with lysosomes
containing the requisite proteolytic enzymes. It is generally
believed that thyroglobulin must be completely
broken down into its constituent amino acids for the
hormones to be released. The molecular mass of thyroglobulin
is 660,000 Da, and the protein is made up of
~300 carbohydrate residues and 5500 amino acid
C
Tg
DIT
MIT
T 4
T 3