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

residues, only two to five of which are thyroxine; thus
this is an extravagant process.
TSH enhances the degradation of thyroglobulin by increasing
the activity of several thiol endopeptidases of the lysosomes.
Endopeptidases selectively cleave thyroglobulin, yielding hormonecontaining
intermediates that subsequently are processed by exopeptidases
(Dunn and Dunn, 2001). The liberated hormones then exit
the cell, presumably at its basal membrane. When thyroglobulin is
hydrolyzed, monoiodotyrosine and diiodotyrosine also are liberated
but usually do not leave the thyroid; rather, they are selectively
metabolized and the iodine, liberated as I − , is reincorporated into
protein. The iodotyrosine deiodinase enzyme, DHAL1, is essential
for conserving iodine and mutations of this gene identified in several
kindreds are associated with goitrous hypothyroidism and cognitive
deficit (Moreno et al., 2008). Normally, all this iodide is reused;
however, when proteolysis is activated intensely by TSH, some of the
iodide reaches the circulation, at times accompanied by trace
amounts of the iodotyrosines.
7. Thyroid Hormone Metabolism and the Conversion of
Thyroxine to Triiodothyronine in Peripheral Tissues. The
normal daily production of thyroxine is estimated to
range between 80 and 100 μg; that of triiodothyronine
is between 30 and 40 μg. Although triiodothyronine is
secreted by the thyroid, metabolism of thyroxine by 5′, or
I
3'
HO O CH 2
5'
5
T NH 2
4 I
I
I
3
outer ring, deiodination in the peripheral tissues
accounts for ~80% of circulating triiodothyronine
(Figure 39–4). In contrast, removal of the iodine on
position 5 of the inner ring produces the metabolically
inactive 3,3′,5′-triiodothyronine (reverse T 3
, rT 3
;
Figure 39–1). Under normal conditions, ~40% of T 4
is
converted to each of T 3
and rT 3
, and ~20% is metabolized
via other pathways, such as glucuronidation in the
liver and excretion in the bile. Normal circulating concentrations
of T 4
in plasma range from 4.5-11 μg/dL;
those of T 3
are ~1/100 of that (60-180 ng/dL).
Key properties of the three iodothyronine deiodinases are
summarized in Table 39–1. The types 1 and 2 deiodinases (D1, D2)
convert thyroxine to triiodothyronine (St. Germain et al., 2009).
These enzymes contribute approximately equally to the plasma T 3
in
rats, but it has not been possible to determine their relative contributions
in humans. D1 is expressed primarily in the liver and kidney,
and also in the thyroid and pituitary (Figure 39–5). It is upregulated
in hyperthyroidism and downregulated in hypothyroidism. A clinically
important feature of D1 is its inhibition by the anti-thyroid drug
propylthiouracil. D1 is localized to the plasma membrane, and the T 3
it produces equilibrates rapidly with the plasma. D2 is expressed primarily
in the CNS (including the pituitary and hypothalamus) and
brown adipose tissue, also in the thyroid, and at very low levels in
other organs such as skeletal muscle. The activity of D2 is unaffected
CHCOOH
1133
CHAPTER 39
THYROID AND ANTI-THYROID DRUGS
I
I
I
I
HO
O
R
HO
O
R
T 3
I
rT 3
I
I
I
I
I
HO O R
HO O R
HO O R
3,5-T 2
3-T 1 3’-T 1
I
3,3’-T I
2
3’,5’-T 2
HO O R
I
I
HO O R
Figure 39–4. Pathways of iodothyronine deiodination.