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

Table 39–1
Properties of Iodothyronine Deiodinases
TYPE 1 (D1) TYPE 2 (D2) TYPE 3 (D3)
Outer ring deiodinase Yes Yes No
Inner ring deiodinase Yes No Yes
Inhibited by PTU Yes No No
Inhibited by amiodarone Yes Yes Unknown
Regulation by thyroid T 3
induces D1 gene Substrate (T 4
) causes T 3
induces D3 gene
hormone expression D2 protein degradation expression
Location Liver, kidney, thyroid, Brain, pituitary, hypothalamus, Brain, placenta, some
pituitary thyroid, brown fat, skeletal sites of inflammation
muscle (very low levels)
Selenocysteine Yes Yes Yes
in active site
by propylthiouracil. D2 localizes to the endoplasmic reticulum,
which facilitates access of D2-generated T 3
to the nucleus. Hence
organs that express D2 tend to use the locally generated T 3
to
increase the occupancy of nuclear T 3
receptors, and D2-generated
T 3
equilibrates slowly with the plasma. D2 is dynamically regulated
by its substrate, thyroxine, such that elevated levels of the enzyme
are found in hypothyroidism and suppressed levels are found in
hyperthyroidism. Thus, D2 autoregulates the intracellular supply of
triiodothyronine in organs in which it is expressed.
Inner ring- or 5-deiodination, the main inactivating pathway
of T 3
metabolism, is catalyzed mainly by the type 3 deiodinase (D3),
and to some extent also by D1. D3 is found at highest levels in
the CNS and placenta, and it also is expressed in skin and uterus
(St. Germain et al., 2009). It is highly expressed in hemangiomas.
Liver
Kidney
Thyroid
D1
T 3
D2
Brain
Pituitary
Heart
BAT
Skeletal muscle
Thyroid
T 4
Placenta
D3 Skin
Brain
Uterus
rT Sites of
3
inflammation
Figure 39–5. Deiodinase isozymes.
D1, type I iodothyronine 5′-deiodinase; D2, type II iodothyronine
5′-deiodinase; D3, type III iodothyronine 5-deiodinase;
BAT, brown adipose tissue.
D3 can be induced at sites of inflammation, and at least in an animal
model this can result in local hypothyroidism (Peeters et al., 2003;
Simonides et al., 2008).
D2 and D3 also play important roles in regulating local T3
levels during development, during which thyroid hormone tends to
promote differentiation and decrease proliferation. Examples include
chondrocyte development and bone differentiation, and auditory
(cochlea) development. In the brain, D2 is expressed in glial cells
and D3 in neurons. Because T 3
receptors are enriched in neurons,
the current model is that glial cells convert T 4
to T 3
, which is then
exported and taken up by neurons where it activates T 3
receptors,
with subsequent degradation by D3 and termination of the T 3
effect.
There is a growing recognition of circumstances where D2 and D3
regulate local thyroid hormone levels independent of the plasma T 4
and T 3
concentrations.
The three deiodinases contain the rare amino acid selenocysteine
in their active sites. Incorporation of selenocysteine into the
growing peptide chain is a complex process involving multiple proteins.
Mutations in one such protein, SECIS binding protein 2, are
associated with abnormal circulating thyroid hormone levels
(Dumitrescu et al., 2005).
Transport of Thyroid Hormones in the Blood. Iodine in the
circulation is normally present in several forms, with
95% as organic iodine and ~5% as iodide. Most organic
iodine is thyroxine (90-95%); triiodothyronine represents
a relatively minor fraction (~5%). The thyroid
hormones are transported in the blood in strong but
noncovalent association with certain plasma proteins
(Schussler, 2000).
Thyroxine-binding globulin (TBG) is the major carrier of thyroid
hormones. It is an acidic glycoprotein with a molecular mass
of ~63,000 Da that binds one molecule of T 4
per molecule of protein