rapidly than T
4
and has a metabolic clearance rate (MCR)
25 times as high as that of T
4
(Table 33-1).
Mutations in a human serum albumin gene that substi-
tute either histidine or proline for arginine at position 218
increase binding affinity for T4. These mutations are auto-
somal dominant and occur with relatively high frequency.
Carriers of these mutations have high levels of total serum
T
4
but their free-T
4
and TSH concentrations are within the
normal range. Individuals are euthyroid (normal thyroid)
and their conditions are known as
familial dysalbumine-
mic hyperthyroxinemia (FDH).
Two reactions account for the metabolic fate of about
80% of the T
4
in plasma: about 40% is converted to
T
3
via 5'-deiodination (activation), and another 40% of
the T
4
is converted to rT
3
by 5'-deiodination (inactiva-
tion). These two reactions are catalyzed by three enzymes
designated types I, II, and III iodothyronine deiodinases
(Figure 33-5 and Table 33-2). Types I and II both catalyze
the 5'-deiodination reaction but differ with respect to sub-
strate specificity, tissue distribution, and regulation. Type
III is a 5-deiodinase, which catalyzes the removal of io-
dine from position 5 of the inner ring. Type I is deiodinase
selenocysteine-containing microsomal enzyme present
in the liver, kidney, and thyroid, with specificity for
section 33.3
Transport and Metabolism of Thyroid Hormones
thyronines bearing iodine at position 5'. It is responsi-
ble for catalyzing the formation of most of the circulating
T
3
and is a high-capacity
(Km
~1
pM)
processor of T4. A
unique feature of the type I enzyme is that it is sensitive to
inhibition by
propylthiouracil
(PTU), a known inhibitor
of thyroid gland function that has little or no effect on
the activity of the other deiodinases. It is also inhibited in
conditions such as starvation, caloric restriction, and non-
thyroid-related illnesses, which may deplete the cofactor
supply and/or depress enzyme synthesis. The type II deio-
dinase is less abundant and has a higher specificity and a
higher affinity for T
4
than type I. The type II enzyme is
present in the pituitary, brain, brown fat, and skin, and is
responsible for intracellular T
3
formation that leads to a
cellular response; whereas the type I enzyme produces T
3
for export to other cells, and the type II enzyme is self-
serving, producing its own supply of intracellular T3. A
unique feature of the type II enzyme is that it is sensitive
to inhibition by T
4
by an unknown mechanism. The activ-
ity of the type II enzyme is increased in hypothyroidism
and is depressed in hyperthyroidism, whereas these con-
ditions have the opposite effect on the activity of the other
two deiodinases. The type III deiodinase is mainly in-
volved with the degradation of T
3
and the inactivation of
775
T
3
(active horm one)
5 -D eio d in a se
(T y p e III)
rT
3
(inactive)
FIGURE 33-5
Activating and inactivating pathways
of T
4
.
