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this time by risingplasma titers ofTH(
Cai&Brown, 2004;Huang,Cai,Remo,
&Brown,2001;Manzon&Denver,2004
; discussedmore below). Physiolog-
ical roles for tissue monodeiodinases in the timing of metamorphosis
are supported by experiments with iopanoic acid and transgenesis over-
expression of
Dio3
(
Becker et al., 1997; Buscaglia et al., 1985; Cai & Brown,
2004; Galton, 1989; Huang et al., 2001; Huang, Marsh-Armstrong, &
Brown, 1999; Marsh-Armstrong, Huang, Remo, Liu, & Brown, 1999
).
1.1.2 Plasma TH transport proteins
Thyroxine synthesized by thyroid follicular cells diffuses into the blood-
stream where it is reversibly bound by plasma proteins that transport the
hormone from the site of production to its target tissues (
Fig. 7.1
). Two
plasma-binding proteins that bind T
4
and T
3
with moderate to high affinities
have been identified in vertebrates. Thyroxine-binding globulin (TBG)
binds T
4
with high affinity and low capacity but is found only in large, eu-
therian mammals (
Power et al., 2000
). Transthyretin (TTR; also known as
prealbumin) is found in all vertebrates and it binds T
4
with moderate affinity
and intermediate capacity. Both TBG and TTRs can also bind T
3
, although
in most cases with 10 times lower affinity than T
4
(
Power et al., 2000
);
although, the situation in amphibia is the reverse, where TTR binds T
3
with
greater affinity than T
4
(
Yamauchi, Kasahara, Hayashi, & Horiuchi, 1993;
Yamauchi, Nakajima, Hayashi, & Hara, 1999; Yamauchi, Prapunpoj, &
Richardson, 2000; Yamauchi et al., 1998
). The two primary sites for
TTR expression in vertebrates are the liver and the choroid plexus (although
it is expressed at other sites;
Power et al., 2000
). In amphibians, TTR is
expressed primarily in the liver (
Power et al., 2000
). An essential function
of TTR is its interaction with retinol-binding protein, which acts as a carrier
for all-
trans
-retinol in the blood. The functional significance of this interac-
tion is not known, but it is intriguing that T
3
and 9-
cis
-retinoic acid (which is
a metabolite of all-
trans
-retinol) serve as ligands for the TR-retinoid
X receptor (RXR) heterocomplex that regulates TH target genes. Serum
albumin also binds T
3
and T
4
in many species with low affinity and high
capacity, and
Power et al. (2000)
suggested that albumin might be the
principal T
4
-binding protein in amphibia.
Circulating TTR is present in tadpoles during premetamorphosis and
prometamorphosis when thyroid activity is increasing, but declines at
metamorphic climax (
Prapunpoj, Yamauchi, Nishiyama, Richardson,
& Schreiber, 2000; Yamauchi et al., 2000, 1998
). The free hormone
hypothesis (
Ekins, 1990; Mendel, 1989
) leads to the prediction that TTR
