Toxicology of Industrial Compounds

270 ENDOCRINE TOXICOLOGY OF THE THYROID
Table 19.3
(Aylward et al., 1994) and increases the accumulation of thyroxine in
treated rat liver in vivo (Oppenheimer et al., 1968).
Thyroxine transport (Figure 19.9) is regulated by specific components
located within the plasma membrane in various cell types including
fibroblasts and hepatocytes and is an important prerequisite for both
hormone metabo lism and nuclear hormonally-mediated events (Pliam and
Goldfine, 1977; Krenning et al., 1981; Blondeau, 1986). Investigations
indicate that there exist two distinct transport systems specific to
thyroxine: a high-affinity, low capacity, energy-dependent ATP-ase linked
transport system and a low-affinity, high capacity transport mechanism
(Sorimachi and Robbins, 1978; Krenning et al., 1981, 1983; Blondeau,
1986; Rao, 1991).
Many of the compounds listed as indirect carcinogens in rat (due to an
ability to induce liver microsomal enzymes and increase glucuronidated
thyroxine elimination in the bile) have been shown to increase hepatic UDP-
GT activity or cause liver hypertrophy indicative of following repeated
dosing (Comer et al., 1985; McClain, 1989; Johnson et al., 1993).
However, there have been no attempts to provide a definitive link between
UDP-GT induction and thyroid pathology or to prove a primary
endocrinological effect via UDP-GT. Our previous work with temelastine
in the rat in vivo (Atterwill et al., 1989) was able to demonstrate that the
increased clearance of T 4 from the rat circulation appeared within a few
hours of a single compound dosing (Atterwill et al., 1989). Even