Toxicology of Industrial Compounds

272 ENDOCRINE TOXICOLOGY OF THE THYROID
Table 19.4 Species and energy dependence of enhanced thyroxine accumulation in
vitro
Key: ↑T 4, increase; ↓T 4, decrease; ↔T 4, no change; Temperature? ATP?,
temperature/ATP dependent; NA, not applicable.
hepatocellular T 4 accumulation. The correlation between in vivo—in vitro
species-specific toxicological effects is also evident (Figure 19.10 and
Table 19.4). One of the features of temelastineinduced thyroid toxicology
in vivo was the apparent species-specificity to the rat (Atterwill et al.,
1989; Poole et al., 1989). Temelastine-mediated thyroid follicular
hypertrophy and hyperplasia was not observed in dog, mouse or monkey
following temelastine treatment (Figure 19.10). In vitro, no enhanced
thyroxine accumulation in response to temelastine or phenobarbital was
observed in guinea pig or dog hepatocytes (Aylward et al., 1994). In
support of these findings, it has been demonstrated that the guinea pig is
insensitive to thyroid pathological changes after phenobarbital or βnaphthoflavone
administration in vivo (Johnson et al., 1993; Wyatt et al.,
1993). In support of, and as an extension of these findings, we now present
important new findings to demonstrate conclusively that some of the rapid
‘effectors’ of thyroid toxicity via the liver, such as temelastine, do so
independently of a primary action on UDP-GT, whereas other cytochrome
P450 inducers such as phenobarbital may have a combined effect. This
work was carried out using hepatocytes prepared from UDP-GT system
deficient Gunn rats.
Studies on Gunn rat hepatocytes in vitro
Hepatocytes were prepared from the normal or Gunn rat (deficient in UDP-
GT isozymes conjugating thyroxine) and exposed to either temelastine or
phenobarbital (2 or 20 µM) for 3 h as before (Aylward et al., 1994). The
results show (Figure 19.11) that whereas temelastine was able to enhance
thyroxine accumulation in both types of hepatocytes, phenobarbital only
produced alterations in hormone accumulation in normal cells, supporting