A new parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies

Takashi Yamada; Ryuichi Hasegawa; Satoshi Nishikawa; Yuki Sakuratani; Jun Yamada; Tatsuhiro Yamashita; Koichi Yoshinari; Yasushi Yamazoe; Eiichi Kamata; Atsushi Ono; Akihiko Hirose; Makoto Hayashi

doi:10.2131/jts.38.291

Letter

A new parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies

Takashi Yamada, Ryuichi Hasegawa, Satoshi Nishikawa, Yuki Sakuratani, Jun Yamada, Tatsuhiro Yamashita, Koichi Yoshinari, Yasushi Yamazoe, Eiichi Kamata, Atsushi Ono, Akihiko Hirose, Makoto Hayashi

Author information

Takashi Yamada
Chemical Management Center, National Institute of Technology and Evaluation
Ryuichi Hasegawa
Chemical Management Center, National Institute of Technology and Evaluation
Satoshi Nishikawa
Chemical Management Center, National Institute of Technology and Evaluation
Yuki Sakuratani
Chemical Management Center, National Institute of Technology and Evaluation
Jun Yamada
Chemical Management Center, National Institute of Technology and Evaluation
Tatsuhiro Yamashita
BioIT Business Development Office, Fujitsu Limited
Koichi Yoshinari
Graduate School of Pharmaceutical Sciences, Tohoku University
Yasushi Yamazoe
Graduate School of Pharmaceutical Sciences, Tohoku University
Eiichi Kamata
Biological Safety Research Center, National Institute of Health Sciences
Atsushi Ono
Biological Safety Research Center, National Institute of Health Sciences
Akihiko Hirose
Biological Safety Research Center, National Institute of Health Sciences
Makoto Hayashi
BioSafety Research Center

Keywords: Hypothyroidism mechanism, Hypertrophy, Hyperplasia, Follicular cells, Hepatomegaly, Relative organ weights

JOURNAL FREE ACCESS

2013 Volume 38 Issue 2 Pages 291-299

DOI https://doi.org/10.2131/jts.38.291

Details

Abstract

Hypothyroidism induced by xenobiotic treatment was analyzed for possible underlying mechanism(s) on the basis of different responses of the thyroid gland and the liver, using a newly-created database of repeated-dose toxicity of 500 chemicals. Two mechanisms are proposed: direct inhibition of thyroid hormone biosynthesis in the thyroid gland, and stimulated degradation of thyroid hormone by induction of hepatic drug-metabolizing enzymes. In the database there were 10 chemicals inducing hypertrophy/hyperplasia of follicular cells in the thyroid gland and having data on thyroid glands. On the basis of the chemical structure and information available in the literature, we judged three chemicals to be typical thioamide derivatives that act directly on the thyroid gland, and the others as non-thioamide derivatives that were unlikely to have any direct action on the thyroid gland. All these chemicals were classified into two groups using the ratios of relative weight increase rate of thyroid gland versus that of the liver. These values were at least 1.7, but 3.2 or more in the most of the cases for thioamide derivatives, and 1.2 or less for non-thioamide derivatives. This background analysis suggests the feasibility of parameter-supported speculation on the possible underlying mechanism when new repeated-dose toxicity data on hypothyroidism becomes available.

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