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ToxSci Advance Access originally published online on July 14, 2004
Toxicological Sciences 2004 81(2):309-315; doi:10.1093/toxsci/kfh225
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Toxicological Sciences vol. 81 no. 2 © Society of Toxicology 2004; all rights reserved.

A Possible Mechanism for Decrease in Serum Thyroxine Level by Polychlorinated Biphenyls in Wistar and Gunn Rats

Yoshihisa Kato*,1, Shinichi Ikushiro{dagger}, Koichi Haraguchi{ddagger}, Tomoaki Yamazaki*, Yuriko Ito*, Hiroshi Suzuki*, Ryohei Kimura*, Shizuo Yamada*, Tohru Inoue§ and Masakuni Degawa*

* School of Pharmaceutical Sciences and COE Program in the 21st Century, University of Shizuoka, 52-1, Yada, Shizuoka 422-8526, Japan; {dagger} Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan; {ddagger} Daiichi College of Pharmaceutical Sciences, 22-1, Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan; § Center for Biological Safety & Research, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Received May 17, 2004; accepted June 22, 2004

We have previously demonstrated that in mice, the decrease in serum thyroxine (T4) level by polychlorinated biphenyls (PCBs) occurs without an increase in the UDP-glucuronosyltransferase (T4-UDP-GT) for T4 glucuronidation, although the PCB-induced decrease in rats is generally thought to occur through induction of T4-UDP-GT, UGT1A1, and UGT1A6. In the present study, to further clarify the relationship between the decrease in serum T4 level and the increase in UGT1A activity by PCB in rats, we examined the relationship using Wistar rats and Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. The serum total T4 level was markedly decreased not only in the Wistar rats but also in the Gunn rats 4 days after treatment with a PCB, Kanechlor-500 (KC500, 100 mg/kg) or 2,2',4,5,5'-pentachlorobiphenyl (PentaCB, 112 mg/kg), and there was no significant difference in magnitude of the decrease between the two rat strains. At the same time, the level and activity of T4-UDP-GT were significantly increased by treatment with either KC500 or PentaCB in Wistar rats but not in Gunn rats. In addition, no significant change in the level of serum total triiodothyronine (T3) and thyroid-stimulating hormone by the KC500 treatment was observed in either Wistar or Gunn rats. Furthermore, significant decrease in the activity of hepatic type-I deiodinase, which mediates the deiodization of T4 and T3, by treatment with KC500 or PentaCB was observed in both Wistar and Gunn rats. From the serum of KC500- or PentaCB-treated Wistar and Gunn rats, mono- and di-hydroxylated PCB metabolites, which would bind to T4 binding serum protein (transthyretin), were detected. In conclusion, the present results suggest that the decrease in serum total T4 level by either KC500 or PentaCB in Gunn rats was not dependent on the increase in hepatic T4-UDP-GT activity. The findings further suggest that the PCB-mediated decrease in serum T4 level might occur, at least in part, through formation of the hydroxylated PCB metabolites. Furthermore, even in Wistar rats, the PCB-mediated decrease in serum T4 level might occur not only through the increase in hepatic T4-UDP-GT but also via formation of hydroxylated PCB metabolites.

Key Words: polychlorinated biphenyls; Kanechlor-500; thyroid hormones; UDP-glucuronosyltransferases; Wistar rats; Gunn rats.


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