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A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats

Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa, Japan (Y.K.); Faculty of Engineering, Toyama Prefectural University, Toyama, Japan (S.I., T.S.); School of Pharmaceutical Sciences and Center of Excellence (COE) Program in the 21^st Century, University of Shizuoka, Shizuoka, Japan (R.T., S.U., S.Y., M.D.); Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (K.H.); Faculty of Nutritional Sciences, Nakamura Gakuen University, Fukuoka, Japan (N.K.); and Division of Cellular & Molecular Toxicology, National Institute of Health Sciences, Tokyo, Japan (J.K.)

We have previously suggested that the decrease in the levels of serum total thyroxine (T₄) and free T₄ by a single administration to rats of Kanechlor-500 (KC500) at a dose of 100 mg/kg is not necessarily dependent on the increase in hepatic T₄-UDP-glucuronosyltransferase (UDP-GT). In the present study, we determined whether or not a consecutive treatment with KC500 at a relatively low dose (10 mg/kg i.p., once daily for 10 days) results in a decrease in the level of serum total T₄ and further investigated an exact mechanism for the KC500-induced decrease in the T₄. At 4 days after final treatment with KC500, the serum total T₄ and free T₄ levels were markedly decreased in both Wistar and UGT1A-deficient Wistar (Gunn) rats, whereas significant increases in hepatic T₄-UDP-GT activity were observed in Wistar rats but not in Gunn rats. The level of serum thyroid-stimulating hormone was not significantly changed in either Wistar or Gunn rats. Clearance from serum of the [¹²⁵I]T₄ administered to the KC500-pretreated Wistar and Gunn rats was faster than that to the corresponding control (KC500-untreated) rats. The accumulated level of [¹²⁵I]T₄ was increased in several tissues, especially the liver, in the KC500-pretreated rats. The present findings demonstrated that a consecutive treatment with KC500 resulted in a significant decrease in the level of serum total T₄ in both Wistar and Gunn rats and further indicated that the KC500-induced decrease would occur through increase in accumulation of T₄ in several tissues, especially the liver, rather than increase in hepatic T₄-UDP-GT activity.

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