Abstract
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.
Footnotes
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This work was supported in part by the Grant-in-Aid for Scientific Research (C) (no. 18510061; Y.K.) and for Scientific Research (B) (no. 19310042; K.H., Y.K.) from Japan Society for the Promotion of Science, and by a Health and Labour Sciences Research Grant for Research on Risk of Chemical Substances (H16-Kagaku-003; Y.K.) from the Ministry of Health, Labour and Welfare of Japan.
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doi:10.1124/dmd.107.017327.
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ABBREVIATIONS: PCB, polychlorinated biphenyl; KC500, Kanechlor-500; T3, triiodothyronine; T4, thyroxine; TTR, transthyretin; TSH, thyroid-stimulating hormone; UDP-GT, UDP-glucuronosyltransferase.
- Received June 19, 2007.
- Accepted July 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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