Abstract
Serum total thyroxine (T4) and free T4 levels were markedly decreased 7 days after treatment with 3,3′,4,4′,5-pentachlorobiphenyl (CB126) (2.5 mg/kg i.p.) in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 mice but not in TCDD-resistant DBA/2 mice. At the same time, the level and activity of hepatic T4-UDP-glucuronosyltransferase (T4-UGT) were significantly increased in C57BL/6 mice but not in DBA/2 mice. Furthermore, the amounts of biliary [125I]T4 and [125I]T4 glucuronide after injection of [125I]T4 were increased by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice. Clearance of [125I]T4 from serum was also promoted by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice. On the other hand, no significant changes in the steady-state volumes of distribution of [125I]T4 and in the concentration ratio (Kp value) of the liver to serum by CB126 pretreatment were observed in either strain of mice. Because liver weight was increased by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice, hepatic total [125I]T4 was increased only in C57BL/6 mice. The present findings indicate that CB126-mediated decrease in serum T4 occurs through the increase in hepatic T4-UGT and the enhanced accumulation of hepatic T4 along with development of liver hypertrophy.
Footnotes
This work was supported in part by the Japan Society for the Promotion of Science [Grants-in-Aid for Scientific Research 20510070 and 19310042].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029348
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- PCB
- polychlorinated biphenyl
- CB126
- 3,3′,4,4′,5-pentachlorobiphenyl
- UGT
- UDP-glucuronosyltransferase
- T4
- thyroxine
- TTR
- transthyretin
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- TSH
- thyroid-stimulating hormone
- TBG
- thyroxine-binding globulin.
- Received July 3, 2009.
- Accepted September 25, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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