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4-Hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice Occurs through Increase in Accumulation of Thyroxine in the Liver

Yoshihisa Kato, Koichi Haraguchi, Makiko Kubota, Yoshiki Seto, Shin-ichi Ikushiro, Toshiyuki Sakaki, Nobuyuki Koga, Shizuo Yamada and Masakuni Degawa
Drug Metabolism and Disposition October 2009, 37 (10) 2095-2102; DOI: https://doi.org/10.1124/dmd.109.028621
Yoshihisa Kato
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Koichi Haraguchi
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Makiko Kubota
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Yoshiki Seto
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Shin-ichi Ikushiro
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Toshiyuki Sakaki
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Nobuyuki Koga
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Shizuo Yamada
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Masakuni Degawa
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Abstract

4-Hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl (4-OH-CB187) was selected as a major hydroxylated polychlorinated biphenyl metabolite detected from serum of wildlife and humans and was examined for its effect on level of serum thyroid hormone in mice. Four days after treatment of C57BL/6 and DBA/2 mice with 4-OH-CB187 (1.0 mg/kg), the serum total thyroxine (T4) and free T4 levels were decreased in both strains of mice. On the other hand, no significant changes in the level and activity of the T4-UDP-glucuronosyltransferases, including UGT1a and UGT1a1, by the 4-OH-CB187 treatment were observed in either strain of mice. No 4-OH-CB187-mediated change in level of serum thyroid-stimulating hormone was observed in either strain of mice. Binding levels of [125I]T4 to serum proteins after administration of [125I]T4 were significantly changed in 4-OH-CB187-pretreated mice: a decrease in the level of serum [125I]T4-transthyretin (TTR) complex and an increase in the binding level of [125I]T4 to serum albumin and thyroxine binding protein in both strains of mice. Clearance from serum of T4 was promoted by 4-OH-CB187 pretreatment in both C57BL/6 and DBA/2 mice, and the levels of T4 in several tissues, especially the liver, were increased. In addition, 4-OH-CB187-mediated decreases in serum total T4 and free T4 levels were observed in wild-type and TTR-heterozygous mice but not in TTR-deficient mice. The present findings show that 4-OH-CB187 shows a definite ability to decrease serum T4 level and further indicate that the 4-OH-CB187-induced decrease would occur through increase in accumulation of T4 in the liver.

  • OH-PCB, hydroxylated polychlorinated biphenyl
  • PCB, polychlorinated biphenyl
  • 4-OH-CB107, 4-hydroxy-2,3,3′,4′,5-pentachlorobiphenyl
  • 3-OH-CB153, 3-hydroxy-2,2′,4,4′,5,5′-hexachlorobiphenyl
  • 4-OH-CB146, 4-hydroxy-2,2′,3,4′,5,5′-hexachlorobiphenyl
  • 3′-OH-CB138, 3′-hydroxy-2,2′,3,4,4′,5′-hexachlorobiphenyl
  • 4-OH-CB187, 4-hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl
  • TTR, transthyretin
  • T4, thyroxine
  • UDPGT, UDP-glucuronosyltransferase
  • TSH, thyroid-stimulating hormone
  • HPLC, high-performance liquid chromatography
  • TBG, thyroxine binding globulin.

Footnotes

  • This work was supported in part by grants-in-aid for Scientific Research (C) [Grant 20510070] and for Scientific Research (B) [Grant 19310042] from Japan Society for the Promotion of Science.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    • Received May 27, 2009.
    • Accepted July 6, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (10)
Drug Metabolism and Disposition
Vol. 37, Issue 10
October 2009
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4-Hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice Occurs through Increase in Accumulation of Thyroxine in the Liver

Yoshihisa Kato, Koichi Haraguchi, Makiko Kubota, Yoshiki Seto, Shin-ichi Ikushiro, Toshiyuki Sakaki, Nobuyuki Koga, Shizuo Yamada and Masakuni Degawa
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2095-2102; DOI: https://doi.org/10.1124/dmd.109.028621

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4-Hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl-Mediated Decrease in Serum Thyroxine Level in Mice Occurs through Increase in Accumulation of Thyroxine in the Liver

Yoshihisa Kato, Koichi Haraguchi, Makiko Kubota, Yoshiki Seto, Shin-ichi Ikushiro, Toshiyuki Sakaki, Nobuyuki Koga, Shizuo Yamada and Masakuni Degawa
Drug Metabolism and Disposition October 1, 2009, 37 (10) 2095-2102; DOI: https://doi.org/10.1124/dmd.109.028621
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