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Research ArticleArticle

Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

L. A. Martin, D. T. Wilson, K. R. Reuhl, M. A. Gallo and C. D. Klaassen
Drug Metabolism and Disposition March 2012, 40 (3) 588-595; DOI: https://doi.org/10.1124/dmd.111.042796
L. A. Martin
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D. T. Wilson
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K. R. Reuhl
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M. A. Gallo
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C. D. Klaassen
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Abstract

Polychlorinated biphenyl (PCB) congeners differentially reduce serum thyroxine (T4) in rats, but little is known about their ability to affect biliary excretion of T4. Thus, male Sprague-Dawley rats were orally administered Aroclor-1254, Aroclor-1242 (32 mg/kg per day), PCB-95, PCB-99, PCB-118 (16 mg/kg per day), PCB-126 (40 μg/kg per day), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (3.9 μg/kg per day), or corn oil for 7 days. Twenty-four hours after the last dose, [125I]T4 was administered intravenously, and blood, bile, and urine samples were collected for quantifying [125I]T4 and in bile [125I]T4 metabolites. Serum T4 concentrations were reduced by all treatments, but dramatic reductions occurred in response to Aroclor-1254, PCB-99 [phenobarbital (PB)-type congener], and PCB-118 (mixed-type congener). None of the treatments increased urinary excretion of [125I]T4. Aroclor-1254, PCB-118, TCDD, and PCB-126 (TCDD-type congener) increased biliary excretion of T4-glucuronide by 850, 756, 710, and 573%, respectively, corresponding to marked induction of hepatic UDP-glucuronosyltransferase (UGT) activity toward T4. PCB-95 and PCB-99 did not induce UGT activity; therefore, the increased biliary excretion of T4-glucuronide was related to the affinity of congeners for the aryl hydrocarbon receptor. The disappearance of [125I]T4 from serum was rapid (within 15-min) and was increased by Aroclor-1254, PCB-99 and PCB-118. Thus, reductions in serum T4 in response to PCBs did not always correspond with UGT activity toward T4 or with increased biliary excretion of T4-glucuronide. The rapid disappearance of [125I]T4 from the serum of rats treated with PB-like PCBs suggests that increased tissue uptake of T4 is an additional mechanism by which PCBs may reduce serum T4.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES013714, ES09716] [Training Grants ES07079, ES05022, ES07148]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK-081461]; and the National Institutes of Health National Center for Research Resources [Grant RR021940].

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

    http://dx.doi.org/10.1124/dmd.111.042796.

  • ABBREVIATIONS:

    T3
    triiodothyronine
    T4
    thyroxine
    PCN
    pregnenolone-16α-carbonitrile
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    PCB
    polychlorinated biphenyl
    AhR
    aryl hydrocarbon receptor
    PB
    phenobarbital
    PCB-126
    3,3′4,4′,5-pentachlorobiphenyl
    PCB-95
    2,2′,3,5′,6-pentachlorobiphenyl
    PCB-99
    2,2′,4,4′,5-pentachlorobiphenyl
    PCB-118
    2,3′,4,4′,5-pentachlorobiphenyl
    HPLC
    high-performance liquid chromatography
    UGT
    UDP-glucuronosyltransferase
    EROD
    ethoxyresorufin-O-deethylase
    PROD
    pentoxyresorufin-O-deethylase
    3-MC
    3-methylcholanthrene
    Mrp2
    multidrug resistance protein-2.

  • Received September 17, 2011.
  • Accepted December 5, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

PCB CONGENERS ON BILIARY EXCRETION OF THYROXINE

L. A. Martin, D. T. Wilson, K. R. Reuhl, M. A. Gallo and C. D. Klaassen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 588-595; DOI: https://doi.org/10.1124/dmd.111.042796

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Research ArticleArticle

PCB CONGENERS ON BILIARY EXCRETION OF THYROXINE

L. A. Martin, D. T. Wilson, K. R. Reuhl, M. A. Gallo and C. D. Klaassen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 588-595; DOI: https://doi.org/10.1124/dmd.111.042796
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