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Research ArticleArticle

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Nichole R. Vansell and Curtis D. Klaassen
Drug Metabolism and Disposition March 2002, 30 (3) 240-246; DOI: https://doi.org/10.1124/dmd.30.3.240
Nichole R. Vansell
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Curtis D. Klaassen
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Abstract

Treatment of rats with the microsomal enzyme inducers pregnenolone-16α-carbonitrile (PCN), 3-methylcholanthrene (3-MC), and Aroclor 1254 [PCB (polychlorinated biphenyl)] has been shown to decrease circulating levels of thyroid hormones as well as increase microsomal glucuronidation of thyroxine (T4). In addition, PCN increases triiodothyronine (T3) uridine diphosphate glucuronosyltransferase (UGT) activity. Members of the UGT1A family are believed to glucuronidate T4, specifically UGT1A1 and UGT1A6, whereas the UGT2 family is believed to glucuronidate T3, namely UGT2B2. The purpose of this study was to determine whether the aforementioned microsomal enzyme inducers increase the mRNAs that encode these and other UGT enzymes in rat liver. Male Sprague-Dawley rats were fed a control diet or a diet containing PCN (1000 ppm), 3-MC (250 ppm), or PCB (100 ppm) for 7 days, at which time livers were collected. Increases in mRNA were detected by QuantiGene branched DNA signal amplification. A 3-fold increase in UGT1A1 mRNA was produced by PCN in addition to increases in UGT1A2 (4-fold) and UGT1A5 (2-fold) mRNA. PCN affected neither UGT2B2 nor any other UGT2B mRNA level. 3-MC and PCB increased UGT1A6 mRNA 6- and 4-fold, respectively. 3-MC and PCB each increased UGT1A7 mRNA 4-fold but did not significantly increase any other UGT mRNAs. These findings suggest that PCN enhances T4 UGT activity by increased expression of UGT1A1 and that 3-MC and PCB enhance T4 UGT activity by increased expression of UGT1A6. These findings also suggest that increased T3 UGT activity produced by PCN is due to a mechanism other than increased transcription of UGT2B2, possibly increased UGT2B2 protein or induction of another UGT enzyme.

Footnotes

  • This study was supported by National Institutes of Health Grant ES-08156; Nichole R. Vansell was supported by National Institutes of Health Training Grant ES-07079.

  • Abbreviations used are::
    UGT
    uridine diphosphate glucuronosyltransferase
    T4
    thyroxine
    T3
    triiodothyronine
    PCN
    pregnenolone-16α-carbonitrile
    3-MC
    3-methylcholanthrene
    PCB
    polychlorinated biphenyl
    bDNA
    branched DNA
    RLU
    relative luminescence units
    PXR
    pregnane-X-receptor
    XRE
    xenobiotic response element
    PB
    phenobarbital
    MOPS
    4-morpholinepropanesulfonic acid
    • Received July 31, 2001.
    • Accepted November 27, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (3)
Drug Metabolism and Disposition
Vol. 30, Issue 3
1 Mar 2002
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Research ArticleArticle

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Nichole R. Vansell and Curtis D. Klaassen
Drug Metabolism and Disposition March 1, 2002, 30 (3) 240-246; DOI: https://doi.org/10.1124/dmd.30.3.240

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Research ArticleArticle

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

Nichole R. Vansell and Curtis D. Klaassen
Drug Metabolism and Disposition March 1, 2002, 30 (3) 240-246; DOI: https://doi.org/10.1124/dmd.30.3.240
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