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Research ArticleArticles

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Haiping Hao, Lifang Zhang, Shan Jiang, Shiqing Sun, Ping Gong, Yuan Xie, Xueyan Zhou and Guangji Wang
Drug Metabolism and Disposition October 2011, 39 (10) 1815-1822; DOI: https://doi.org/10.1124/dmd.111.039172
Haiping Hao
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Lifang Zhang
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Shan Jiang
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Shiqing Sun
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Ping Gong
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Yuan Xie
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Xueyan Zhou
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Guangji Wang
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Abstract

Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5- to 2.5-fold and 2.5- to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.

Footnotes

  • This work was supported by the National Natural Science Foundation of China [Grants 91029746, 30801422, 30973583]; the Program for New Century Excellent Talents in University of China [Grant NCET-09-0770]; and a Foundation for the Author of National Excellent Doctoral Dissertation of China [Grant 200979].

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

    doi:10.1124/dmd.111.039172.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    UGTs
    UDP-glucuronosyltransferases
    TAA
    thioacetamide
    SLE
    Schisandra lignans extract
    DDB
    dimethyl diphenyl bicarboxylate
    TES
    testosterone
    4-MU
    4-methylumbelliferone
    UDPGA
    UDP-glucuronic acid
    HPLC
    high-performance liquid chromatography
    ALT
    alanine aminotransferase
    AST
    aspartate aminotransferase
    AP
    alkaline phosphatase
    ALB
    albumin
    γ-GT
    γ-glutamyl transpeptidase
    T-Bil
    total bilirubin
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    PCR
    polymerase chain reaction
    TBST
    Tris-buffered saline/Tween 20 buffer
    CMC-Na
    sodium carboxymethyl cellulose
    bp
    base pair(s).

  • Received March 1, 2011.
  • Accepted July 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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TAA-INDUCED DYSREGULATIONS OF UGT

Haiping Hao, Lifang Zhang, Shan Jiang, Shiqing Sun, Ping Gong, Yuan Xie, Xueyan Zhou and Guangji Wang
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1815-1822; DOI: https://doi.org/10.1124/dmd.111.039172

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Research ArticleArticles

TAA-INDUCED DYSREGULATIONS OF UGT

Haiping Hao, Lifang Zhang, Shan Jiang, Shiqing Sun, Ping Gong, Yuan Xie, Xueyan Zhou and Guangji Wang
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1815-1822; DOI: https://doi.org/10.1124/dmd.111.039172
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