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.
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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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