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

State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 07/2011; 39(10):1815-22. DOI: 10.1124/dmd.111.039172
Source: PubMed


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.

4 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.
    Drug metabolism and disposition: the biological fate of chemicals 01/2012; 40(4):796-802. DOI:10.1124/dmd.111.043539 · 3.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus is a chronic disease of complex metabolic disorder and associated with various types of complications. UDP-glucuronosyltransferases (UGTs), the major phase II conjugation enzymes, mediate the metabolism of both drugs and endogenous metabolites that may raise great concerns in the condition of diabetes. The aim of this study was to determine whether diabetes could affect UGTs at the intestinal and colonic tract. High-fat diet combined with a low-dose streptozotocin was used to induce type II diabetic model in rat. The mRNA levels and enzymatic activities of UGT1A1, -1A6, and -1A7 in diabetic intestine and colon were higher than those in nondiabetic rats. In contrast, both the activity and mRNA level of UGT2B1 in diabetic rats were lower than that in nondiabetic rats. Notably, the diabetic intestine and colon exhibited an inflammatory state with increased pro-inflammatory cytokines. Various transcriptional factors involved in UGT regulation were unanimously upregulated in diabetic intestine and colon. These findings strongly suggest that the regulating pathways of UGT1 family are adaptively upregulated in the diabetic gastrointestinal tract. Given the essential regulatory role of the gastrointestinal site in drug disposition, such changes in UGTs may have a dynamic and complex impact on therapeutic drugs and endogenous metabolomes.
    Drug Metabolism and Pharmacokinetics 04/2013; 28(5). DOI:10.2133/dmpk.DMPK-13-RG-020 · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: UDP-Glucuronosyltransferase (UGT) is an important class of phase II metabolizing enzymes, playing a pivotal role in detoxifying various substances and in the pathological procedures of some diseases. The present study aims to uncover the potential dysregulation pattern of UGTs in trinitrobenzene sulfonic acid (TNBS) induced colitis. Colitis was induced by intra-rectally administered with a single dose of TNBS (100 mg/kg). The expression and enzyme activity of hepatic UGTs of colitis rats were all down-regulated significantly except UGT1A7 for which the mRNA level was up-regulated. In contrast, UGT isoforms in the small intestine were relatively unaffected. In colon, where the inflammation occurs, the mRNA level and enzyme activity of UGT1A1 and 1A6 were down-regulated, but those of UGT1A7 and 2B1 up-regulated. The mRNA levels of various transcription factors, including AhR, CAR, PXR, PPARγ, and FXR were all decreased, except for AhR and CAR in small intestine and colon. Our data suggests that colitis induces an isoform-dependent and tissue-specific dysregulation of UGTs and their related transcription factors.
    Drug Metabolism and Pharmacokinetics 08/2013; 28(4). DOI:10.2133/dmpk.DMPK-12-RG-097 · 2.57 Impact Factor
Show more


4 Reads