title: Thioacetamide intoxication triggers transcriptional up-regulation but enzyme inactivation of UDP-glucuronosyltransferases.
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.
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors: Haiping
authors: H
authors: Hao
authors: Lifang
authors: L
authors: Zhang
authors: Shan
authors: S
authors: Jiang
authors: Shiqing
authors: S
authors: Sun
authors: Ping
authors: P
authors: Gong
authors: Yuan
authors: Y
authors: Xie
authors: Xueyan
authors: X
authors: Zhou
authors: Guangji
authors: G
authors: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D020011:Protective Agents / Q000494:pharmacology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry / Q000378:metabolism; D013853:Thioacetamide / Q000633:toxicity*; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D004149:Dioxoles; D017705:Lignans; D020011:Protective Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; D013853:Thioacetamide; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D014453:Glucuronosyltransferase