State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Drug Metab Dispos. 2011 Oct;39(10):1815-22. doi: 10.1124/dmd.111.039172. Epub 2011 Jul 6.
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.
硫代乙酰胺（TAA）是一种有效的肝毒性物质，已被广泛用于开发实验性肝纤维化/肝硬化模型。尽管 TAA 的肝毒性已被广泛研究，但对于其对与肝纤维化发展相关的 UDP-葡糖醛酸基转移酶（UGTs）的潜在影响知之甚少。本研究旨在揭示 TAA 诱导的大鼠肝纤维化中 UGTs 的调控模式，并确定肝保护剂的潜在拮抗作用。TAA 治疗 8 周可显著诱导主要 UGT 同工酶的转录上调，包括 UGT1A1、UGT1A6 和 UGT2B1，同时伴有大多数典型的肝功能血清标志物和纤维化评分的显著升高。在 TAA 中毒时，主要 UGT 同工酶的 mRNA 和蛋白水平分别增加到正常对照的 1.5-2.5 倍和 2.5-3.3 倍。五味子属木脂素提取物和二甲基二苯基双羧酸酯这两种肝保护剂可显著消除 TAA 诱导的所有三种 UGT 同工酶的上调。然而，TAA 处理后 UGTs 的酶活性保持不变。蛋白表达和酶活性的分离可能归因于 TAA 在 NADPH 依赖性生物激活作用下对 UGTs 的失活作用。本研究表明，UGTs 的转录上调可能是其在肝纤维化/肝硬化中保持活性的另一种机制。
