Abstract

Activation of the constitutive androstane receptor (CAR, NR1I3) by chemical compounds induces liver hyperplasia in rodents. 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a mouse CAR agonist, is most often used to study chemically induced liver hyperplasia and hepatocyte proliferation in vivo. TCPOBOP is a potent murine liver chemical mitogen, which induces rapid liver hyperplasia in mice independently of liver injury. In recent years, great amount of data has been accumulated on the transcription program that characterizes the TCPOBOP-induced hepatocyte proliferation. However, there are only few data about the metabolic requirements of hepatocytes that divide upon exposure to xenobiotics. In the present study, we have employed liquid chromatography – mass spectrometry technology combined with statistical analysis to investigate metabolite profile of small biomolecules, in order to identify key metabolic changes in the male mouse liver tissue after TCPOBOP administration. Analysis of biochemical pathways of the differentially affected metabolites in the mouse liver demonstrated significant TCPOBOP-mediated enrichment of several processes including those associated with nucleotide metabolism, amino acid metabolism, and energy substrate metabolism. Our findings provide evidence to support the conclusion that the CAR agonist, TCPOBOP, initiates an intracellular program that promotes global coordinated metabolic activities required for hepatocyte proliferation. Our metabolic data might provide novel insight into the biological mechanisms that occur during the TCPOBOP-induced hepatocyte proliferation in mice.

中文翻译：

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组成型雄甾烷受体激动剂启动肝细胞增殖所需的代谢活动

摘要

化合物激活组成型雄甾烷受体（CAR、NR1I3）可诱导啮齿动物肝脏增生。1,4-双[2-(3,5-二氯吡啶氧基)]苯 (TCPOBOP) 是一种小鼠 CAR 激动剂，最常用于研究体内化学诱导的肝脏增生和肝细胞增殖。TCPOBOP 是一种有效的小鼠肝脏化学有丝分裂原，可诱导小鼠肝脏快速增生，而不受肝损伤的影响。近年来，关于TCPOBOP诱导肝细胞增殖的转录程序积累了大量数据。然而，关于暴露于异生素时分裂的肝细胞的代谢需求的数据很少。在本研究中，我们采用液相色谱-质谱技术结合统计分析来研究小生物分子的代谢谱，以鉴定TCPOBOP给药后雄性小鼠肝组织的关键代谢变化。对小鼠肝脏中不同影响的代谢物的生化途径的分析表明，TCPOBOP 介导的几个过程显着富集，包括与核苷酸代谢、氨基酸代谢和能量底物代谢相关的过程。我们的研究结果提供了证据支持以下结论：CAR 激动剂 TCPOBOP 启动了细胞内程序，促进肝细胞增殖所需的全局协调代谢活动。我们的代谢数据可能为 TCPOBOP 诱导小鼠肝细胞增殖过程中发生的生物学机制提供新的见解。