Novosibirsk State University, Novosibirsk, 630090, Russia.
Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, 630117, Russia.
Biochemistry (Mosc). 2023 Aug;88(8):1061-1069. doi: 10.1134/S0006297923080023.
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.
化学化合物激活组成型雄烷受体（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）是一种鼠类 CAR 激动剂，常用于研究体内化学诱导的肝增生和肝细胞增殖。TCPOBOP 是一种强效的鼠类肝脏化学促分裂原，可独立于肝损伤诱导小鼠快速肝增生。近年来，大量数据积累了描述 TCPOBOP 诱导的肝细胞增殖的转录程序。然而，关于暴露于外源化学物质时分裂的肝细胞的代谢需求的数据却很少。在本研究中，我们采用液相色谱-质谱联用技术结合统计分析，研究小分子生物的代谢物谱，以鉴定 TCPOBOP 给药后雄性小鼠肝组织中的关键代谢变化。对差异影响代谢物的生化途径进行分析，表明在小鼠肝脏中，存在多个与核苷酸代谢、氨基酸代谢和能量底物代谢相关的过程显著受 TCPOBOP 介导的富集。我们的研究结果为 CAR 激动剂 TCPOBOP 启动促进肝细胞增殖所需的细胞内全局协调代谢活动的假设提供了证据。我们的代谢数据可能为理解 TCPOBOP 诱导的小鼠肝细胞增殖过程中的生物学机制提供新的视角。
