Institute of Experimental and Clinical Pharmacology and Toxicology, Dept. of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany.
Toxicology. 2013 Jun 7;308:113-21. doi: 10.1016/j.tox.2013.03.019. Epub 2013 Apr 8.
The constitutive androstane receptor (CAR) controls the expression of drug-metabolizing enzymes and regulates hepatocyte proliferation. Studies with transgenic mice with an early postnatal conditional hepatocyte-specific knockout of the β-catenin gene Ctnnb1 revealed that β-catenin deficiency decreases the magnitude of induction of drug-metabolizing enzymes by CAR activators, abrogates zonal differences in the hepatocytes' susceptibility to these compounds, and impacts on hepatocyte proliferation. These data, however, do not allow distinguishing between effects caused by β-catenin deficiency during postnatal liver development and acute effects of β-catenin deficiency in the adult animal at the time point of CAR activation. Therefore, CAR activation was now studied in a different mouse model allowing for the hepatocyte-specific knockout of β-catenin in adult mice. Treatment of these mice with 3mg/kg body weight of the model CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) confirmed previous findings related to the coordinate regulation of drug metabolism by β-catenin and CAR. More importantly, the present study clarified that the impact of β-catenin signaling on CAR-mediated enzyme induction in the liver is not merely due to developmental defects caused by a postnatal lack of β-catenin, but depends on the presence of β-catenin at the time point of xenobiotic treatment. The study also revealed interesting differences between the two mouse models: hepatic zonation of TCPOBOP-dependent induction of drug-metabolizing enzymes was restored in mice with late knockout of β-catenin, and the strong proliferative response of female mice was exclusively abolished when using animals with a late β-catenin knockout. This suggests a β-catenin-dependent postnatal priming of hepatocytes during postnatal liver development, later affecting the proliferative response of adult animals to CAR-activating xenobiotics.
组成型雄烷受体 (CAR) 控制药物代谢酶的表达并调节肝细胞增殖。使用具有β-连环蛋白基因 Ctnnb1 早期出生后条件性肝细胞特异性敲除的转基因小鼠的研究表明，β-连环蛋白缺乏会降低 CAR 激活剂诱导药物代谢酶的幅度，消除这些化合物在肝细胞中易感性的区域差异，并影响肝细胞增殖。然而，这些数据无法区分出生后肝发育过程中由于β-连环蛋白缺乏引起的影响和 CAR 激活时成年动物中β-连环蛋白急性缺乏的影响。因此，现在在允许成年小鼠中肝细胞特异性敲除β-连环蛋白的另一种小鼠模型中研究了 CAR 激活。用模型 CAR 激活剂 1,4-双-[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP）以 3mg/kg 体重处理这些小鼠，证实了与β-连环蛋白和 CAR 协调调节药物代谢相关的先前发现。更重要的是，本研究阐明了β-连环蛋白信号对 CAR 介导的肝脏中酶诱导的影响不仅仅是由于出生后缺乏β-连环蛋白引起的发育缺陷，而是取决于外源性处理时β-连环蛋白的存在。该研究还揭示了两种小鼠模型之间的有趣差异：TCPOBOP 依赖性诱导的药物代谢酶在β-连环蛋白晚期敲除的小鼠中恢复了肝区带化，并且当使用晚期β-连环蛋白敲除动物时，雌性小鼠的强烈增殖反应被完全消除。这表明在出生后肝发育过程中存在β-连环蛋白依赖性的肝细胞“预编程”，随后影响成年动物对 CAR 激活的外源性物质的增殖反应。
