Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Toxicology. 2011 Dec 18;290(2-3):203-7. doi: 10.1016/j.tox.2011.09.007. Epub 2011 Sep 29.
The expression of genes involved in xenobiotic detoxification is under the control of the circadian clock. The aryl hydrocarbon receptor (AhR) is one of the transcription factors responsible for the induction of detoxification enzymes in response to xenobiotic toxins, and the expression of AhR has been suggested to be regulated by a circadian oscillator. In this study, we investigated whether toxin-mediated activation of the AhR signaling pathway was modulated by CLOCK protein, a key component of the mammalian circadian clock. The expression of AhR and its DNA binding ability in the lungs of wild-type mice showed significant 24-h oscillation. Clock mutant (Clk/Clk) mice, producing CLOCK protein deficient in transcriptional activity, failed to show significant oscillation in the expression of AhR. The mRNA levels of AhR in the lungs of Clk/Clk mice were significantly lower than in wild-type mice. A single intraperitoneal injection of benzo[α]pyrene, a ligand of AhR, induced the expression of Cyp1a1 in the lungs of wild-type mice, but the induction varied depending on the benzo[α]pyrene injection time. The dosing time-dependency of benzo[α]pyrene-induced Cyp1a1 expression was also modulated by Clock gene mutation. These findings suggest that CLOCK protein affects the toxin-induced expression of detoxification enzymes through modulating the activity of AhR. Our present findings provide a molecular link between the circadian clock and xenobiotic detoxification.
参与外来化合物解毒的基因表达受生物钟的控制。芳香烃受体 (AhR) 是负责诱导解毒酶以应对外来毒素的转录因子之一，并且 AhR 的表达被认为受生物钟振荡器的调节。在这项研究中，我们研究了毒素介导的 AhR 信号通路的激活是否受生物钟关键组成部分 CLOCK 蛋白的调节。野生型小鼠肺部 AhR 的表达及其 DNA 结合能力显示出明显的 24 小时振荡。产生转录活性缺乏 CLOCK 蛋白的 Clock 突变（Clk/Clk）小鼠未能显示 AhR 表达的显著振荡。Clk/Clk 小鼠肺部 AhR 的 mRNA 水平明显低于野生型小鼠。单次腹腔注射 AhR 的配体苯并[α]芘诱导野生型小鼠肺部 Cyp1a1 的表达，但诱导取决于苯并[α]芘的注射时间。Clock 基因突变也调节了苯并[α]芘诱导 Cyp1a1 表达的时间依赖性。这些发现表明 CLOCK 蛋白通过调节 AhR 的活性影响毒素诱导的解毒酶表达。我们目前的研究结果为生物钟和外来化合物解毒之间提供了分子联系。
