The biological clock is an endogenous biological timing system, which controls metabolic functions in almost all organs. Nutrient metabolism, substrate processing, and detoxification are circadian controlled in livers. However, how the clock genes respond to toxins and influence toxicity keeps unclear. We identified the clock gene Per1 was specifically elevated in mice exposed to toxins such as carbon tetrachloride (CCl₄). Mice lacking Per1 slowed down the metabolic rate of toxins including CCl₄, capsaicin, and acetaminophen, exhibiting relatively more residues in the plasma. Liver injury and fibrosis induced by acute and chronic CCl₄ exposure were markedly alleviated in Per1-deficient mice. These processes involved the binding of PER1 protein and hepatocyte nuclear factor-1alpha (HNF-1α), which enhances the recruitment of HNF-1α to cytochrome P450 2E1 (Cyp2e1) promoter and increases Cyp2e1 expression, thereby promoting metabolism for toxins in the livers. These results indicate that PER1 mediates the metabolism of toxins and appropriate suppression of Per1 response is a potential therapeutic target for toxin-induced hepatotoxicity.

生物钟是一种内源性的生物计时系统，它控制着几乎所有器官的代谢功能。营养代谢、底物处理和解毒在肝脏中受昼夜节律控制。然而，时钟基因如何对毒素作出反应并影响毒性尚不清楚。我们发现时钟基因Per1在暴露于四氯化碳 (CCl ₄ )等毒素的小鼠中特别升高。缺乏Per1 的小鼠减慢了包括 CCl ₄、辣椒素和对乙酰氨基酚在内的毒素的代谢率，在血浆中显示出相对更多的残留物。急性和慢性 CCl ₄暴露引起的肝损伤和纤维化在Per1中显着减轻- 缺乏小鼠。这些过程涉及 PER1 蛋白与肝细胞核因子-1α (HNF-1α) 的结合，从而增强 HNF-1α 向细胞色素 P450 2E1 ( Cyp2e1 ) 启动子的募集并增加Cyp2e1表达，从而促进肝脏中毒素的代谢。这些结果表明 PER1 介导毒素代谢，适当抑制Per1反应是毒素诱导的肝毒性的潜在治疗靶点。