Abstract

Rhein is a key ingredient in many herbal remedies and is widely used. However, herbs containing rhein are frequently associated with poisoning incidents, especially in elderly subjects. Acute and subchronic toxicity of rhein in Kunming mice (KM) was investigated in this experiment. Acute toxicity tests showed a 40% lethality at a given rhein dose of 4000 mg/kg, and the LD50 of rhein was calculated by the bliss method to be greater than 2185.6 mg/kg. In subchronic toxicity, d-gal-induced aged and immature animals were randomized into three groups that were exposed to rhein of 0, 175, and 375 mg/kg/d for 75 days, respectively. No mortality was observed in immature mice group, whereas 55.5% (5/9) subjects in aged mice groups died in the high dosage group. AST, ALT, IL-6, TNF-α levels and typical histopathological changes indicate that rhein causes liver injury. In addition, our investigation explored possible hepatotoxic mechanisms of rhein and experimental results showed increased ROS production, NRF-2 and MDA levels and decreased SOD levels, demonstrating that rhein causes oxidative stress. MMP and mitochondrial swelling levels were able to assess the impact of rhein on mitochondrial function. Furthermore, the effect of rhein on apoptosis can be detected by flow cytometry. Our studies suggested that rhein induces oxidative stress leading to mitochondria dysfunction and apoptotic activation. Multidrug resistance protein (MRP) is an efflux transporter protein and is capable of transporting cellular oxidative stress-related substances. To further clarify the role of MRP in rhein induced oxidative stress, we examined MRP expression in the liver. However, the expression of MRP has no statistical significance.

摘要

莱茵是许多草药中的关键成分，并被广泛使用。然而，含有大黄酸的草药经常与中毒事件有关，尤其是在老年人身上。本实验研究了大黄酸对昆明小鼠（KM）的急性和亚慢性毒性。急性毒性试验表明，在给定的大黄酸剂量为 4000 mg/kg 时有 40% 的致死率，通过 bliss 法计算大黄酸的 LD50 大于 2185.6 mg/kg。在亚慢性毒性中，d-gal 诱导的老年和未成熟动物被随机分为三组，分别暴露于 0、175 和 375 mg/kg/d 的大黄酸 75 天。在未成熟小鼠组中未观察到死亡，而在高剂量组中，老年小鼠组中有55.5%（5/9）的受试者死亡。AST、ALT、IL-6、TNF-α水平和典型的组织病理学变化表明大黄酸引起肝损伤。此外，我们的研究探索了大黄酸可能的肝毒性机制，实验结果显示增加的 ROS 产生、NRF-2 和 MDA 水平以及降低的 SOD 水平，表明大黄酸引起氧化应激。MMP 和线粒体肿胀水平能够评估大黄酸对线粒体功能的影响。此外，大黄酸对细胞凋亡的影响可以通过流式细胞术检测。我们的研究表明，大黄酸诱导氧化应激，导致线粒体功能障碍和凋亡激活。多药耐药蛋白（MRP）是一种外排转运蛋白，能够转运细胞氧化应激相关物质。为了进一步阐明 MRP 在大黄酸诱导的氧化应激中的作用，我们检测了 MRP 在肝脏中的表达。然而，MRP的表达没有统计学意义。