Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, P.R China.
Food Funct. 2018 Nov 14;9(11):5891-5902. doi: 10.1039/c8fo01078a.
Acetaminophen (APAP) is commonly used to relieve pain and fever in a clinical setting, but its excessive use can lead to serious hepatotoxicity. Our previous study demonstrated that polydatin (PD) can effectively attenuate d-galactose- and alcohol-induced hepatotoxicity, however, its effect on APAP-induced hepatotoxicity is still unknown. In this study, we explore the protective effect and potential mechanism of PD against APAP-induced hepatotoxicity in mice. The results indicate that PD effectively improves the survival of mice with APAP-induced hepatotoxicity, significantly alleviating histopathologic alterations in the liver, and decreasing the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). PD significantly and dose-dependently reduces oxidative stress by lowering the content of oxidized glutathione (GSSG), reactive oxygen species (ROS), nitric oxide (NO) and malonaldehyde (MDA), while enhancing the hepatic activities of glutathione (GSH), glutathione peroxidase (GSH-Px) and the GSH/GSSG ratio. Meanwhile, PD also substantially inhibits the levels and mRNA expressions of inducible nitric oxide synthase (iNOS) and NADPH oxidase 2 (NOX2). Additionally, PD markedly arrests apoptosis by assuaging TUNEL-positive hepatocytes and the apoptotic index, decreasing the levels and expression of cytochrome c (CytC), cleaved-caspase-9, apoptotic protease activating factor 1 (Apaf-1), cleaved-caspase-3, and Bax and increasing the level and expression of Bcl-2. Overall, PD pretreatment shows a potent protective effect against APAP-induced hepatotoxicity by relieving oxidative stress and inhibiting apoptosis.
对乙酰氨基酚（APAP）常用于临床缓解疼痛和发热，但过量使用会导致严重的肝毒性。我们之前的研究表明，白藜芦醇（PD）可以有效减轻半乳糖和酒精引起的肝毒性，然而，其对 APAP 诱导的肝毒性的作用尚不清楚。在这项研究中，我们探讨了 PD 对小鼠 APAP 诱导的肝毒性的保护作用及其潜在机制。结果表明，PD 能有效提高 APAP 诱导的肝毒性小鼠的存活率，显著改善肝脏组织病理学改变，降低血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。PD 能显著降低氧化型谷胱甘肽（GSSG）、活性氧（ROS）、一氧化氮（NO）和丙二醛（MDA）含量，从而有效减轻氧化应激，呈剂量依赖性。同时，PD 还能显著降低诱导型一氧化氮合酶（iNOS）和 NADPH 氧化酶 2（NOX2）的水平和 mRNA 表达。此外，PD 还能通过减轻 TUNEL 阳性肝细胞和凋亡指数，降低细胞色素 c（CytC）、裂解型半胱天冬酶-9（cleaved-caspase-9）、凋亡蛋白酶激活因子 1（Apaf-1）、裂解型半胱天冬酶-3（cleaved-caspase-3）和 Bax 的水平和表达，增加 Bcl-2 的水平和表达，显著抑制细胞凋亡。总之，PD 预处理通过缓解氧化应激和抑制细胞凋亡，对 APAP 诱导的肝毒性具有很强的保护作用。
