Wang Zi, Hu Jun-Nan, Yan Meng-Han, Xing Jing-Jing, Liu Wen-Cong, Li Wei
College of Chinese Medicinal Materials, Jilin Agricultural University , Changchun 130118, China.
J Agric Food Chem. 2017 Oct 25;65(42):9226-9236. doi: 10.1021/acs.jafc.7b03361. Epub 2017 Oct 16.
Frequent overdose of acetaminophen (APAP) is one of the most common and important incentives of acute hepatotoxicity. Prior to this work, our research group confirmed that black ginseng (Panax ginseng, BG) showed powerful protective effects on APAP-induced ALI. However, it is not clear which kind of individual ginsenoside from BG plays such a liver protection effect. The objective of the current investigation was to evaluate whether ginsenoside Rg5 (G-Rg5) protected against APAP-induced hepatotoxicity and the involved action mechanisms. Mice were administrated with G-Rg5 at two dosages of 10 or 20 mg/kg for 7 consecutive days. After the last treatment, all of the animals that received a single intraperitoneal injection of APAP (250 mg/kg) showed severe liver toxicity after 24 h, and the liver protection effects of G-Rg5 were examined. The results clearly indicated that pretreatment with G-Rg5 remarkably inhibited the production of serum tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) compared with the APAP group. Meanwhile, G-Rg5 decreased the hepatic malondialdehyde (MDA) content, the protein expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 2E1 (CYP2E1) in the liver tissues. G-Rg5 decreased APAP caused the hepatic overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Furthermore, analysis of immunohistochemistry and Western blotting also indicated that G-Rg5 pretreatment inhibited activation of apoptotic pathways mainly via increasing the expression of Bcl-2 protein, decreasing the expression of Bax protein, proliferating cell nuclear antigen (PCNA), cytochrome c, caspase-3, caspase-8, and caspase-9. Liver histopathological observation provided further evidence that pretreatment with G-Rg5 could significantly inhibit hepatocyte necrosis, inflammatory cell infiltration, and apoptosis caused by APAP. In conclusion, the present study clearly demonstrates that G-Rg5 exerts a liver protection effect against APAP-induced acute hepatotoxicity mainly via a caspase-mediated anti-apoptotic effect.
对乙酰氨基酚（APAP）的频繁过量服用是急性肝毒性最常见且重要的诱因之一。在本研究开展之前，我们的研究团队证实黑参（Panax ginseng，BG）对APAP诱导的急性肺损伤具有强大的保护作用。然而，尚不清楚BG中的哪种人参皂苷发挥了这种肝脏保护作用。本研究的目的是评估人参皂苷Rg5（G-Rg5）是否能预防APAP诱导的肝毒性及其相关作用机制。将小鼠连续7天给予10或20 mg/kg两种剂量的G-Rg5。在最后一次治疗后，所有单次腹腔注射APAP（250 mg/kg）的动物在24小时后均表现出严重的肝毒性，并检测G-Rg5的肝脏保护作用。结果清楚地表明，与APAP组相比，G-Rg5预处理显著抑制了血清肿瘤坏死因子（TNF-α）和白细胞介素-1β（IL-1β）的产生。同时，G-Rg5降低了肝组织中丙二醛（MDA）含量、4-羟基壬烯醛（4-HNE）和细胞色素P450 2E1（CYP2E1）的蛋白表达水平。G-Rg5降低了APAP引起的肝脏中环氧合酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的过度表达。此外，免疫组织化学和蛋白质印迹分析还表明，G-Rg5预处理主要通过增加Bcl-2蛋白的表达、降低Bax蛋白、增殖细胞核抗原（PCNA）、细胞色素c、半胱天冬酶-3、半胱天冬酶-8和半胱天冬酶-9的表达来抑制凋亡途径的激活。肝脏组织病理学观察提供了进一步的证据，表明G-Rg5预处理可显著抑制APAP引起的肝细胞坏死、炎性细胞浸润和凋亡。总之，本研究清楚地表明，G-Rg5主要通过半胱天冬酶介导的抗凋亡作用对APAP诱导的急性肝毒性发挥肝脏保护作用。
