Abstract

CYP2E1 plays a crucial role in the bio-activation of toxic substances leading to liver damage. In this context, CYP2E1 converts paracetamol (PCM) to N-acetyl-p-benzoquinone imine (NAPQI), which is prone to cause hepatotoxicity. Hence, we aimed to explore the protective effect of glabridin on widely used PCM-induced liver injury model in the present study and, after that, correlated with the role of CYP2E1 toward its efficacy. Glabridin was isolated from Glycyrrhiza glabra and characterized before the investigation in an in-vivo mice model of PCM-induced liver injury. Glabridin after oral treatment at 5–20 mg/kg showed a considerable improvement in serum biochemical parameters (ALT and AST) and oxidative stress markers (MDA, GSH, SOD, and catalase) in comparison to only PCM-treatment. Histopathological examination of the liver depicted that glabridin exhibited substantial protection from PCM-induced liver injury compared to the disease control group. Significant down-regulation of CYP2E1 protein and its mRNA expression levels were observed in the glabridin-treated groups compared to PCM-induced respective elevation of CYP2E1. Moreover, activation of NF-κB was significantly inhibited by glabridin. Therefore, glabridin has the potential to protect PCM-induced liver injury through CYP2E1 inhibition-mediated normalization of oxidative stress. Further research is warranted to establish glabridin as a phytotherapeutics for liver protection for which no effective and safe oral drug is available to date.

摘要

CYP2E1在导致肝损伤的有毒物质的生物活化中起着至关重要的作用。在这种情况下，CYP2E1 将扑热息痛 (PCM) 转化为容易引起肝毒性的 N-乙酰基-对苯醌亚胺 (NAPQI)。因此，我们旨在探索光甘草定对本研究中广泛使用的 PCM 诱导的肝损伤模型的保护作用，然后与 CYP2E1 对其疗效的作用相关。从光甘草中分离出光甘草定，并在体内研究前对其进行了表征PCM诱导的肝损伤小鼠模型。与仅 PCM 治疗相比，口服 5-20 mg/kg 光甘草定后血清生化参数（ALT 和 AST）和氧化应激标志物（MDA、GSH、SOD 和过氧化氢酶）有显着改善。肝脏的组织病理学检查表明，与疾病对照组相比，光甘草定对 PCM 引起的肝损伤表现出显着的保护作用。与 PCM 诱导的 CYP2E1 相应升高相比，在光甘草定治疗组中观察到 CYP2E1 蛋白及其 mRNA 表达水平显着下调。此外，光甘草定显着抑制NF-κB的活化。因此，光甘草定有可能通过 CYP2E1 抑制介导的氧化应激正常化来保护 PCM 诱导的肝损伤。