Pacific University College of Arts & Sciences, 2043 College Way UC #4882, Forest Grove, OR 97116, USA.
Pacific University School of Pharmacy, 222 S.E. 8th Avenue #451, Hillsboro, OR 97123, USA.
Chem Biol Interact. 2017 Nov 1;277:129-136. doi: 10.1016/j.cbi.2017.09.007. Epub 2017 Sep 13.
Due to its widespread availability, acetaminophen (APAP) is the leading cause for drug-induced liver injury in many countries including United States and United Kingdom. When used as recommended, APAP is relatively safe. However, in overdose cases, increased metabolism of APAP to N-acetyl-para-benzoquinoneimine (NAPQI), a reactive metabolite, leads to glutathione (GSH) depletion, oxidative stress, and cellular injury. Throughout this process, a variety of factors play important roles in propagating toxicity, including c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family. Because of its involvement in multiple cellular processes, biomarkers associated with MAPK signaling have generated interest as a mechanistic target for protecting against APAP-induced liver injury and hepatocellular injury, in general. This review summarizes mechanistic details by which natural products, specifically those containing polyphenolic moieties, are capable of attenuating APAP-induced toxicity, at least in part through an ability to modulate MAPKs. These compounds include carnosic acid, chlorogenic acid, davallialactone, extracts from Hibiscus sabdariffa, quercetin-based compounds, and resveratrol. Despite variations in the experimental designs across these studies, common pathways and biomarkers were implicated in cytoprotection when polyphenolic compounds were given with APAP, such as enhanced antioxidant gene expression and reversal of APAP-induced changes in oxidative stress markers and MAPK signaling. Overall, an emphasis should be placed on method standardization for future studies if we are to gain a more in-depth understanding of how polyphenolic moieties contribute to cytoprotection during an APAP overdose event.
由于其广泛的可用性，对乙酰氨基酚（APAP）是包括美国和英国在内的许多国家导致药物性肝损伤的主要原因。当按推荐使用时，APAP 相对安全。然而，在过量使用的情况下，APAP 代谢为活性代谢物 N-乙酰-对苯醌亚胺（NAPQI）会导致谷胱甘肽（GSH）耗竭、氧化应激和细胞损伤。在整个过程中，多种因素在传播毒性方面发挥着重要作用，包括 c-Jun N-末端激酶（JNK），一种丝裂原激活蛋白激酶（MAPK）家族的成员。由于其参与多种细胞过程，与 MAPK 信号相关的生物标志物已作为一种针对 APAP 诱导的肝损伤和肝细胞损伤的机制靶点引起了人们的兴趣。本综述总结了天然产物（特别是含有多酚部分的天然产物）能够减轻 APAP 诱导的毒性的机制细节，至少部分是通过调节 MAPK 的能力。这些化合物包括迷迭香酸、绿原酸、紫堇内酯、玫瑰茄提取物、槲皮素类化合物和白藜芦醇。尽管这些研究的实验设计存在差异，但当多酚化合物与 APAP 一起给予时，共同的途径和生物标志物被牵连到细胞保护中，例如增强抗氧化基因表达和逆转 APAP 诱导的氧化应激标志物和 MAPK 信号的变化。总的来说，如果我们要更深入地了解多酚部分如何在 APAP 过量事件中促进细胞保护，就应该强调未来研究的方法标准化。
