School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 4054577, China.
School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510000, China.
Toxins (Basel). 2021 Oct 13;13(10):723. doi: 10.3390/toxins13100723.
Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole-protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of (containing one PA: monocrotaline) and (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole-protein adducts formed in the rats' livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole-protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole-protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole-protein adducts-which directly correlated with the elevation of serum ALT activity-was a common insult leading to PA-ILI, suggesting a potential for using pyrrole-protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.
吡咯里西啶生物碱（PAs）具有 1,2-不饱和的 necine 碱基，是具有肝毒性的植物毒素。急性 PA 中毒是由 PA 衍生的反应性吡咯代谢物与细胞蛋白之间形成加合物引起的。本研究旨在探讨肝吡咯蛋白加合物的形成与 PA 诱导的肝损伤（PA-ILI）之间的相关性，并进一步探索利用这些加合物快速筛选含有 PA 的天然产物的肝毒性。将 （含有 1 种 PA：野百合碱）和 （含有 2 种 PAs：山梗菜碱和山梗菜菲林）的水提取物以不同剂量口服给予大鼠 24 h，以研究 PA-ILI。通过评估血清丙氨酸氨基转移酶（ALT）活性、肝谷胱甘肽（GSH）水平和处理大鼠的肝组织学变化来评估 PA-ILI 的严重程度。通过建立良好的分光光度法测定大鼠肝脏中形成的吡咯蛋白加合物的水平。生物和组织学结果显示，含不同 PA 的草药提取物处理的大鼠表现出剂量依赖性肝毒性，各组之间的毒性严重程度有显著差异。血清 ALT 活性和肝吡咯蛋白加合物的量均呈剂量依赖性增加。此外，ALT 活性的升高与肝吡咯蛋白加合物的形成密切相关，而与不同 PA 的结构无关。这些发现表明，肝吡咯蛋白加合物的形成与血清 ALT 活性的升高直接相关，这是导致 PA-ILI 的共同损伤，表明使用吡咯蛋白加合物筛选肝毒性和对含有 PA 的天然产物进行排序具有潜力，因为这些天然产物通常含有结构不同的多种 PA。
