Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou 550025, PR China.
Chem Res Toxicol. 2022 Oct 17;35(10):1821-1830. doi: 10.1021/acs.chemrestox.2c00130. Epub 2022 Jul 15.
L. (DBL), an effective traditional Chinese medicine, has been restricted because of multiple reports that it can cause severe hepatotoxicity. 8-Epidiosbulbin E acetate (EEA), one of the main components of DBL, can induce severe liver injury. It has been reported that EEA can be metabolized by CYP3A to the corresponding -enedial intermediate which alkylates the lysine residues of proteins to form pyrroline derivatives. The present study unexpectedly found that the reactive intermediate reacted with the amide groups of asparagine (Asn) and glutamine (Gln) residues of hepatic proteins of mice treated with EEA. The amide-derived protein modification increased with the increase in the dose administered. Like the adduction of the primary amine of lysine residues, the electrophilic metabolite reacted with the amide groups of Asn and Gln residues to offer the corresponding pyrrolines. The structures of the pyrrolines were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.
白芍总苷（DBL）是一种有效的中药，但由于多份报告称其可能导致严重肝毒性，已被限制使用。8-表蜕皮甾酮乙酸酯（EEA）是 DBL 的主要成分之一，可导致严重的肝损伤。据报道，EEA 可被 CYP3A 代谢为相应的 -enedial 中间产物，该中间产物烷基化蛋白质的赖氨酸残基，形成吡咯啉衍生物。本研究出人意料地发现，反应性中间产物与经 EEA 处理的小鼠肝蛋白中天冬酰胺（Asn）和谷氨酰胺（Gln）残基的酰胺基反应。随着给予的剂量增加，酰胺衍生的蛋白质修饰增加。与赖氨酸残基的伯胺加合一样，亲电代谢物与 Asn 和 Gln 残基的酰胺基反应，提供相应的吡咯啉。吡咯啉的结构通过质谱和核磁共振波谱得到证实。
