Yang Xiaojing, Li Weiwei, Sun Ying, Guo Xiucai, Huang Wenlin, Peng Ying, Zheng Jiang
Wuya College of Innovation, Shenyang Pharmaceutical University , Shenyang, Liaoning 110016, P. R. China.
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
Chem Res Toxicol. 2017 Feb 20;30(2):532-539. doi: 10.1021/acs.chemrestox.6b00260. Epub 2017 Jan 31.
Many pyrrolizidine alkaloids (PAs) can cause liver injury in animals and humans. Different hepatotoxic PAs can produce similar hepatotoxic effects, but the degree of their toxicities may vary widely. Retrorsine (RTS) and monocrotaline (MCT) share the same core structure (retronecine) and similar metabolic activation pathway. RTS and MCT both produced liver injury, but the former was more hepatotoxic than the latter. Enzyme kinetic study demonstrated that the value of V/K for RTS was 5.5-fold larger than that of MCT. Additionally, RTS produced higher levels of pyrrole-glutathione (GSH) conjugates and protein covalent binding than MCT at the same dose. Furthermore, RTS induced significant hepatic GSH depletion but MCT did little. This comparative study provides clear evidence that the generation of the reactive pyrrolic intermediates plays a critical role in PA-induced hepatotoxicity.
许多吡咯里西啶生物碱（PAs）可在动物和人类中引起肝损伤。不同的肝毒性PAs可产生相似的肝毒性作用，但其毒性程度可能差异很大。倒千里光碱（RTS）和野百合碱（MCT）具有相同的核心结构（倒千里光裂碱）和相似的代谢活化途径。RTS和MCT均导致肝损伤，但前者的肝毒性比后者更强。酶动力学研究表明，RTS的V/K值比MCT大5.5倍。此外，在相同剂量下，RTS产生的吡咯-谷胱甘肽（GSH）结合物和蛋白质共价结合水平高于MCT。此外，RTS可导致肝脏GSH显著耗竭，但MCT的作用很小。这项比较研究提供了明确的证据，表明活性吡咯中间体的生成在PA诱导的肝毒性中起关键作用。
