摘要
目的研究吡咯里西啶生物碱(pyrrolizidine alkaloids,PAs)中倒千里光碱(retrorsine,RTS)的反应性代谢产物在体外和体内与RNA的相互作用。方法通过液相色谱-串联质谱法(LC-MS/MS)分析合成反应、肝微粒体孵育和给药RTS的小鼠中腺苷和鸟苷与RTS的反应性代谢产物形成的加合物。结果在体外合成反应液,肝脏微粒体孵育液和给药RTS的小鼠肝脏组织中检测到了RTS的反应性代谢产物与腺苷和鸟苷形成的双分子嘌呤加合物,体内观察到的所有加合物的生成量呈剂量依赖性,并在给药后2 h达到峰值。结论首次发现RTS的反应性代谢产物与RNA反应形成RNA双分子加合物,可能是RTS导致肝毒性的重要原因之一。
Objective To investigate of the interaction between reactive metabolite of retrorsine(RTS)in pyrrolizidine alkaloids(PAs)with RNA in vitro and in vivo.Methods Adducts formed by adenosine and guanosine with reactive metabolites of RTS in the synthesis reactions,liver microsomal incubations and RTS-administered mice were analyzed by LC-MS/MS.Results RNA adducts(bis-purines)derived from a reactive metabolite of RTS with adenosine and guanosine were detected in mixture of synthesis reaction,liver microsomal incubations and liver tissues of mice administered RTS.The observed all adducts reached the peak at 2 h after administration in dose-dependent manners in vivo.Conclusion For the first time,we found that reactive metabolite of RTS can react with RNA to form RNA adducts in the form of bis-purines,which may be one of the mechanisms responsible for RTS induced hepatotoxicity.
作者
程婷
江婷婷
周梦悦
李靖
李维维
郑江
CHENG Ting;JIANG Tingting;ZHOU Mengyue;LI Jing;LI Weiwei;ZHENG Jiang(School of Pharmacy,Guizhou Medical University,Guiyang 550004,China;Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China)
出处
《沈阳药科大学学报》
CAS
CSCD
北大核心
2022年第9期1059-1069,共11页
Journal of Shenyang Pharmaceutical University
基金
国家自然科学基金资助项目(81803623)
贵州省自然科学基金资助项目(黔科合基础[2019]1257)。
