State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550001, PR China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, Guizhou 550004, PR China; School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550004, PR China.
Toxicol Appl Pharmacol. 2022 May 15;443:116007. doi: 10.1016/j.taap.2022.116007. Epub 2022 Apr 1.
8-Epidiosbulbin E acetate (EEA), a furan-containing diterpenoid lactone, is one of main component of Dioscorea bulbifera L. (DBL). It has been reported that EEA induces severe hepatotoxicity in mice and that its hepatotoxicity is associated with metabolic activation. The present study demonstrated that exposure to EEA (50, 100 or 200 μM) induced DNA damage, including significant DNA fragmentation, increases of tail DNA and olive tail moment, H2AX phosphorylation and PARP-1 activation, in cultured mouse primary hepatocytes. Similar observation was obtained in mice administered EEA at 50, 100 or 200 mg/kg. Pre-treatment with 10 μM ketoconazole (KTC), 200 μM vitamin C (VC), or 200 μM glutathione ethyl ester (GSH-OEt) reversed the over-production of reactive oxygen species (ROS) induced by EEA and attenuated susceptibility of hepatocytes to EEA-induced cytotoxicity and DNA damage in mouse primary hepatocytes. In contrast, pre-treatment with 1.0 mM L-buthionine sulfoximine (BSO) potentiated over-production of ROS, cytotoxicity and DNA damage induced by EEA. In summary, EEA induced DNA damage in cultured primary hepatocytes and the liver of mice. ROS, possibly along with DNA alkylation, participated in the observed DNA damage.
8-表二氢薯蓣次碱乙酸酯（EEA），一种含呋喃的二萜内酯，是黄姜（DBL）的主要成分之一。有报道称，EEA 会在小鼠中引起严重的肝毒性，并且其肝毒性与代谢激活有关。本研究表明，暴露于 EEA（50、100 或 200 μM）会在培养的小鼠原代肝细胞中诱导 DNA 损伤，包括明显的 DNA 片段化、尾巴 DNA 和橄榄尾巴时间的增加、H2AX 磷酸化和 PARP-1 激活。在给予 EEA 50、100 或 200mg/kg 的小鼠中也观察到了类似的结果。用 10 μM 酮康唑（KTC）、200 μM 维生素 C（VC）或 200 μM 谷胱甘肽乙酯（GSH-OEt）预处理可逆转 EEA 诱导的活性氧（ROS）过度产生，并减轻原代肝细胞对 EEA 诱导的细胞毒性和 DNA 损伤的敏感性。相比之下，用 1.0mM L-丁硫氨酸亚砜（BSO）预处理会增强 EEA 诱导的 ROS、细胞毒性和 DNA 损伤的产生。总之，EEA 会在培养的原代肝细胞和小鼠肝脏中引起 DNA 损伤。ROS，可能与 DNA 烷化一起，参与了观察到的 DNA 损伤。
