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.
Wenjing Dong,Bingwei Yang,Yawen Wang,Jia Yuan,Yunqi Fan,Erqun Song,Yang Song
Polybrominated diphenyl ethers (PBDEs) are emerging organic environmental pollutants, which were accused of various toxic effects. Here, we studied the role of a potential PBDEs quinone metabolite, PBDEQ, on cytotoxicity, oxidative DNA damage, and the alterations of signal cascade in HeLa cells. PBDEQ exposure leads to reactive oxygen species (ROS) accumulation, mitochondrial membrane potential (MMP) loss, lactate dehydrogenase (LDH) release, increasing terminal transferase-mediated dUTP-biotin nick end labeling (TUNEL) positive foci, and the elevation of apoptosis rate. Furthermore, we showed PBDEQ exposure result in increased DNA migration, micronucleus frequency, and the promotion of 8-OHdG and phosphorylation of histone H2AX (γ-H2AX) levels. Mechanism study indicated that PBDEQ caused poly(ADP-ribose) polymerase 1 (PARP-1) activation and apoptosis-inducing factor (AIF) nuclear translocation. All together, these results confirmed the occurrence of parthanatos-like cell death upon PBDEQ exposure.
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