Exogenous Iron Increases Fasciocidal Activity and Hepatocellular Toxicity of the Synthetic Endoperoxides OZ78 and MT04
Exogenous Iron Increases Fasciocidal Activity and Hepatocellular Toxicity of the Synthetic Endoperoxides OZ78 and MT04
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DOI：
10.3390/ijms20194880
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Kraehenbuehl, Stephan
中科院分区：
文献类型：
--
作者：
Brecht, Karin;Kirchhofer, Carla;Kraehenbuehl, Stephan
合成过氧化物 OZ78 和 MT04 最近成为候选药物。然而，铁对这些化合物的杀筋膜活性和肝细胞毒性的影响尚不清楚。我们研究了在氯化亚铁和氯化铁存在和不存在的情况下 OZ78 和 MT04 的体外杀筋膜活性和肝细胞毒性，并在小鼠中进行了毒理学研究。进行了与抗疟药物青蒿琥酯（AS）（一种半合成过氧化物）进行比较的研究。 Fe2+ 或氯化血红素证实并增强了 OZ78 和 MT04 的杀筋膜作用。在 HepG2 细胞中，AS 浓度依赖性地减少细胞 ATP 并损害细胞膜完整性。相比之下，OZ78或MT04在100μM时没有毒性，并分别使细胞ATP降低13％和19％，但在500μM时没有膜毒性。Fe2+或氯化血红素的添加显着增加了OZ78和MT04的毒性。 AS 抑制线粒体电子传递链的复合物 I、II 和 IV，MT04 损害复合物 I 和 II，而 OZ78 无毒性。所有三种化合物均以浓度依赖性方式增加细胞活性氧 (ROS)，Fe2+ 或氯化血红素进一步增加细胞活性氧 (ROS)。口服高达 800 mg OZ78 或 MT04 的小鼠没有表现出相关的肝毒性。总之，我们证实了 OZ78 和 MT04 的杀筋膜活性，Fe2+ 或氯化血红素可增强该活性。 OZ78 和 MT04 对 HepG2 细胞有毒，这是由于铁存在下与 ROS 生成相关的线粒体损伤所致。在小鼠体内未观察到相关的肝毒性，可能是由于有限的暴露和/或高抗氧化肝能力。
The synthetic peroxides OZ78 and MT04 recently emerged as fasciocidal drug candidates. However, the effect of iron on fasciocidal activity and hepatocellular toxicity of these compounds is unknown. We investigated the in vitro fasciocidal activity and hepatocellular toxicity of OZ78 and MT04 in absence and presence of Fe(II)chloride and hemin, and conducted a toxicological study in mice. Studies were performed in comparison with the antimalarial artesunate (AS), a semisynthetic peroxide. Fasciocidal effects of OZ78 and MT04 were confirmed and enhanced by Fe2+ or hemin. In HepG2 cells, AS reduced cellular ATP and impaired membrane integrity concentration-dependently. In comparison, OZ78 or MT04 were not toxic at 100 mu M and reduced the cellular ATP by 13% and 19%, respectively, but were not membrane-toxic at 500 mu M. The addition of Fe2+ or hemin increased the toxicity of OZ78 and MT04 significantly. AS inhibited complex I, II, and IV of the mitochondrial electron transport chain, and MT04 impaired complex I and II, whereas OZ78 was not toxic. All three compounds increased cellular reactive oxygen species (ROS) concentration-dependently, with a further increase by Fe2+ or hemin. Mice treated orally with up to 800 mg OZ78, or MT04 showed no relevant hepatotoxicity. In conclusion, we confirmed fasciocidal activity of OZ78 and MT04, which was increased by Fe2+ or hemin. OZ78 and MT04 were toxic to HepG2 cells, which was explained by mitochondrial damage associated with ROS generation in the presence of iron. No relevant hepatotoxicity was observed in mice in vivo, possibly due to limited exposure and/or high antioxidative hepatic capacity.