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Amavadin是自然积累于毒蘑菇鹅膏菌中的小分子钒复合物。近年来amavadin在肿瘤治疗研究中显现出一定的活性,但是其毒理机制并不清楚。本工作研究amavadin作用于大鼠肾线粒体的毒性效应及其可能作用机制。该研究结果表明,amavadin显著诱导线粒体通透性转换孔(PTP)开放,该作用并非和ROS生成相关。以琥珀酸为呼吸底物时,amavadin浓度依赖地抑制ROS生成;以苹果酸为呼吸底物时,200μM amavadin显著促进ROS的产生。在苹果酸呼吸底物中,线粒体复合体I抑制剂鱼藤酮能够显著促进amavadin诱导的活性氧生成增加;在琥珀酸呼吸底物中,鱼藤酮对amavadin抑制ROS生成的效应没有影响。以上结果提示,amavadin可能作用于线粒体呼吸链鱼藤酮抑制位点下游,线粒体复合体I末端的泛醌结合位点是最有可能的作用靶点。
Amavadin is a small molecule vanadium complex that naturally accumulates in poisonous mushroom amanita. In recent years, amavadin has shown some activity in cancer treatment research, but its toxicological mechanism is not clear. This study was to investigate the toxic effect of amavadin on rat renal mitochondria and its possible mechanism. The results of this study indicate that amavadin significantly induces the opening of the mitochondrial permeability transition pore (PTP), which is not associated with ROS production. With succinate as a respiratory substrate, amavadin inhibited ROS production in a concentration-dependent manner. When malate was used as a respiratory substrate, 200μM amavadin significantly promoted ROS production. In the malate respiration substrate, rotenone, a mitochondrial complex I inhibitor, significantly increased the amavadin-induced increase in reactive oxygen species (ROS) production; in the succinate respiratory substrates, rotenone had no effect on the effect of amavadin on ROS production. The above results suggest that amavadin may act downstream of the rotenone inhibitory site of the respiratory chain of mitochondria and that the ubiquinone binding site at the I-terminal end of the mitochondrial complex is the most likely target.