Amavadin诱导大鼠肾线粒体通透性转换孔开放与活性氧生成无关

doi:10.5246/jcps.2014.12.105

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (12): 830-836.DOI: 10.5246/jcps.2014.12.105

Amavadin诱导大鼠肾线粒体通透性转换孔开放与活性氧生成无关

霍辰伊, 刘会雪^*

北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2014-06-05 修回日期:2014-06-12 出版日期:2014-12-25 发布日期:2014-06-29
通讯作者: Tel.: 86-10-82801539

Amavadin induced PTP opening not through the promotion of ROS generation in rat kidney mitochondria

Chenyi Huo, Huixue Liu^*

Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2014-06-05 Revised:2014-06-12 Online:2014-12-25 Published:2014-06-29
Contact: Tel.: 86-10-82801539

摘要/Abstract

摘要：

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, 200 μM 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。

关键词: Amavadin, 钒化合物, 线粒体, 活性氧物种, 通透性转换孔开放

Abstract:

Amavadin is a natural vanadium compound that accumulates to high level in poisonous Amanita mushrooms. Recently, amavadin was found to have potential therapeutic effect in cancer treatment. However, its toxicity and the possible mechanism of actions are still not clear. In this study, we investigated the toxic effects of amavadin on rat kidney mitochondriaand the possible mechanism. We found that amavadin induced significantly permeability transition pore (PTP) opening in the mitochondria. Amavadin concentration-dependently inhibited the generation of reactiveoxygen species (ROS) in succinate buffer, and at high concentration of 200 μM it increased the ROS generation in malate buffer. With the addition of rotenone, the ROS generation in malate buffer was strongly enhanced than that induced by amavadin alone, but remained unchanged in succinate buffer. Results from the present study suggest that amavadin act upon electron transport chain downstream of rotenone, and the ubiquinone binding site in complex I is the most possible binding site.

Key words: Amavadin, Vanadium compound, Mitochondria, Reactive oxygen species, Permeability transition pore

中图分类号:

R915

Supporting:

霍辰伊, 刘会雪. Amavadin诱导大鼠肾线粒体通透性转换孔开放与活性氧生成无关[J]. 中国药学(英文版), 2014, 23(12): 830-836.

Chenyi Huo, Huixue Liu. Amavadin induced PTP opening not through the promotion of ROS generation in rat kidney mitochondria[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(12): 830-836.

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Amavadin诱导大鼠肾线粒体通透性转换孔开放与活性氧生成无关

Amavadin induced PTP opening not through the promotion of ROS generation in rat kidney mitochondria

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