论文部分内容阅读
Tetrandrine is an alkaloid with a remarkable pharmacological profile that we previous reported causes hepatotoxicity through mitochondrial dysfunction.Here,we demonstrate that cytochrome P450(CYP450) plays an important role in mitochondrial dysfunction induced by the administration of tetrandrine.The over production of reactive oxygen species(ROS) and the depletion of reduced glutathione were both induced by tetrandrine.Of multiple ROS inhibitors that we tested,only inhibitors of CYP450(SKF-525A and others) reduced the ROS level and ameliorated the depletion of GSH.Confocal microscopy showed the onset of the mitochondrial permeability transition(MPT) after tetrandrine treatment,that could be inhibited by SKF-525A and a ROS scavenger(vitamin c,Vc).SKF-525A also recovered decreased ATP levels and the depletion of mitochondrial membrane potential induced by tetrandrine.These results suggest that MPT plays a critical role in tetrandrine-induced mitochondrial dysfunction and that ROS generated by CYP450 contribute to the MPT induced by tetrandrine.
Tetrandrine is an alkaloid with a remarkable pharmacological profile that previously reported causes hepatotoxicity through mitochondrial dysfunction. Here, we demonstrate that cytochrome P450 (CYP450) plays an important role in mitochondrial dysfunction induced by the administration of tetrandrine.The over production of reactive oxygen species (ROS) and the depletion of reduced glutathione were both induced by tetrandrine.Of multiple ROS inhibitors that we tested, only inhibitors of CYP450 (SKF-525A and others) reduced the ROS level and ameliorated the depletion of GSH.Confocal microscopy showed the onset of the mitochondrial permeability transition (MPT) after tetrandrine treatment, that could be inhibited by SKF-525A and a ROS scavenger (vitamin c, Vc). SKF-525A also also recovered decreased ATP levels and the depletion of mitochondrial membrane potential induced by tetrandrine. These results suggest that MPT plays a critical role in tetrandrine-induced mitochondrial dysfunction and that ROS genera ted by CYP450 contribute to the MPT induced by tetrandrine.