Department of Biological Sciences, Wayne State University, Detroit, MI, 48202, USA.
Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA.
Sci Rep. 2020 Jul 16;10(1):11785. doi: 10.1038/s41598-020-68725-5.
The widely used mood stabilizer valproate (VPA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. To gain insight into these mechanisms, we determined the effects of VPA on energy metabolism in yeast. VPA treatment increased levels of glycolytic intermediates, increased expression of glycolysis genes, and increased ethanol production. Increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. Interestingly, yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected. These findings have implications for mechanisms of therapeutic action and toxicity.
广泛使用的心境稳定剂丙戊酸钠（VPA）会引起能量代谢紊乱，这与药物的治疗机制和药物毒性都有关。为了深入了解这些机制，我们在酵母中确定了 VPA 对能量代谢的影响。VPA 处理增加了糖酵解中间产物的水平，增加了糖酵解基因的表达，并增加了乙醇的产生。糖酵解的增加可能是对线粒体功能障碍的反应，这反映在膜电位和耗氧量的降低。有趣的是，酵母、小鼠肝和分离的牛细胞色素 c 氧化酶被药物直接抑制，而其他氧化磷酸化复合物（III 和 V）的活性不受影响。这些发现对治疗作用和毒性的机制有影响。
