CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, Portugal; Department of Life Sciences, University of Coimbra, Portugal.
Department of Biomedical Sciences, University of Minnesota Medical School, USA.
Chem Biol Interact. 2018 Dec 25;296:198-210. doi: 10.1016/j.cbi.2018.10.002. Epub 2018 Oct 4.
Triterpenoids have multiple biological properties, although little information is available regarding their toxicity. The present study evaluates the toxicity of two new synthetic lupane derivatives using distinct biological models including synthetic lipids membranes, isolated liver and heart mitochondria fractions, and cell lines in culture. The two novel triterpenoids caused perturbations in the organization of synthetic lipid bilayers, leading to changes in membrane fluidity. Inhibition of cell proliferation and mitochondrial and nuclear morphological alterations were also identified. Inhibition of mitochondrial oxygen consumption, transmembrane electric potential depolarization and induction of the mitochondrial permeability transition pore was observed, although effects on isolated mitochondrial fractions were tissue-dependent (e.g. liver vs. heart). The size and length of hydrocarbon chains in the two molecules appear to be determinant for the degree of interaction with mitochondria, especially in the whole cell environment, where more barriers for diffusion exist. The results suggest that the positively charged triterpenoids target mitochondria and disrupt bioenergetics.
三萜类化合物具有多种生物学特性，但关于其毒性的信息却很少。本研究使用不同的生物学模型（包括合成脂质膜、分离的肝和心脏线粒体部分以及培养的细胞系）评估了两种新型合成羽扇豆烷衍生物的毒性。这两种新型三萜类化合物引起了合成脂质双层结构的紊乱，导致膜流动性发生变化。还发现细胞增殖抑制和线粒体和核形态改变。观察到抑制线粒体耗氧量、跨膜电势去极化和诱导线粒体通透性转换孔，但对分离的线粒体部分的作用取决于组织（例如肝与心）。两个分子中碳氢链的大小和长度似乎是与线粒体相互作用程度的决定因素，特别是在存在更多扩散障碍的整个细胞环境中。研究结果表明，带正电荷的三萜类化合物靶向线粒体并破坏生物能量学。
