Marchandeau Jean-Pierre, Labbe Gilles
Disposition, Safety and Animal Research,sanofi-aventis R&D, Vitry-sur-Seine, France.
Methods Mol Biol. 2011;691:243-53. doi: 10.1007/978-1-60761-849-2_14.
Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects, such as lactic acidosis and rhabdomyolysis, in some patients. Several in vitro and in vivo investigations can be performed in order to determine if drugs can disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition pore (MPT). Among these investigations, mitochondrial respiration is a relatively easy test to measure the potential toxicity of a drug. The use of cells instead of isolated mitochondria allows one to test the toxic effect of a parent compound and its metabolites. The use of rat hepatocytes can detect drugs involved in drug-induced liver injuries (DILI). The method consists in measuring oxygen consumption by using a Clark electrode in a chamber containing a suspension of hepatocytes pre-incubated with drug.
线粒体功能障碍是药物在某些患者中导致肝损伤及其他严重副作用（如乳酸性酸中毒和横纹肌溶解）的主要机制。为了确定药物是否会干扰线粒体脂肪酸氧化（FAO）和氧化磷酸化（OXPHOS）过程、消耗肝线粒体DNA（mtDNA）或触发线粒体通透性转换孔（MPT）的开放，可以进行多项体外和体内研究。在这些研究中，线粒体呼吸是一种相对容易的测试，用于测量药物的潜在毒性。使用细胞而非分离的线粒体可以测试母体化合物及其代谢物的毒性作用。使用大鼠肝细胞可以检测与药物性肝损伤（DILI）相关的药物。该方法包括在一个含有预先用药物孵育的肝细胞悬液的小室中，使用克拉克电极测量氧气消耗。
