Mingatto F E, Santos A C, Uyemura S A, Jordani M C, Curti C
Department of Physics and Chemistry, University of Sõ Paulo, RibeirãoPreto, Brazil.
Arch Biochem Biophys. 1996 Oct 15;334(2):303-8. doi: 10.1006/abbi.1996.0459.
The in vitro interference of some of most important nonsteroidal anti-inflammatory drugs (NSAIDs) with the respiration of rat kidney (renal cortex) mitochondria and ATP synthesis was evaluated. Acetylsalicylic acid, diclofenac sodium, mefenamic acid, and piroxicam both uncoupled and inhibited oxidative phosphorylation in mitochondria energized with glutamate plus malate or with succinate, while dipyrone only uncoupled and paracetamol only inhibited it. The drug concentrations affecting mitochondrial respiration were in the low to middle micromolar range for diclofenac, mefenamic acid, and piroxicam, and in the low millimolar range for acetylsalicylic acid, dipyrone, and paracetamol. The pattern of inhibition, except for the paracetamol, was similar to that expressed by the respiratory chain inhibitors. NSAIDs also inhibited the rate of ATP synthesis in mitochondria energized with glutamate plus malate, as well as the phosphorylation potential of mitochondria. The IC50 values for rate of ATP synthesis, using 2 mM ADP, were about 0.1 mM for diclofenac sodium and mefenamic acid, 0.7 mM for piroxicam, and in the range of 5-8 mM for acetylsalicylic acid, dipyrone, and paracetamol. The potential for renal energetic cytotoxicity of NSAIDs is discussed considering their ability to interact with the oxidative phosphorylation in rat renal cortex mitochondria. A comparison is made with the interference of salicylate, the main metabolite of acetylsalicylic acid, and a classical uncoupler of oxidative phosphorylation.
评估了一些最重要的非甾体抗炎药（NSAIDs）对大鼠肾脏（肾皮质）线粒体呼吸和ATP合成的体外干扰作用。乙酰水杨酸、双氯芬酸钠、甲芬那酸和吡罗昔康在以谷氨酸加苹果酸或琥珀酸供能的线粒体中，既解偶联又抑制氧化磷酸化，而安乃近仅解偶联，对乙酰氨基酚仅抑制氧化磷酸化。影响线粒体呼吸的药物浓度，双氯芬酸、甲芬那酸和吡罗昔康处于低至中微摩尔范围，乙酰水杨酸、安乃近和对乙酰氨基酚处于低毫摩尔范围。除对乙酰氨基酚外，抑制模式与呼吸链抑制剂表现出的模式相似。NSAIDs还抑制以谷氨酸加苹果酸供能的线粒体中的ATP合成速率，以及线粒体的磷酸化电位。使用2 mM ADP时，双氯芬酸钠和甲芬那酸的ATP合成速率IC50值约为0.1 mM，吡罗昔康为0.7 mM，乙酰水杨酸、安乃近和对乙酰氨基酚在5 - 8 mM范围内。考虑到NSAIDs与大鼠肾皮质线粒体氧化磷酸化相互作用的能力，讨论了其对肾脏能量代谢的细胞毒性潜力。并与乙酰水杨酸的主要代谢产物水杨酸盐以及经典的氧化磷酸化解偶联剂的干扰作用进行了比较。
