Pivato Leandro Silva, Constantin Rodrigo Polimeni, Ishii-Iwamoto Emy L, Kelmer-Bracht Ana Maria, Yamamoto Nair Seiko, Constantin Jorgete, Bracht Adelar
Laboratory of Liver Metabolism, Department of Biochemistry, University of Maringá, 87020900 Maringá, Brazil.
J Biochem Mol Toxicol. 2006;20(5):230-40. doi: 10.1002/jbt.20139.
The action of carbenoxolone on hepatic energy metabolism was investigated in the perfused rat liver and isolated mitochondria. In perfused livers, carbenoxolone (200-300 microM) increased oxygen consumption, glucose production and glycolysis from endogenous glycogen. Gluconeogenesis from lactate or fructose, an energy-dependent process, was inhibited. This effect was already evident at a concentration of 25 microM. The cellular ATP levels and the adenine nucleotide content were decreased by carbenoxolone, whereas the AMP levels were increased. In isolated mitochondria, carbenoxolone stimulated state IV respiration and decreased the respiratory coefficient with the substrates beta-hydroxybutyrate and succinate. The ATPase of intact mitochondria was stimulated, the ATPase of uncoupled mitochondria was inhibited, and the ATPase of disrupted mitochondria was not altered by carbenoxolone. These results indicate that carbenoxolone acts as an uncoupler of oxidative phosphorylation and, possibly, as an inhibitor of the ATP/ADP exchange system. The inhibitory action of carbenoxolone on mitochondrial energy metabolism could be contributing to induce the mitochondrial permeability transition (MPT), a key phenomenon in apoptosis. The results of the present study can explain, partly at least, the in vivo hepatotoxic actions of carbenoxolone that were found in a previous clinical evaluation.
在灌注大鼠肝脏和分离的线粒体中研究了甘珀酸对肝脏能量代谢的作用。在灌注肝脏中，甘珀酸（200 - 300微摩尔）增加了氧消耗、葡萄糖生成以及内源性糖原的糖酵解。乳酸或果糖的糖异生（一个能量依赖过程）受到抑制。这种作用在25微摩尔浓度时就已明显。甘珀酸降低了细胞ATP水平和腺嘌呤核苷酸含量，而AMP水平升高。在分离的线粒体中，甘珀酸刺激状态IV呼吸，并降低了底物β - 羟基丁酸和琥珀酸的呼吸系数。完整线粒体的ATP酶受到刺激，解偶联线粒体的ATP酶受到抑制，而破碎线粒体的ATP酶不受甘珀酸影响。这些结果表明，甘珀酸作为氧化磷酸化的解偶联剂起作用，并且可能作为ATP/ADP交换系统的抑制剂。甘珀酸对线粒体能量代谢的抑制作用可能有助于诱导线粒体通透性转换（MPT），这是细胞凋亡中的一个关键现象。本研究结果至少可以部分解释先前临床评估中发现的甘珀酸的体内肝毒性作用。
