EFFECTS OF INDOMETHACIN ON RESPIRATION AND THE ALPHA-GLYCEROLPHOSPHATE SHUTTLE IN RAT-KIDNEY MITOCHONDRIA
EFFECTS OF INDOMETHACIN ON RESPIRATION AND THE ALPHA-GLYCEROLPHOSPHATE SHUTTLE IN RAT-KIDNEY MITOCHONDRIA
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DOI：
10.1016/0006-2952(79)90305-8
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发表时间：
1979-01-01
影响因子：
5.8
通讯作者：
DAWSON, AG
中科院分区：
文献类型：
--
作者：
COONEY, GJ;DAWSON, AG
消炎药消炎痛刺激大鼠肾脏线粒体的State 4呼吸，表明解偶联活性在0.1-0.2 mM浓度时最大。吲哚美辛还抑制氧化谷氨酸或琥珀酸的线粒体中的State 3呼吸，但不抑制氧化抗坏血酸和四甲基苯二胺的线粒体中的State 3呼吸。这种抑制不能被2，4-二硝基苯酚解除，这表明吲哚美辛在细胞色素c之前直接抑制沿呼吸链的电子传递。当浓度比显著解偶联或呼吸抑制所需的浓度低一个数量级时，吲哚美辛严重限制还原当量从线粒体外NADH通过重建的α-甘油磷酸穿梭转移到呼吸链。显然，该药物对线粒体α-甘油磷酸脱氢酶活性有很强的抑制作用。这种抑制显然是相对特异的，因为消炎痛对另一种FAD连接酶琥珀酸脱氢酶的活性几乎没有影响。α-甘油磷酸穿梭的抑制与先前观察到的吲哚美辛对大鼠肾小管葡萄糖代谢的影响有关。
The anti-inflammatory drug indomethacin stimulated State 4 respiration in rat kidney mitochondria, indicating an uncoupler activity which was maximal at a concentration of 0.1-0.2 mM. Indomethacin also inhibited State 3 respiration in mitochondria oxidizing glutamate or succinate, but not in mitochondria oxidizing ascorbate together with tetramethylphenylene diamine. This inhibition was not relieved by 2,4-dinitrophenol and suggested that indomethacin directly inhibited electron transport along the respiratory chain at a point prior to cytochrome c. At concentrations one order of magnitude lower than that required for substantial uncoupling or respiratory inhibition, indomethacin severely restricted the transfer of reducing equivalents from extramitochondrial NADH to the respiratory chain via a reconstructed .alpha.-glycerolphosphate shuttle. Apparently the drug exerted a strong inhibitory effect on mitochondrial .alpha.-glycerolphosphate dehydrogenase activity. This inhibition apparently was relatively specific since indomethacin had little effect on the activity of succinate dehydrogenase, another FAD-linked enzyme. The inhibition of the .alpha.-glycerolphosphate shuttle is discussed in relation to the previously observed effects of indomethacin on glucose metabolism in isolated rat kidney tubules.