Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism.
Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism.
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DOI：
10.1016/0006-291x(86)90972-1
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发表时间：
1986-02
影响因子：
3.1
通讯作者：
R. Ramsay;R. Ramsay;J. Salach;J. Dadgar;J. Dadgar;T. Singer;T. Singer
中科院分区：
文献类型：
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作者：
R. Ramsay;R. Ramsay;J. Salach;J. Dadgar;J. Dadgar;T. Singer;T. Singer
4-苯基- n -甲基吡啶（MPP+）是神经毒性胺MPTP的氧化产物，对完整线粒体中处于状态3的NAD+连接底物的氧化抑制作用比4-苯基吡啶要大得多。随着解偶联剂的加入，MPP+的抑制作用逐渐减弱，而4-苯基吡啶的抑制作用仍然存在。这与MPP+通过能量依赖的过程在线粒体内快速浓缩的事实一致，而4-苯基吡啶似乎是随着浓度梯度被动进入的。因此，加入解偶联剂后电梯度的崩溃使4-苯基吡啶的抑制作用不受影响，但导致MPP+从线粒体外排并逆转其抑制作用。在分离的内膜中，4-苯基吡啶对呼吸链中NADH氧化的抑制作用远大于MPP+。MPTP和4-苯基- n -甲基吡啶酮对MPP+的抑制作用较强，而n -甲基吡啶对MPP+的抑制作用相对较小。由于nadh -铁氰化物活性在Vmax时不被MPP+抑制，因此该阻滞不在电子进入黄蛋白的入口处。
4-Phenyl-N-methylpyridinium (MPP+), the xxidation product of the neurotoxic amine MPTP, is considerably more inhibitory to the oxidation of NAD+-linked substrates in intact mitochondria in State 3 than is 4-phenylpyridine. On adding uncouplers, the inhibition by MPP+progressively diminishes, while the effect of 4-phenylpyridine remains. This is in accord with the fact that MPP+is rapidly concentrated in the mitochondria by an energy-dependent process, while 4-phenylpyridine seems to enter passively with the concentration gradient. Collapse of the electrical gradient after addition of uncouplers thus leaves the inhibiton by 4-phenylpyridine unaffected but causes efflux of MPP+from the mitochondria and a reversal of its inhibitory action. In isolated inner membranes the inhibition of NADH oxidation via the respiratory chain by 4-phenylpyridine is much greater than by MPP+. MPTP and 4-phenyl-N-methylpyridinone also inhibit more than MPP+, whereas N-methylpyridinium has relatively little effect. The block is not at the point of entry of electrons into the flavoprotein since the NADH-ferricyanide activity is not inhibited by MPP+at Vmax.