Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation
Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation
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DOI：
10.1016/s0028-3908(98)00215-9
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发表时间：
1999-04-01
影响因子：
4.7
通讯作者：
Ravindranath, V
中科院分区：
文献类型：
--
作者：
Balijepalli, S;Boyd, MR;Ravindranath, V
我们研究了多种经典和非典型抗精神病药物对线粒体NADH泛醌氧化还原酶(Complex I)活性的影响。在此模型中，与氟哌啶醇(10 NM)孵育的小鼠脑片矢状面显示出对复合体I的抑制作用，呈时间和浓度依赖性。类似浓度的氟哌啶醇代谢产物(HPP+)不能抑制复合体I的活性；实际上，只有当HPP+的浓度增加10000倍(100 MM)时，才能获得类似的抑制作用。用氟哌啶醇处理脑片可导致谷胱甘肽(GSH)的丢失，而用GSH和α-硫辛酸预处理脑片可消除氟哌啶醇所致的复合体I活性的丧失。氟哌啶醇处理的脑片线粒体与硫醇还原剂二硫苏糖醇孵育后，完全再生了复合体I的活性，证明硫醇氧化是一种可行的抑制机制。在不同抗精神病药物的比较中，氟哌啶醇对复合体I的抑制作用最强，其次是氯丙嗪、氟奋乃静和利培酮，而非典型的抗精神病药氯氮平(100mM)对复合体I的活性没有抑制作用。目前的研究支持经典的抗神经药如氟哌啶醇通过氧化修饰酶复合体来抑制线粒体复合体I的观点。(C)1999爱思唯尔科学有限公司。保留所有权利。
We have examined the: effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10 000-fold higher concentration of HPP+ (100 mu M). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 mu M) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex. (C) 1999 Elsevier Science Ltd. All rights reserved.