Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells
Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells
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DOI：
10.1016/j.neuropharm.2003.10.015
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发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Schapira, AHV
中科院分区：
文献类型：
--
作者：
Korlipara, LVP;Cooper, JM;Schapira, AHV
托卡朋和恩他卡朋是儿茶酚-O-甲基转移酶（COMT）抑制剂，在帕金森病（PD）的治疗中用作左旋多巴的替代物。托卡朋的使用受到其肝毒性的限制，其原因仍不确定。托卡朋化合物是分离线粒体中线粒体呼吸的解偶联剂，该作用可能与其对肝功能的影响有关。我们研究了COMT抑制剂对培养细胞的作用，将其与经典的解偶联剂羰基氰化物对-（三氟甲氧基）苯腙（FCCP）进行比较，以深入了解其潜在毒性的机制。托卡朋和FCCP对人神经母细胞瘤SH-SY 5 Y细胞有毒性，并导致ATP合成显著减少。恩他卡朋对SH-SY 5 Y无毒性。托卡朋和FCCP显示出对线粒体DNA耗尽的细胞具有相同的毒性，因此缺乏功能性呼吸链。这项研究表明，托卡朋显着抑制ATP的合成在培养的细胞反映了一个经典的解偶联剂的影响。然而，其毒性也可能涉及一种机制，独立于其对氧化磷酸化的影响。(C)2003 Elsevier Ltd.保留所有权利。
Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors used as adjuncts to levodopa in the treatment of Parkinson's disease (PD). The use of tolcapone has been limited by its hepatotoxicity, the cause of which remains uncertain. Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and this action may be relevant to its effect on liver function. We have examined the actions of COMT inhibitors on cultured cells, comparing them with those of the classical uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), in order to provide insight into their mechanism of potential toxicity. Tolcapone and FCCP were shown to be toxic to human neuroblastoma SH-SY5Y cells and caused a profound reduction in ATP synthesis. Entacapone was not toxic to SH-SY5Y. Tolcapone and FCCP were shown to be equally toxic to cells depleted of mtDNA and thus devoid of a functional respiratory chain. This study demonstrates that tolcapone markedly inhibits ATP synthesis in cultured cells mirroring the effects of a classical uncoupler. However its toxicity may also involve a mechanism independent of its effects upon oxidative phosphorylation. (C) 2003 Elsevier Ltd. All rights reserved.