MITOCHONDRIAL RESPIRATORY INHIBITION BY N-METHYLATED BETA-CARBOLINE DERIVATIVES STRUCTURALLY RESEMBLING N-METHYL-4-PHENYLPYRIDINE
MITOCHONDRIAL RESPIRATORY INHIBITION BY N-METHYLATED BETA-CARBOLINE DERIVATIVES STRUCTURALLY RESEMBLING N-METHYL-4-PHENYLPYRIDINE
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DOI：
10.1073/pnas.87.23.9368
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发表时间：
1990-12-01
影响因子：
11.1
通讯作者：
COLLINS, MA
中科院分区：
文献类型：
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作者：
ALBORES, R;NEAFSEY, EJ;COLLINS, MA
线粒体积累和呼吸抑制是帕金森病诱导剂N-甲基-4-苯基-1，2，3，6-四氢吡啶的毒性代谢产物N-甲基-4-苯基吡啶离子(MPP+)作用的关键步骤。我们研究了2-甲基化β-卡宾(2-Me.beta.Cs)和2-甲基化3，4-二氢-β-卡宾(2-MeDH.beta.Cs)的呼吸特性，它们包含MPP+结构。作为吲哚胺衍生物，它们可能在特发性帕金森症中起到内源性作用。用速率肝线粒体抑制NAD+连接的耗氧量(预孵育6min)的顺序为：MPP+=2-甲基三尖杉酯&Gt；2-甲基三尖杉酯=2-甲基三尖杉酯碱.mchgt。2-甲基三尖杉酯醇；-2-甲基去甲肾上腺素；6-羟基-2-甲基三氢骆驼蓬。2-甲基哈曼。与MPP+类似，2-MeDH.beta.C/2-Me.beta.C抑制作用可被四苯基硼增强，被二硝基苯酚逆转，与阳离子形式的参与一致。然而，中性形式的参与是由2-MeDHβC/2-MeβC抑制时间进程来指示的，这与MPP+不同。中性形式可能是通过吲哚氮去质子化而产生的，因为不能N-去质子化的阳离子β-卡宾的特性反映了MPP+而不是2-Meβ-Cs。琥珀酸支持的呼吸也被2-甲基-β-Cs/2-甲基-β-Cs显著阻断，但四苯基硼和2，9-二甲基去甲肾上腺素的结果表明，阳离子形式对NAD+连接的呼吸的抑制作用不如阳离子形式重要。我们认为，某些2-MeDH.beta.Cs/2-Me.beta.Cs/2-Me.beta.Cs的相对有效的抑制作用涉及被动线粒体进入的中性形式和作用于几个呼吸部位的阳离子和中性形式。呼吸抑制可以合理地解释已报道的2-甲基β-Cs的神经毒性。
Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated .beta.-carbolines (2-Me.beta.Cs) and 2-methylated 3,4-dihydro-.beta.-carbolines (2-MeDH.beta.Cs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rate liver mitochondria, the order for inhibition of NAD+-linked O2 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline .mchgt. 2-methylharmalol >-2-methylnorharman > 6-OH-2-methylharmalan .mchgt. 2-methylharman. Similar to MPP+, 2-MeDH.beta.C/2-Me.beta.C inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDH.beta.C/2-Me.beta.C inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic .beta.-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-Me.beta.Cs. Succinate-supported respiration was also significantly blocked by 2-MeDH.beta.Cs/2-Me.beta.Cs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDH.beta.Cs/2-Me.beta.Cs/2-Me.beta.Cs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-Me.beta.Cs.