Sayre L M, Singh M P, Arora P K, Wang F, McPeak R J, Hoppel C L
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio.
Arch Biochem Biophys. 1990 Aug 1;280(2):274-83. doi: 10.1016/0003-9861(90)90330-2.
Analogues of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were evaluated for inhibition of respiration in intact mitochondria (Mw) and in electron transport particles (ETP). MPP+ exhibits relatively weak inhibitory activity in ETP, but potent inhibition in Mw occurs on account of its energy-dependent accumulation inside mitochondria. The permeant anion tetraphenylborate potentiates the inhibition in both Mw and ETP. Replacement of the 4-phenyl ring of MPP+ by a variety of aromatic and nonaromatic rings, and of the N-methylpyridinium group by other cationic aromatic heterocycles, preserves the inhibitory patterns seen for MPP+. The general observation of enhanced inhibitory potency in Mw for all these permanently charged cations is consistent with our contention that energy-dependent accumulation inside mitochondria represents a passive Nernstian concentration in response to the transmembrane electrochemical gradient. Nonetheless, the magnitude of the inhibitory potentiation seen in Mw relative to ETP varies widely with structure. In particular, less lipophilic analogues, especially those bearing a localized, rather than resonance-stabilized, permanent positive charge, exhibit similar inhibitory activity to MPP+ in ETP, but the inhibition in Mw is not comparably enhanced. For these same analogues, the inhibitory activity in ETP is only weakly potentiated by tetraphenylborate. Since succinate was found to completely reverse the respiratory inhibition in Mw induced by all types of MPP+ analogues investigated, a common site 1 inhibition appears to be involved; thus the different inhibitory patterns observed must be due to structural factors governing membrane transport and distribution properties.
1-甲基-4-苯基吡啶鎓（MPP⁺）是多巴胺能神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶的神经毒性代谢产物，其类似物被评估对完整线粒体（Mw）和电子传递颗粒（ETP）呼吸的抑制作用。MPP⁺在ETP中表现出相对较弱的抑制活性，但由于其在线粒体内能量依赖性积累，在Mw中会产生强效抑制。渗透性阴离子四苯硼酸盐可增强Mw和ETP中的抑制作用。用各种芳香和非芳香环取代MPP⁺的4-苯环，并用其他阳离子芳香杂环取代N-甲基吡啶鎓基团，保留了MPP⁺的抑制模式。对于所有这些带永久电荷的阳离子，在Mw中抑制效力增强的普遍观察结果与我们的观点一致，即线粒体内能量依赖性积累代表了对跨膜电化学梯度的被动能斯特浓度。尽管如此，Mw相对于ETP中观察到的抑制增强幅度随结构变化很大。特别是，亲脂性较低的类似物，尤其是那些带有局部而非共振稳定的永久正电荷的类似物，在ETP中表现出与MPP⁺相似的抑制活性，但在Mw中的抑制作用没有相应增强。对于这些相同的类似物，四苯硼酸盐对ETP中的抑制活性仅产生微弱增强。由于发现琥珀酸能完全逆转所有研究的MPP⁺类似物在Mw中诱导的呼吸抑制，似乎涉及共同的位点1抑制；因此观察到的不同抑制模式一定是由于控制膜转运和分布特性的结构因素所致。
